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Contributors

Syndromes of the Head and Neck

CONSULTING EDITOR
RICHARD H. HAUG, DDS
Professor and Chief, Oral and Maxillofacial Surgery, Carolinas
Center for Oral Health, Charlotte, North Carolina

EDITOR
DEAN M. DeLUKE, DDS, MBA
Associate Professor and Director of Predoctoral Oral and
Maxillofacial Surgery, Virginia Commonwealth University
School of Dentistry and Virginia Commonwealth University
Medical Center, Richmond, Virginia

AUTHORS
DAVID ALFI, DDS, MD

JAIME GATENO, DDS, MD

Assistant Professor of Clinical Surgery, Department of Oral


and Maxillofacial Surgery, Houston Methodist Specialty
Physician Group, Houston, Texas; Weill Medical College
Cornell University, New York, New York

Professor of Clinical Surgery, Chairman, Department of Oral


and Maxillofacial Surgery, Houston Methodist Specialty
Physician Group, Houston, Texas; Weill Medical College
Cornell University, New York, New York

CAROLYN DICUS BROOKES, DMD, MD

BRENT A. GOLDEN, DDS, MD

Chief Resident, Department of Oral and Maxillofacial Surgery,


University of North Carolina, Chapel Hill, North Carolina

Clinical Assistant Professor, Department of Oral and


Maxillofacial Surgery, University of North Carolina, Chapel
Hill, North Carolina

LISA MARIE DI PASQUALE, DDS


Resident, Division of Oral and Maxillofacial Surgery,
University of Connecticut School of Dental Medicine,
Farmington, Connecticut

STEPHANIE J. DREW, DMD


Assistant Clinical Professor, Hofstra School of Medicine,
Hempstead, New York; Stony Brook University Medical
Center, Stony Brook, New York; Private Practice, The New
York Center for Orthognathic and Maxillofacial Surgery,
West Islip, New York

SIDNEY EISIG, DDS


George Guttman Professor and Chair, Hospital Dentistry,
Oral and Maxillofacial Surgery, Columbia University College
of Dental Medicine; Chief, Hospital Dental Service,
New York-Presbyterian/Columbia University Medical Center,
New York, New York

JOHN E. FANTASIA, DDS


Professor, Hofstra North Shore-Long Island Jewish School of
Medicine, New Hyde Park, New York

ALIA KOCH, DDS, MD


Assistant Professor of Dental Medicine, Hospital
Dentistry, Oral and Maxillofacial Surgery, Columbia
University College of Dental Medicine; Attending,
New York-Presbyterian/Columbia University Medical
Center, New York, New York

IOANNIS G. KOUTLAS, DDS, MS


Associate Professor, Division of Oral and Maxillofacial
Pathology, School of Dentistry, University of Minnesota,
Minneapolis, Minnesota

DIN LAM, DMD, MD


Clinical Assistant Professor, Oral and Maxillofacial Surgery,
Virginia Commonwealth University, Richmond, Virginia

DAVID W. LUI, DMD, MD


Assistant Professor, Department of Oral and Maxillofacial
Surgery, Virginia Commonwealth University School of
Dentistry; Assistant Professor, Division of Oral and
Maxillofacial Surgery, Department of Surgery, Medical
College of Virginia Medical Center, Richmond, Virginia

iii

iv

Contributors
ROMAN G. MEYLIKER, DMD

DAVID M. SHAFER, DMD

Resident, Department of Oral and Maxillofacial Surgery,


Virginia Commonwealth University School of Dentistry;
Division of Oral and Maxillofacial Surgery, Department of
Surgery, Medical College of Virginia Medical Center,
Richmond, Virginia

Associate Professor, Chair and Residency Program Director,


Division of Oral and Maxillofacial Surgery, University of
Connecticut School of Dental Medicine, Farmington,
Connecticut

RITA SHIANG, PhD


VICTOR NANNINI, DDS
Private Practice, Long Island Oral and Maxillofacial Surgery,
P.C., Mineola, New York; Division of Oral and Maxillofacial
Surgery, Attending Faculty, Nassau University Medical
Center, East Meadow, New York

STEPHEN A. SACHS, DDS


The New York Center for Orthognathic and Maxillofacial
Surgery, Clinical Professor Oral and Maxillofacial Surgery,
State University of New York at Stony Brook, Clinical
Professor of Dental Medicine, Hofstra North Shore-Long
Island Jewish School of Medicine, New York

Associate Professor, Department of Human and Molecular


Genetics, Virginia Commonwealth University, Richmond,
Virginia

SAMIR SINGH, DMD


Resident, Department of Oral and Maxillofacial Surgery,
Virginia Commonwealth University School of Dentistry;
Division of Oral and Maxillofacial Surgery, Department of
Surgery, Medical College of Virginia Medical Center,
Richmond, Virginia

TIMOTHY A. TURVEY, DDS


Professor and Chairman, Department of Oral and
Maxillofacial Surgery, University of North Carolina, Chapel
Hill, North Carolina

Contents

Syndromes of the Head and Neck

Dedication

ix

Preface: Syndromes of the Head and Neck

xi

Dean M. DeLuke

Craniosynostosis Syndromes

103

Carolyn Dicus Brookes, Brent A. Golden, and Timothy A. Turvey


Crouzon syndrome
Apert syndrome
Pfeiffer syndrome
Muenke syndrome

Syndromes Affecting Bone

103
104
106
106

111

Stephen A. Sachs
Osteopetrosis
Osteopathia striata with cranial sclerosis
Infantile cortical hyperostosis: Caffey Silverman syndrome
Segmental regional odontomaxillary dysplasia
Cherubism
Syndromic brous dysplasia: McCune Albright syndrome
Osteogenesis imperfecta
Marfan syndrome
Cleidocranial dysplasia (dysostosis)
Congenital hemolytic anemias

Metabolic and Autoimmune Syndromes

111
113
113
114
115
116
117
118
119
120

123

Victor Nannini
Fabry disease
Williams syndrome
Hurler syndrome
Hunter syndrome
Heerfordt syndrome

Sjogren
syndrome

Syndromes Affecting Skin and Mucosa

123
124
125
126
127
128

135

Ioannis G. Koutlas
Ehlers-Danlos syndromes
Parry-Romberg syndrome
Witkop syndrome
Ectodermal dysplasia syndromes
Hypohidrotic ectodermal dysplasia
Osler-Rendu-Weber syndrome
Ascher syndrome
Behcet syndrome
Felty syndrome

135
137
139
139
140
141
143
143
145

vi

Contents
Reactive arthritis
Stevens-Johnson syndrome
Progeria

145
147
148

Hamartoneoplastic Syndromes

153

David M. Shafer and Lisa Marie Di Pasquale


Gorlin syndrome
Gardner syndrome

Klippel-Trenaunay-Weber
syndrome
Sturge-Weber syndrome
Peutz-Jeghers syndrome
Cowden syndrome
Multiple Endocrine Neoplasia syndromes
Proteus syndrome
Neurobromatosis
Tuberous sclerosis

Branchial Arch Syndromes

153
154
155
156
157
158
159
160
161
162

167

David Al, Din Lam, and Jaime Gateno


Treacher Collins syndrome
Goldenhar syndrome

Mobius
syndrome

Clefting Syndromes

167
168
171

175

Stephanie J. Drew
Velocardiofacial syndrome (Shprintzen syndrome)
Van Der Woude syndrome 1 and 2
Pierre Robin sequence
CHARGE syndrome
Stickler syndrome

178
179
179
180
181

Syndromes Affecting the Central Nervous System

183

David W. Lui, Roman G. Meyliker, and Samir Singh


Lesch-Nyhan syndrome
Marcus Gunn syndrome
Cavernous sinus syndrome
Superior orbital ssure syndrome
Trotter syndrome
Horner syndrome
Frey syndrome
Ramsay-Hunt syndrome
Melkersson-Rosenthal syndrome

Chromosomal Syndromes

183
184
185
187
187
188
190
191
192

197

Rita Shiang
Down syndrome
Klinefelter syndrome
Turner syndrome

197
198
200

Contents
Syndromes with Unusual Facies

205

Alia Koch and Sidney Eisig


Cornelia de Lange syndrome
Prader-Willi syndrome
Fetal alcohol syndrome
Whistling face syndrome
Noonan syndrome

Syndromes with Unusual Dental Findings or Gingival Components

205
205
207
207
209

211

John E. Fantasia
Papillon-Lefevre syndrome
Hereditary gingival bromatosis type 1
Klippel-Feil syndrome
Oral-facial-digital syndrome type I
Oligodontia
Taurodontism

211
212
213
214
215
217

vii

viii

Syndromes of the Head and Neck

ATLAS OF THE ORAL AND MAXILLOFACIAL


SURGERY CLINICS OF NORTH AMERICA
FORTHCOMING ISSUES

PREVIOUS ISSUES

March 2015

March 2014

Diagnosis and Management of Neck Masses

Syndromes of the Head and Neck

September 2015

September 2013

Adjuncts for Care of the Surgical Patient

Ofce Procedures for the Oral and Maxillofacial


Surgeon

David E. Webb, Editor

Sidney Bourgeois, Editor

Landon D. McLain, Editor

Stuart E. Lieblich, Editor


March 2013

Craniomaxillofacial Trauma
David Bitoni, Editor

RELATED ISSUE OF INTEREST

Oral and Maxillofacial Surgery Clinics of North America, November 2013, Volume 25, Issue 4
Trauma and Reconstruction
David S. Precious, Editor

THE CLINICS ARE NOW AVAILABLE ONLINE!

Access your subscription at:


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Syndromes of the Head and Neck

Dedication
To: Dr. Dominick J. DeLuke and Dr. Leon Eisenbud.
In recognition of their many contributions to the profession, and with thanks for allowing me to see a little further by
standing on their shoulders.

Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) ix


1061-3315/14/$ - see front matter 2014 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.cxom.2014.07.001

oralmaxsurgeryatlas.theclinics.com

Syndromes of the Head and Neck

Preface

Syndromes of the Head and Neck

Dean M. DeLuke, DDS, MBA


Editor

The purpose of this issue of the Atlas of the Oral and Maxillofacial Surgery Clinics of North America is to serve as an aid
to identification of the more common syndromes of the head
and neck. As such, it should be useful to a varied audience,
including not only the oral and maxillofacial surgeon but also
the oral pathologist, the practitioner of oral medicine, and
members of the craniofacial teamdthe orthodontist, pediatric dentist, speech and language specialist, geneticist, plastic surgeon, ENT specialist, pediatrician, nurse coordinator,
and others.
In keeping with the established format for the Atlas of the
Oral and Maxillofacial Surgery Clinics of North America, it was
necessary to limit the size and scope of this work. We have
therefore included 70 of the more important head and neck
syndromes and organized them using the same nosology as
in the landmark text of Robert Gorlin, first published with
Pindborg in 1964. Each syndrome is presented in a highly
capsulized format, with sections devoted to





Inheritance patterns
Clinical features (with histology, if relevant)
Differential diagnosis
Treatment considerations

While the emphasis in this issue is mainly on identification, clinical applications have also been presented wherever
pertinent. For consistency when identifying the syndromes,
we followed the custom of not using the possessive form,
even though we might sometimes be more accustomed
(incorrectly, I might add) to seeing the possessive form of the

eponym. So, for example, we will refer to Gardner syndrome,


not Gardners syndrome.
One of my mentors to whom this work is dedicated,
Dr Leon Eisenbud, was often known to urge his students and
residents: Anytime you can, you should curl up with your
copy of Gorlins Syndromes of the Head and Neck and just
browse through it. Leon, no doubt, had spent countless
hours doing just that, for he was a master at identification
and recognition of syndromes, functioning in an era before
the age of instant Internet searches, before Lexicomp, in a
time when even a Medline search required a trip to the
medical library. In that era, you had to have much of the
information in your memory bank, or at the very least, you
had to know what textbook to pick up or where to begin your
literature search. In this issue, we have condensed this
important information into one source.
I would like to extend my sincere thanks and appreciation
to each of the article authors. It was a distinct privilege to have
been able to include the contributions of so many wellrecognized leaders in the specialties of oral and maxillofacial
surgery, oral pathology, and genetics in this issue of the Atlas
of the Oral and Maxillofacial Surgery Clinics of North America.
Dean M. DeLuke, DDS, MBA
Virginia Commonwealth University School of Dentistry and
Virginia Commonwealth University Medical Center
521 North 11th Street, Room 311
Richmond, VA 23298, USA

Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) xi


1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.07.002

E-mail address:
dmdeluke@vcu.edu

oralmaxsurgeryatlas.theclinics.com

Craniosynostosis Syndromes
Carolyn Dicus Brookes, DMD, MD, Brent A. Golden, DDS, MD,
Timothy A. Turvey, DDS*
KEYWORDS
 Craniofacial dysostosis  Craniosynostosis syndromes  Crouzon  Apert  Pfeiffer  Muenke
KEY POINTS
 Craniosynostosis syndromes have wide phenotypic variability. Understanding of the underlying genetic causes continues to
develop.
 Children with these syndromes are best managed at a multidisciplinary craniofacial center.
 Early management focuses on airway protection, preservation of vision and hearing, and feeding.
 Timing of craniofacial reconstruction is driven by growth and development of the area of interest.
 In the past, intellectual disability was assumed. However, many patients with craniofacial dysostosis syndromes live rich
lives and have normal or even exceptional intellect provided they are raised in a nurturing, stimulating environment.

Craniosynostosis is premature fusion of cranial sutures, and it


occurs in 1:2000 to 1:2500 live births.1,2 Most cases are nonsyndromic. Craniosynostosis syndromes, more than 150 of
which have been identified, affect 1:25,000 to 1:100,000 infants.2,3 The most common are reviewed in this article.
Craniosynostosis syndromes are diagnosed based on clinical
features. Abnormal head shape and midface deficiency with
exorbitism are typical craniofacial expressions,1,2,4e6 and
syndromes with these traits may be called craniofacial dysostosis syndromes. Limb and visceral manifestations further
delineate each syndrome.
Fibroblast growth factor receptor (FGFR) and TWIST mutations are the most commonly associated with craniosynostosis
syndromes. Although genotype-phenotype correlations have
been characterized, phenotypically similar patients may have
genetically distinct syndromes and identical mutations have
been found in patients with different clinical diagnoses.2,7,8
Fibroblast growth factors participate in myriad processes
including skeletogenesis and limb development. Gain-of-function mutations in FGFR1, FGFR2, and FGFR3 cause the FGFRrelated craniosynostosis syndromes, which include Crouzon,
Apert, Pfeiffer, Beare-Stevenson, Jackson-Weiss, and Muenke
syndromes as well as Crouzon syndrome with acanthosis nigricans and FGFR2-related isolated coronal synostosis. These
syndromes account for approximately 17% of craniosynostosis
cases.9

The authors have nothing to disclose.


Department of Oral & Maxillofacial Surgery, University of North
Carolina-Chapel Hill, 149 Brauer Hall, CB #7450, Chapel Hill, NC 275997450, USA
* Corresponding author.
E-mail address: Tim_Turvey@unc.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 103110
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.04.001

Crouzon syndrome
Genetics
 FGFR2 mutations
 Autosomal dominant; complete penetrance, variable
expressivity
 Occasionally de novo
 1.6:100,000; 4.5% of craniosynostosis cases2,10

Clinical features
Cardinal features:
 Craniosynostosis
 Midface/orbital hypoplasia
 Clinically normal hands/feet
Crouzon syndrome, like all craniofacial dysostosis syndromes,
is classically characterized by premature fusion of the coronal
and frontosphenoidal sutures and the sphenoethmoidal synchondrosis.11 Fusion results in brachycephaly; midface deficiency; and a short, wide anterior cranial base. The forehead is
prominent because of compensatory growth at unaffected sutures. Additional sutures may be involved and rarely there is no
sutural involvement (Fig. 1).6,12,13
Exophthalmos is always present, largely because of orbital
hypoplasia with retruded supraorbital, infraorbital, and lateral
orbital rims. The widened cranial base can result in hypertelorism. Most patients have exotropia;14 orbital dystopia and
strabismus can be observed.15 Approximately 20% of patients
develop optic atrophy.14
Anteroposterior and vertical midface hypoplasia are
consistent features. Dental crowding, crossbite, and apertognathia are typical. Cleft lip and palate are rare.15

oralmaxsurgeryatlas.theclinics.com

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Dicus Brookes et al.

Fig. 1 Crouzon syndrome. Frontal views of a child with Crouzon syndrome. The only prior procedures performed were placement of PET
and VP shunt. PET, pressure equalization tubes; VP, ventriculoperitoneal.

Other features
 Typically normal intellect
 Hydrocephalus (up to 30%); occasional nonprogressive
ventriculomegaly16,17
 Hearing loss common18
 Classically normal limbs/axial skeleton (occasional mild
anomalies)19e23
 Cardiovascular anomalies rare

Differential diagnosis
If choanal atresia is present, consider Crouzon syndrome with
acanthosis nigricans. Apert, Pfeiffer, Jackson-Weiss, and
Saethre-Chotzen syndromes are diagnostic considerations.6

Apert syndrome
Genetics
 FGFR2 mutations
 Specific mutations linked to clinical features (ie, severe
craniofacial involvement)24
 Most are de novo
 Sometimes
autosomal
dominant;
complete
penetrance.2
 1:100,000; 4% to 5% of craniosynostosis cases2,25,26

Clinical features
Cardinal features:
 Craniosynostosis
 Midface/orbital hypoplasia
 Bilateral syndactyly of hands/feet (minimally second to
fourth digits)

Craniofacial anomalies are generally more severe in Apert


than in Crouzon syndrome.13 Asymmetry frequently affects
the cranial base, orbits, and midface.15 Megalencephaly is
common.27
Infants with Apert syndrome have bicoronal synostosis
with a midline calvarial defect from glabella to the posterior
fontanelle that predictably obliterates over time.12,13
The anterior cranial base is short. Patients often have a
flattened occiput and a wide, steep forehead. The skull is
wide with temporal bulging; temporal fat pads are prominent
(Fig. 2).15,28
The orbits are hypoplastic; exophthalmos and hypertelorism
are always observed.14 Supraorbital and infraorbital rims are
retruded. The lateral orbital wall is ballooned; lateral orbital
rim projection is near normal. Palpebral fissures are often
downslanting.15 Exotropia, refractive errors, and strabismus
are common;14 optic atrophy is seen more in Crouzon syndrome.29,30 Eyebrows may be interrupted over a bony defect at
the lateral supraorbital rim.15
The midface is retrusive. The nose is short with a depressed
bridge and rounded tip.15 Ears tend to be large and may be low
set.15,31
Lips are hypotonic.15 Lateral palatal swellings contain mucopolysaccharides and grow with age; the palate is highly
arched.32,33 The soft palate is often long and thick.33 Cleft
palate is seen more than in Crouzon syndrome or the general
population. Delayed and ectopic dental eruption are common.
Most patients have dental crowding, crossbite, and apertognathia (Fig. 3).15,34,35
Other manifestations
 Ventriculomegaly common; progressive hydrocephalus
rare16,36
 Mental retardation more common than in Crouzon
syndrome

Craniosynostosis Syndromes

105

Fig. 2 Apert syndrome. (AeC) Frontal, lateral and superior views of a 3-D CT reconstruction of an infant with Apert syndrome. Note the
wide midline calavarial defect and turribrachycephaly.

Fig. 3 Apert syndrome. (A) Frontal and profile views of another infant with Apert syndrome. (B) Hands and feet of the same child
demonstrating polysyndactyly. (C) Palatal view of the same patient as a teenager. Note the significant crowding, lateral palatal swellings,
and highly arched palate.

106

Dicus Brookes et al.

 May have normal intellect


 Hearing loss common37,38
 Hard and soft tissue syndactyly (at least second to fourth
digits)39
 Cardiovascular/genitourinary anomalies w10%40
 Cervical spine anomalies (C5eC6 fusion) common20
 Light skin/hair, hyperhidrosis, acneiform lesions41,42

Differential diagnosis
Crouzon, Pfeiffer, Saethre-Chotzen, Jackson-Weiss, and Carpenter syndromes are considered, but the pattern of syndactyly usually clinches the diagnosis.6

Pfeiffer syndrome
Genetics43e45
 FGFR2 mutations
 Type 1 subset: FGFR1 mutation
 Frequently no identifiable mutation
 Type 1: autosomal dominant; complete penetrance, variable expressivity
 Some type 1, types 2 and 3: de novo
 Combined prevalence 1:100,0002,44

Clinical features
Cardinal features
 Craniosynostosis
 Midface/orbital hypoplasia
 Broad thumbs/great toes (rarely thumbs normal)4,46
 Variable partial soft tissue syndactyly (second and third
digits)44
Three phenotypic types of Pfeiffer syndrome have been
delineated.43
Patients with type I Pfeiffer syndrome are most likely to
have normal intelligence, although mild mental retardation
can be seen.43 The skull is turribrachycephalic. Midface retrusion, exophthalmos, hypertelorism, and nasal bridge
depression are variable. Strabismus is common, as is a high
arched palate with dental crowding.45,47
Features of type 2 Pfeiffer syndrome include cloverleaf skull,
severe exophthalmos, and central nervous system involvement
such as hydrocephalus. Elbow ankylosis or synostosis, choanal
atresia, and cleft palate may be present. Intellectual disability
is common. Patients often die early.2,6,43
Patients with type 3 Pfeiffer syndrome have a more severe
phenotype than those with type 1 with severe exophthalmos
and a very short anterior cranial base without cloverleaf skull.
Visceral anomalies and elbow ankylosis may be present. Early
death is common.43
Conductive hearing loss affects more than 80% of patients
regardless of subtype. Tracheostomy is often required for patients with types 2 and 3. Hydrocephalus and acquired tonsillar
herniation have been reported in most patients with type 1 and
all patients with type 3.48 Cervical fusion (typically C2eC3) is
seen more in types 2 and 3 (Fig. 4).49,50
Classical prognosis is poor for patients with types 2 and 3
Pfeiffer syndrome; however, some of these patients show
normal or only mildly delayed neurodevelopment.2

Fig. 4 Lateral cephalometric radiograph of a patient with


Pfeiffer syndrome. Note the severe midface deficiency and the
cervical spine fusion.

Differential diagnosis
Differential diagnosis includes Saethre-Chotzen and JacksonWeiss syndromes, although in the latter thumbs are
unaffected.43

Muenke syndrome
Genetics
 FGFR3 mutation
 Autosomal dominant; incomplete penetrance, variable
expressivity
 Sometimes de novo51
 1:30,00052; 8% of craniosynostosis cases9

Clinical features
Coronal synostosis (usually bilateral) and various minor anomalies characterize Muenke syndrome.
Phenotypic variation is considerable: additional sutures may
be involved or patients may be simply macrocephalic or even
normocephalic (Figs. 5 and 6).51e53 Females are affected more
severely.52e54 Mild midface hypoplasia, downslanting palpebral
fissures, mild ptosis, and high arched palate may be seen.
Strabismus is common.52 Ventriculomegaly, hydrocephalus,
and cervical spine anomalies are rare.16,55
Minor clinical anomalies of the hands and feet (brachydactyly, clinodactyly) affect some. Soft tissue syndactyly is
rare. Radiographic hand and foot abnormalities may be noted
despite an unremarkable clinical examination.51,55
Almost all patients have sensorineural hearing loss.53
Normal intellect is typical, although developmental delay affects roughly one-third of patients.51,52

Differential diagnosis
Muenke syndrome may be confused with other craniofacial
dysostosis syndromes or nonsyndromic craniosynostosis; genetic testing for all patients with coronal synostosis is thus

Craniosynostosis Syndromes

107

Fig. 5 Muenke syndrome. (A) Frontal and profile views of an infant with Muenke syndrome. (B) Frontal and lateral views of a 3-D CT
reconstruction of the same patient.

Fig. 6 Muenke syndrome. Frontal, lateral, and superior views of a 3-D CT reconstruction of another patient with Muenke syndrome. Note
the dramatic phenotypic variation.

108

Dicus Brookes et al.

advocated.51,52 If Muenke syndrome is diagnosed, genetic


counseling and early assessment for and management of
hearing loss and developmental delay are indicated.53 Further,
patients with Muenke syndrome seem to require reoperation
more often than do their nonsyndromic counterparts.54

Treatment considerations in craniosynostosis


syndromes
Patients with craniosynostosis syndromes are best managed by
a multidisciplinary craniofacial team. Treatment is individually
tailored; protocol details vary from center to center. Core
considerations relevant to patients with syndromic craniosynostosis are reviewed here.

Airway and feeding


Obstructive sleep apnea is common.56e58 Midface deficiency,
choanal stenosis or atresia, a long thick velum, laryngotracheal
anomalies, and central apneas all contribute to airway
compromise. If a specific level of obstruction is identified it
may be addressed. As lymphoid tissue reaches its peak size,
tonsillectomy or adenoidectomy may be indicated. Midfacial
advancement may prove helpful for children and adolescents.
Nasopharyngeal tubes, continuous positive airway pressure, or
tracheostomy are sometimes required.
Assessment for airway obstruction and central apnea begins
in infancy; reassessment frequency is determined by diagnosis
and individual features.
Although infants are obligate nasal breathers, those with
craniosynostosis syndromes may be forced to breathe through
their mouths; this can impede feeding. Nasogastric or gastrostomy tubes may be required to supplement intake.

Central nervous system


Increased intracranial pressure (ICP) is a concern whenever
sutures fuse prematurely; it is seen more frequently in syndromic than nonsyndromic craniosynostosis. Venous congestion, hydrocephalus, and upper airway obstruction likely all
contribute to intracranial hypertension.16,59

Fig. 7

Signs and symptoms of increased ICP include a bulging


fontanelle, papilledema, radiographic beaten copper skull
appearance (Fig. 7), headaches, nausea or vomiting, and irritability; diagnosis can be challenging, especially in the very
young.16
Increased ICP may require a ventriculoperitoneal shunt,
endoscopic third ventriculostomy, or early/repeat cranial
decompression.

Other systems
A comprehensive medical evaluation is performed early in life.
Exophthalmos increases risk for corneal abrasion, exposure
keratitis, and globe trauma. Unaddressed strabismus can lead
to amblyopia. Early assessment by a pediatric ophthalmologist
is indicated, for these reasons and to monitor for papilledema.
Ocular lubrication, tarsorrhaphy, or early fronto-orbital
advancement are strategies to protect the globes.
Patients require regular evaluation for middle ear disorders
and hearing loss, which are common.
Timing of cleft palate repair depends on speech acquisition;
it may be delayed relative to routine cleft management.
Dental development should be monitored by a pediatric
dentist and an orthodontist.
Limb anomalies are managed by pediatric orthopedists.
Visceral anomalies are managed by the appropriate specialists.
Genetic evaluation and counseling are crucial.
The potential psychosocial and educational impact of these
conditions necessitates ongoing monitoring by a trained psychiatrist or psychologist.

Craniofacial treatment sequence


Timing of intervention is based on growth of the affected region; adjustments to timing are prompted by functional or
psychosocial concerns.
Brain growth drives rapid increase in cranial vault size
during the first year of life. Cranial vault decompression and
reconstruction is undertaken during this period to prevent
increased ICP and its untoward effects. A staged approach
to cranial dysmorphology is often required. Fronto-orbital
advancement, involving fused suture release, anterior vault

Beaten copper skull appearance on a child with Crouzon syndrome prior to surgical intervention.

Craniosynostosis Syndromes
and orbital expansion, and forehead and orbital bandeau
reshaping, is typically performed in the first year of life.
Posterior expansion by conventional osteotomy or distraction may also be indicated. Reoperation is performed as
indicated.
Midfacial advancement to address orbital and zygomatic
deformities is performed in early childhood (after 5e7 years of
age), at which time the cranial vault and orbits approximate
90% of adult size.60 Midfacial advancement techniques include
monobloc advancement, facial bipartition, and subcranial Le
Fort III osteotomy; a technique is selected based on the individual patients situation. The anteroposterior deficiency at
the orbital rim and the dentate level nearly always differ;
treatment at this phase is directed toward correction of the
orbital and forehead deficiencies.
Further midfacial advancement and onlay grafting is nearly
always required at skeletal maturity. Orthodontic decompensation and orthognathic surgery are then performed.
Esthetic nasal and soft tissue surgery are best delayed until
after orthognathic surgery.

Summary
The craniosynostosis syndromes are varied but they share
several common features and therefore share guiding principles of management. Individual care is best rendered through a
multidisciplinary team with established protocols that offer
flexibility for and attention to individual patient needs. This
collaborative care model has significantly improved outcomes
in patients with these conditions. Decades ago it was common
for these patients to be condemned to asylums or sheltered in
homes with no social interaction. Today many are well
educated, productive members of society. These changes have
occurred because of comprehensive team care and recognition
that these conditions are often more socially than intellectually incapacitating.
Early priorities are airway management, protection of vision
and hearing, and nutritional support. Craniofacial surgical
intervention is staged with cranial vault reconstruction in the
first year of life, correction of the total midface and orbital
deficiency after 5 to 7 years of age, and maxillomandibular
advancement in the teenage years. Given the low incidence of
these syndromes, critical evaluation of outcomes by those
involved with the care of these patients is crucial to ensure
optimal outcomes.

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18. Orvidas LJ, Fabry LB, Diacova S, et al. Hearing and otopathology
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20. Hemmer KM, McAlister WH, Marsh JL. Cervical spine anomalies in
the craniosynostosis syndromes. Cleft Palate J 1987;24:328.
21. Anderson PJ, Hall C, Evans RD, et al. The cervical spine in Crouzon
syndrome. Spine 1997;22:402.
22. Anderson PJ, Hall CM, Evans RD, et al. The elbow in syndromic
craniosynostosis. J Craniofac Surg 1998;9:201.
23. Murdoch-Kinch CA, Ward RE. Metacarpophalangeal analysis in
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Genet 1997;73:61.
24. Von Gernet S, Golla A, Ehrenfels Y, et al. Genotype-phenotype
analysis in Apert syndrome suggests opposite effects of the two
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25. Tolarova MM, Harris JA, Ordway DE, et al. Birth prevalence, mutation rate, sex ratio, parents age, and ethnicity in Apert syndrome. Am J Med Genet 1997;72:394.
26. Cohen MM, Kreiborg S, Lammer EJ, et al. Birth prevalence study
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27. Cohen MM, Kreiborg S. Growth pattern in the Apert syndrome. Am
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29. Khong JJ, Anderson P, Gray TL, et al. Ophthalmic findings in Apert
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30. Tay TM, Martin F, Rowe N, et al. Prevalence and causes of visual
impairment in craniosynostosis syndromes. Clin Experiment Ophthalmol 2006;34:434.

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35. Kreiborg S, Cohen MM. The oral manifestations of Apert syndrome. J Craniofac Genet Dev Biol 1992;12:41.
36. Quintero-Rivera F, Robson CD, Reiss RE, et al. Intracranial
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37. Gould HJ, Caldarelli DD. Hearing and otopathology in Apert syndrome. Arch Otolaryngol 1982;108:347.
38. Rajenderkumar D, Bamiou DE, Sirimanna T. Audiological profile in
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39. Cohen MM, Kreiborg S. Hands and feet in the Apert syndrome. Am
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40. Cohen MM, Kreiborg S. Visceral anomalies in the Apert syndrome.
Am J Med Genet 1993;45:758.
41. Margolis S, Siegel IM, Choy A, et al. Oculocutaneous albinism
associated with Aperts syndrome. Am J Ophthalmol 1977;84:830.
42. Cohen MM, Kreiborg S. Letter to the editor: cutaneous manifestations of Apert syndrome. Am J Med Genet 1995;58:94.
43. Cohen MM. Pfeiffer syndrome update, clinical subtypes, and
guidelines for differential diagnosis. Am J Med Genet 1993;45:300.
44. Vogels A, Fryns JP. Pfeiffer syndrome. Orphanet J Rare Dis
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45. Greig AV, Wagner J, Warren SM, et al. Pfeiffer syndrome: analysis
of a clinical series and development of a classification syndrome.
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46. Kerr NC, Wilroy RS, Kaufman RA. Type 3 Pfeiffer syndrome with
normal thumbs. Am J Med Genet 1996;66:138.
47. Cohen MM. An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Orig Artic Ser 1975;11:137.
48. Fearon JA, Rhodes J. Pfeiffer syndrome: a treatment evaluation.
Plast Reconstr Surg 2009;123:1560.
49. Moore MH, Lodge ML, Clark BE. Spinal anomalies in Pfeiffer syndrome. Cleft Palate Craniofac J 1995;32:251.
50. Anderson PJ, Hall CM, Evans RD, et al. Cervical spine in Pfeiffers
syndrome. J Craniofac Surg 1996;7:275.
51. Muenke M, Gripp KW, McDonald-McGinn DM, et al. A unique point
mutation in the fibroblast growth factor receptor 3 gene (FGFR3)
defines a new craniosynostosis syndrome. Am J Hum Genet 1997;
60:555.
52. Agochukwu NB, Doherty ES, Muenke M. Muenke syndrome. In:
Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews

Dicus Brookes et al.

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1993e2013. Updated 2010 Dec 7. Available at: http://www.ncbi.
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Doherty ES, Lacbawan F, Hadley DW, et al. Muenke syndrome
(FGFR3-related craniosynostosis): expansion of the phenotype
and review of the literature. Am J Med Genet A 2007;143A:
3204.
Thomas GP, Wilkie AO, Richards PG, et al. FGFR3 P250R
mutation increases the risk of reoperation in apparent nonsyndromic coronal craniosynostosis. J Craniofac Surg 2005;16:
347.
Trusen A, Beissert M, Collmann H, et al. The pattern of skeletal
anomalies in the cervical spine, hands and feet in patients with
Saethre-Chotzen syndrome and Muenke-type mutation. Pediatr
Radiol 2003;33:168.
Pijpers M, Poels PJ, Vaandrager JM, et al. Undiagnosed obstructive sleep apnea syndrome in children with syndromal craniofacial
synostosis. J Craniofac Surg 2004;15:670.
Al-Saleh S, Riekstins A, Forrest CR, et al. Sleep-related disordered
breathing in children with syndromic craniosynostosis. J Craniomaxillofac Surg 2011;39:153.
Driessen C, Joosten KF, Bannink N, et al. How does obstructive
sleep apnoea evolve in syndromic craniosynostosis? A prospective
cohort study. Arch Dis Child 2013;98:538.
Tamburrini G, Caldarelli M, Massimi L, et al. Intracranial pressure
monitoring in children with single suture and complex craniosynostosis: a review. Childs Nerv Syst 2005;21:913.
Waitzman AA, Posnick JC, Armstrong DC, et al. Craniofacial
skeletal measurements based on computed tomography: part II.
Normal values and growth trends. Cleft Palate Craniofac J 1992;
29:118.

Further readings
Forrest CR, Hopper RA. Craniofacial syndromes and surgery. Plast
Reconstr Surg 2012;131:86e.
Hennekam RC, Krantz ID, Allanson JE. Gorlins syndromes of the
head and neck. 5th edition. New York: Oxford University Press;
2010. p. 732e91.
McCarthy JG, Warren SM, Bernstein J, et al. Parameters of care for
craniosynostosis. Cleft Palate Craniofac J 2012;49:1S.
Posnick JC, Ruiz RL. The craniofacial dysostosis syndromes: current
surgical thinking and future directions. Cleft Palate Craniofac J
2000;37:433.
Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-related craniosynostosis
syndromes. In: Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews [Internet]. Seattle (WA): University of Washington; 1998.
p. 1993e2013. Updated 2011 Jun 7. Available at: http://www.ncbi.
nlm.nih.gov/books/NBK1455/. Accessed December 22, 2013.

Syndromes Affecting Bone


Stephen A. Sachs, DDS
KEYWORDS
 Dysmorphic facies  Facial bones  Jaw diseases  Genetic bone diseases
KEY POINTS
 Look beyond the primary jaw pathology for clues of syndromic involvement. Observe the skin, and always consider
extrafacial skeletal involvement.
 Study Gorlins Syndromes of the Head and Neck and similar references to increase your rolodex of known syndromes.
 Review the natural history of the pathology and develop a perspective for whether there is an active process and/or a
progressive process.

Introduction
This article is a clinical description of genetic diseases that
affect facial bones, giving rise to dysmorphic facies. It is by no
means complete, rather it is meant to serve as an outline of
skeletal anomalies that can provide structure for oral and
maxillofacial surgeons to screen the patients that they
encounter. The reader should have access to other sources,
such as Gorlin Syndromes of the Head and Neck, Sixth Edition;
Smiths Recognizable Patterns of Human Malformation by
Jones; and The Management of Genetic Syndromes by Cassidy
and Allanson.
When evaluating bone diseases of the jaws and considering
a syndromic etiology, the clinician needs to first characterize
what is observed. Is the process radiolucent or radiopaque?
Does this condition result in skeletal dysplasia, hyperplasia, or
hypoplasia? Is this a local, monostotic, regional, or polyostotic
phenomena? Finally, what other abnormalities are present in
this patient. Is this observed bony pathology a component of a
constellation of findings, that is, a syndrome involving multiple
pathologic entities? If there are multiple disorders, are they
associated with potential for genetic transmission?
Although today there seems to be a limited number of
conditions that affect the maxillofacial skeleton that are truly
genetic in order, as our ability to understand the human
genome and characterize individuals and their genetic
sequence increases, undoubtedly many more clusters of
genetically coded phenotypic expressions will be identified. In
addition, what appears outwardly as an external independent
source of disease or deformity may turn out to be genetically
predetermined. For example, there is no doubt that medication-related osteonecrosis of the jaw (MRONJ) can be related

Disclosure: None.
The New York Center for Orthognathic and Maxillofacial Surgery,
State University of New York at Stony Brook, Hofstra North Shore-Long
Island Jewish School of Medicine, 2001 Marcus Avenue, Lake Success,
New York 11042, USA
E-mail address: drsachs@nycoms.com
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 111122
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.06.002

to the use of bisphosphonates that inhibit osteoclast formation. However, it is becoming apparent that there are clusters
of patients with genetic sequences that increase susceptibility
to this class of drugs, rendering the patient increasingly susceptible to MRONJ. That being said, there are classic syndromes that affect bone and are associated with other physical
abnormalities that are genetically transmitted. These are
illustrated in this article.

Osteopetrosis
Genetics
Osteopetrosis is autosomal recessive in its neonatal form and is
often called marble bone disease. The autosomal dominant
form, often called late onset, is more benign in its clinical
nature and is divided into a Type 1 and Type 2 expression. The
prevalence is about 1 in 250,000 births. There is a higher
incidence of this condition in Costa Rica, Saudi Arabia, and
Denmark (1/20,000).

Clinical features
Osteopetrosis is a generalized disease of bone in which there is
failure of normal bone remodeling by resorption or an overproduction of bone. Various defects in osteoclast or osteoblast
function have been implicated. As a consequence, the bone
becomes dense and radiopaque with a radiographic homogeneity between the cortical and medullary bone (Fig. 1). There
are various clinical forms of this disease. The worst outcomes
nberg disease.
are seen with the neonatal form, Albers-Scho
This entity is generally fatal, although early bone marrow
transplantation can slow the progression of the disease process. Most patients do not live beyond adolescence.
The progressive density of affected bones without a
resorptive phase promotes early fracture and encroachment on
the cranial nerve foramina resulting in diminished vision,
hearing, and fifth nerve function. Extramedullary hematopoiesis may result in hepatosplenomegaly and pancytopenia.

oralmaxsurgeryatlas.theclinics.com

112

Sachs

Fig. 1 Montage of patient with sclerotic bones associated with osteopetrosis. (A) Bowed femur. (B) Dense vertebra with lack of normal
spine. (C) Sclerotic mandible with multiple unerupted molars. (DeF) Enlarged calvarium. (G, H) Sclerotic and thickened zygoma and
mandible. (I) Diffuse ostesclerosis noted on chest x ray. (JeL) Radiodense feet, hands, and pelvis. (From Xue Y, Wang W, Mao T, et al.
Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia. J Craniomaxillofac Surg 2012;40:416e20;
with permission.)

Facial deformities, including frontal bossing and broad face,


occur along with delayed dental eruption.

Differential diagnosis
Although the infantile neonatal form presents with a unique
clinical presentation, the benign form of the disease, which
can affect the mandible, cranium, and cervical spines with a
sclerotic process, needs to be differentiated from other forms
of osteosclerosis, such as Van Buchens disease, osteopathia
straita, and sclerosteosis.

Treatment considerations for the oral and


maxillofacial surgeon
Many unerupted teeth may occur. More than 30% of cases
develop osteomyelitis de novo after dental extractions (Fig. 2).

Fig. 2 Draining cutaneous fistulae secondary to chronic osteomyelitis, a common finding when the osteopetrotic jaws are
subject to trauma, including dental extractions. (Courtesy of
D. Sarasin, DDS, Cedar Rapids, IA.)

Syndromes Affecting Bone

Osteopathia striata with cranial sclerosis


Genetic
This condition is classified as autosomal dominant or X-linked
dominant.

Clinical features
Osteopathia straita is a bone disease that is characterized by
enlarged sclerotic craniofacial bones. The facial appearance is
square and broad. Although dense and enlarged, the midface
lacks projection (Fig. 3A). The encroachment on the cranial
foramina results in cranial nerve dysfunction (Fig. 3B). More
than 50% of patients have hearing loss. Along with characteristic craniofacial changes, the long bones demonstrate a
peculiar linear striation giving a combed-through appearance
(Fig. 3C). Other craniomaxillofacial features include frontal
bossing, hypertelorism, hearing loss, cleft palate, bifid uvula,
and a dense cranial base (Fig. 3D). Temporomandibular joint
ankylosis has been described.
Other systemic findings include ventricular septal defect,
atrial septal defect, laryngeal tracheal malacia, polydactyly,
and syndactyly. This condition is a frequent feature of focal
dermal hypoplasia.

113
However, the unusual linear striations of the long bones are
almost pathognomonic, but can be seen in benign forms of
osteopetrosis.

Considerations for the oral and maxillofacial surgeon


The maxillary growth deficiency when combined with
mandibular enlargement may cause dentofacial deformity,
creating a consideration for orthognathic surgery. Attempts to
osteotomize this bone for repositioning poses great difficulty
and warrants careful consideration.

Infantile cortical hyperostosis: Caffey Silverman


syndrome
Genetics
There is both a familial and sporadic form. It seems that this is
an autosomal dominant abnormality with incomplete penetrance and variable expressivity. It has been associated with a
defect in chromosome q21. It is a prenatal form that is said to
be autosomal recessive and is more prominent and often
associated with early cytology.

Clinical features
Differential diagnosis
The craniofacial presentation needs to be differentiated from
osteopetrosis as well as other craniosclerotic syndromes.

This acute inflammatory process occurs with remarkable


symmetry associated with swelling of the jaws. It is seen in
neonates and infants from the time of birth to 20 months of

Fig. 3 (A) Patient with osteopathia striata; note the pseudo prognathism secondary to maxillary hypoplasia. (B) This 3-dimensional (3D)
cone-beam computed tomography (CT) image demonstrates diffuse sclerosis of the facial bones, orbits, and mandible. As time progresses,
the foramina may close around existing nerves, causing hypoesthesia or dysfunction. (C) Long bone of a patient with osteopathia striata.
Note longitudinal linear striations, as well as fracture of distal fibula. (D) Lateral cephalogram in patient with osteopathia striata. Note
markedly thickened skull base, obliteration of maxillary sinus with sclerotic bone and density to skull, mandible, and cervical spines. ([C]
Courtesy of E. Winn, MD, Long Island, NY.)

114
age. This disease is characterized by painful burning and
swelling over the face and jaws (Fig. 4A). This swelling might
also involve the thorax and extremities (Fig. 4B). This is an
inflammatory process accompanied by fever, with elevated
white blood cell count and increased sedimentation rate.
According to Eversole, The histology is one of elevated
periosteal new bone formation. This may be related to
congenital anomalies of the vessels supplying the periosteum
and causing the involved bones to be hypoxic, become
necrotic, and create overlying soft tissue inflammation and
eventually new bone formation in the periosteum (Fig. 4C).

Consideration for the oral and maxillofacial surgeon


This is a disease of infants and young children that affects the
mandible in 70% of the cases. Residual facial asymmetry with
an abnormal dental occlusion may result. Although no surgery
is required, treatment with anti-inflammatory medication may
be warranted.

Segmental regional odontomaxillary dysplasia

Sachs

Clinical features
SOD is characterized by unilateral expansion of the posterior
maxilla, gingival hyperplasia, lack of one or both premolars,
delayed eruption of teeth, and hypoplastic or ghost teeth. The
affected bone exhibits a course radiopaque appearance not
unlike the ground-glass look of fibrous dysplasia; however, the
trabeculation appears vertical in orientation (Fig. 5A). This
condition usually presents in childhood and affects boys more
frequently than girls. Another unusual feature of this syndrome
is the associated facial cutaneous lesions characterized by
hypertrichosis and hyperpigmentation, which may be considered a Becker nevus (Fig. 5B, C).

Differential diagnosis
Fibrous dysplasia
Ossifying fibroma
Hemimaxillofacial dysplasia
Regional odontodysplasia

Genetics

Treatment considerations for the oral and


maxillofacial surgeon

Segmental regional odontomaxillary dysplasia (SOD) is not a


genetic syndrome, rather it is a collection of signs and symptoms that characterize a single condition. It may be called an
association.

The bone involved with this disease often requires simple


recontouring and may be osteointegrated with dental implants.
This disease seems to attenuate with maturity and may require
repeated surgical interventions until the expansion stops. The

Fig. 4 (A) Infantile cortical hyperostosis: note bilateral tender swelling of the face and erythema of overlying skin. (B) Lower extremity
swelling in patient with Caffey Silverman syndrome. (C) Periosteal new bone formation (arrow) seen in infantile cortical hyperostosis. In
time this will resolve and return to normal form. ([A, C] From Wong YK, Cheng JC. Infantile cortical hyperostosis of the mandible. Br J Oral
Maxillofac Surg 2008;46:498; with permission; and [B] Courtesy of Department of Radiology, Childrens Hospital of Pittsburgh, Pittsburgh,
PA.)

Syndromes Affecting Bone

115

Fig. 5 (A) Cross sections through maxillary bone in a patient with SOD. Note homogeneous radiopacity and missing premolars. As this
process evolves, vertical linear striations may be seen. (B) A 9-year-old with SOD: faint, pigmented hypertrichotic lesion on the right face
associated with a focal osteosclerotic process in the underlying maxilla. (C) Same patient at age 17: note increase in pigmentation and
presence of hair. This is often referred to as Becker nevus.

Becker nevus requires dermatologic evaluation and may


require biopsy, as rare melanoma has been reported in this
lesion.

Cherubism
Genetics
This is an autosomal dominant disease with multiple spontaneously occurring cases. A mutation of gene SH3BT2 is known
to cause cherubism.

Clinical features
Cherubism is a bilateral progressive enlargement of the maxilla
and mandible. First called familial fibrous dysplasia by Jones in
1933, the name was modified to cherubism because of the
angelic or cherubic look of the affected children who appeared
to be looking up to heaven (Fig. 6A). The onset is between ages
2 and 5 years. The swelling of jaws is progressive and can be
extensive. Lesions tend to stop expanding at puberty and
regress during adulthood.
The radiographic picture is characteristically expansile
multilocular soap-bubbleetype radiolucencies. They create

116

Sachs

Fig. 6 (A) A 9-year-old boy with cherubism. Note bilateral facial enlargement with upward pointing pupils and inferior scleral show.
(B) Sagittal section of patient with cherubism. Note orbital extension that created diplopia. The multilocular radiolucencies are typical
of cherubism. Biopsy revealed a multinucleated giant cell lesion consistent with cherubism. (C) The same patient as in (A) seen 20 years
later, showing significant recontouring of the previous expansile process. (D) Radiolucent, soap-bubble appearance of lesion involving
the bilateral mandible and the right maxilla in a patient with cherubism. Note orthodontic therapy aligning the dentition in the
presence of this disease process. (E) The previous expansile multilocular radiolucency seen in (D) has become more sclerotic and
corticated.

sizable deformities extending at times into the orbit


(Fig. 6B), creating proptosis and diplopia. The histology
demonstrates fibrous tissue and large multinucleated giant
cells. These lesions may displace or impact teeth and
generally prevent a normal eruption pattern. Treatment
consists of cosmetic recontouring with intraorbital reductions
when the globe is displaced. The frequent association with
other known syndromes, such as Noonan syndrome, requires
that cases that appear to be isolated cherubism be scrupulously evaluated.
Syndromes associated with cherubism include gingival
fibromatosis (Ramon syndrome), Noonan syndrome, Noonanlike
syndrome with polyarticular villonodular synovitis, and cardiofaciocutaneous syndrome.

Treatment considerations for the oral and


maxillofacial surgeon
Treatment can be planned for esthetic recontouring (Fig. 6C)
and provide an excellent result. As the lesions can be quite
vascular, deliberate hypotension as well as adequate blood
banking is necessary before surgery. Selective extractions,
possible exposures, and proactive orthodontic care is needed
to ensure the development of a functional occlusion (Fig. 6D).
As patients reach adulthood, the lesions tend to burn out,
becoming sclerotic and less expansile (Fig. 6E).

Syndromic fibrous dysplasia: McCune Albright


syndrome

Differential diagnosis
Genetics
Includes fibrous dysplasia, giant cell lesions of the jaws, brown
tumor of hyperparathyroidism.
Typically cherubism does not cause elevation in serum calcium, alkaline phosphatase, or acid phosphatase.

All cases reported have been isolated. A thought is that this an


autosomal dominant lethal gene with normal cells only surviving when in a mosaic state with a normal gene. It has been

Syndromes Affecting Bone


postulated that the etiology of McCune Albright is gene NAS1,
which affects the production of proteins that stimulate various
organ systems, including the gonads, the adrenal cortex, and
some pituitary cell populations, as well as osteoblasts and
melanocytes.

Clinical features
Although most fibrous dysplasias are solitary lesions and are
nonsyndromic, when multiple bones are involved (polyostotic),
one must consider McCune Albright syndrome (Fig. 7). The
hallmarks of this entity are the following:
1. Polyostotic fibrous dysplasia
au lait (coast of California)
2. Cafe
3. Abnormal function of one or more endocrine glands
causing hyperthyroidism, hyperparathyroidism, pituitary
adenomas, acromegaly, precocious puberty, and diabetes
mellitus
The abnormal facial growth pattern is usually unilateral
and often involves the craniofacial bones. Only 3% of patients
with polyostotic fibrous dysplasia have McCune-Albright syndrome. The long bones are most commonly affected, producing a bowing of the femur in what has been termed
shepherds crook or hockey stick abnormality. The facial
bones show expansion and increased radiodensities, including
at the sphenooccipital base of the skull. The orbit, cranium,
skull base, and mandible can be involved with this very typical
ground-glass appearance.

117

Differential diagnosis
Polyostotic fibrous dysplasia.

Treatment considerations for the oral and


maxillofacial surgeon
Once the diagnosis of craniofacial fibrous dysplasia is made, a
search for other bone involvement and an endocrine workup
(including evaluation for neoplasia) should be undertaken. The
asymmetric pattern of maxillofacial bone involvement can be
normalized with orthognathic surgery.

Osteogenesis imperfecta
Genetics
This is an autosomal dominant disease that is caused by
mutation of 2 genes that encode type I collagen, specifically
COL1A1 and COL1A2. The prevalence of this condition is 1 in
20,000 births.

Clinical features
Osteogenesis imperfecta are a group of inherited connective
tissue disorders that affect type I collagen and result in bone
abnormalities characterized by easy fracture (Fig. 8). It is
often called brittle bone disease. In all, there are 9 types. Type
1 is the most common by far and type 2 is always lethal. The

Fig. 7 (A) Expanded maxilla in a patient with McCune-Albright syndrome. This patient went on to have multiple endocrine neoplastic
au lait (coast of California) seen in a
diseases and continued craniofacial bone enlargement over 3 decades. (B) Regular-border cafe
patient with McCune-Albright syndrome. (C) At age 16, despite several contouring procedures, the disease produced a canted and enlarged
right maxilla that was eventually corrected with a LeFort I osteotomy. (D) Radiograph demonstrating an asymmetric maxilla with
opacification of the sinus.

118

Sachs

Fig. 8 (A) A 14-year-old with type 1 osteogenesis imperfecta. Note the class III malocclusion secondary to maxillary hypoplasia. (B) A
14-year-old patient with osteogenesis imperfecta. Note marked mandibular prognathism and abnormal cervical spines. (C) Dentinogenesis
imperfecta in the same patient. This condition, which is generally autosomal dominant, is recessive in patients with osteogenesis
imperfecta. (D) Blue sclera as seen in various forms of osteogenesis imperfecta. This finding results from a thin and translucent scleral
layer, which allows the bluish choroid layer to become more apparent. (E) A patient with osteogenesis imperfecta demonstrating short
stature with bowing of the extremities. The bones in these patients fracture easily and often. Treatment with antiosteoclast medications,
such as bisphosphonates, or with pro-osteoblastic agents has shown some promise in treating these patients. ([E] From Horton WA, Hall JG,
Hecht JT. Achondroplasia. Lancet 2007; 370:162e72; with permission.)

connective tissue defect causes several classic findings,


including brittle, easily fractured bones, deformity of the long
bones (bowing spine and craniofacial skeleton), hypermobile
joints, blue sclera, dentinogenesis imperfecta, hearing loss,
and cardiac defects, including aortic root dilatation and mitral
valve prolapse. These characteristics are present with a varying degree of severity among the different types of osteogenesis imperfecta.

Treatment considerations for the oral and


maxillofacial surgeon
Patients typically present with short stature and a history of
multiple long bone fractures with bowing of the long bones.
Hypoplasia of the maxilla and the pseudoprognathism result in
a Class III malocclusion, which may be addressed surgically.
Bisphosphonates can be used to maintain the mineral content

of the bones. The incidence of fracture decreases after


puberty.

Marfan syndrome
Genetics
This is an autosomal dominant trait with a wide variation in
expression. It involves a mutation of the fibrillin gene FBN1,
which is located on the 15q15-21.3 chromosome.

Clinical features
Marfan syndrome is a genetic connective tissue disorder
affecting the formation of fibrillin type-I. This protein is a
major component of microfibrils, which interact with elastin

Syndromes Affecting Bone


and provide structural anchorage for many body organs. The
condition, first described by the French pediatrician, Marfan,
in 1896, has a large variability in phenotype. It, however, has 3
major target sites: cardiovascular, skeletal, and ocular. In
1996, various criteria for making the diagnosis of Marfan syndrome were established and were further divided into major
and minor criteria.
Typically, patients with Marfan syndrome (Fig. 9) are tall
and slender with long limbs, disproportionate body size, and a
tall droopy face and head. The fingers are long and spiderlike
(arachnodactyly), and may demonstrate the ability to wrap
around the opposite wrist and have the thumb overlap the last
digit (wrist sign). The face is dolichocephalic with downslanting palpebral fissures, patulous lips, and high arch palate
with significant dental crowding. This facial dysmorphology is
exaggerated by the high incidence of obstructive sleep apnea
in these children and young adults.
The cardiac findings are important because they are
essential for the diagnosis and they represent the highest potential for mortality and morbidity in these patients. These
include dilatation of the ascending aorta, mitral valve prolapse, and dissecting aneurysm of the thoracic or abdominal
aorta. These patients also have spontaneous pneumothoraces,
sternal abnormalities, lumbosacral dural ectasia, lens subluxation, and a strong positive family history. Minor findings
include scoliosis, large ears, and cleft palate. The chief causes
of death are the vascular complications associated with aortic
aneurysm dissection.

Treatment considerations for the oral and


maxillofacial surgeon
Patients with Marfan syndrome may present for orthognathic
evaluation for long face syndrome or transverse maxillary

119
deficiency. Once identified, these patients should be evaluated
for aortic aneurysm and may require antibiotic prophylaxis
before oral surgical care. Two important studies in working up
patients with Marfan syndrome are echocardiography, which is
positive in 90% of the cases, and slit lamp examination of the eye.
These patients are often on long-term beta-blocker therapy.

Cleidocranial dysplasia (dysostosis)


Genetics
This syndrome is autosomal dominant, with 20% to 40% of cases
having de novo mutations. It has been determined that there is
a defect in osteoblast maturation and osteogenesis, which is
associated with RUNX2 gene.

Clinical features
This syndrome presents with aplasia or hypoplasia of one or
both clavicles, associated with delayed closure of the fontanelles, exaggerated transverse foramen of the cranium, and
multiple impacted and nonerupted teeth (Fig. 10). Patients
with cleidocranial dysplasia have short stature with a brachycephalic skull. They demonstrate frontal bossing. The maxilla
and zygoma are hypoplastic, creating a skeletal class III relationship. The patients have a broad nasal base and hypertelorism. The paranasal sinuses are underdeveloped or absent.
The absence of clavicular continuity creates a wide range of
shoulder movements. Spina bifida occulta occur throughout the
spine and cone-shaped epiphyses are present in the distal
phalanges. The oral findings include a high arched palate,
submucous or complete clefting of the hard and soft palate,
and delayed union of the mandibular symphysis. These patients
present with multiple impacted and supernumerary teeth, the

Fig. 9 (A) A 12-year-old female with Marfan syndrome presenting with a typical long face, incompetent lips, hypertelorism, and downslanting palpebral fissure. (B) The long fingers in Marfan patients have been described as spiderlike (arachnodactyly). The index finger may
wrap around the wrist with a phalanx to spare (positive wrist sign). The fingers can often be bent backwards and are extremely flexible due
to the defective connective tissue. (C) Mandibular prognathism may be the primary reason for a patient with Marfan syndrome to consult
with an oral and maxillofacial surgeon.

120

Sachs

Fig. 10 (A) A patient with cleidocranial dysplasia demonstrating maxillary hypoplasia, hypertelorism, and frontal bossing. (B) The same
patient with cleidocranial dysplasia (CCD) demonstrating multiple unerupted teeth and class III malocclusion. (C) Panoramic and 3D CT image
demonstrating multiple impacted teeth. Selective extractions and surgical exposures in combination with orthodontics can result in a
functional dentition for these patients. (D) This patient demonstrates easy midline rotation of shoulders due to congenitally absent clavicles.

average being 5. These teeth have an ectopic location and


have crown and root anomalies. It has been shown that they
are missing a layer of cellular cementum, creating an inability
to resorb overlying bone.

Differential diagnosis
The combination of short stature, absent clavicles, and multiple impacted teeth is pathognomonic of this condition.

expression of the disease, many individuals are carriers. It has


been noted that in the Mediterranean areas where malaria is
prevalent, the sickle-cell and thalassemia carrier has a
degree of protection from the malarial parasite and thus the
genetic material continues to pass from generation to
generation.

Clinical features

Congenital hemolytic anemias (alpha and beta


thalassemia, Cooleys anemia, Mediterranean
anemia, sickle-cell anemia)

Various congenital hemolytic anemias induce extramedullary


hematopoiesis. These create a phenotype characterized by
maxillary expansion and excessive vertical displacement with
lip incompetence and marked gingival exposure (Fig. 11A). A
large head with classic hair-on-end radiographic pattern is seen
on skull radiography. Additional radiographic findings include
replacement of the normal pneumatized sinuses with opacifying bone marrow (Fig. 11B).
Both sickle-cell anemia and thalassemia can produce this
typical facies. A defective hemoglobin molecule produces an
anemia. In response to this chronic anemia, increased activity
of bone marrow in extramedullary sites occurs. This would
include the liver, the spleen, the sinuses, and the diploic
spaces of the skull.

Genetics

Considerations for the oral and maxillofacial surgeon

These hemolytic anemias are autosomal recessive, and


although the homozygous recessive form permits the full

First and foremost is the recognition of this phenomenon


and the control of the disease before facial deformities

Treatment considerations for the oral and


maxillofacial surgeon
Removal of the deciduous teeth does not result in permanent
teeth eruption. Surgical removal of impacted teeth combined
with exposure of selective critical teeth and active orthodontics can result in the development of a functional dentition.
Often these surgeries require staging.

Syndromes Affecting Bone

121

Fig. 11 (A) A patient with thalassemia demonstrating a displaced maxilla secondary to extramedullary hematopoiesis filling the
maxillary sinuses. Note the grossly incompetent lips and skin pallor. (B) Lateral cephalogram demonstrating vertical maxillary excess,
obliterated maxillary sinuses, and hair-on-end pattern of the skull. This is secondary to marrow proliferation in the diploe and loss of the
outer skull cortex. (C) Intraoperative photograph showing the excision of a section of the maxilla for treatment of maxillary hyperplasia in
a patient with thalassemia major. (D) Postoperative photograph of the patient in (A) after posterior and superior repositioning of the
maxilla.

can be approached. The marrow displacement can produce


thrombocytopenia and microcytic anemia. These patients,
particularly in a homozygous form, require multiple transfusions. Result of the breakdown of the red blood cell produces large amounts of iron, which are deposited in the
tissues, thus iron chelation is a requirement for treating this
disease. Under the proper circumstances and with the control
of the disease, a surgical approach to the correction of the
gnathopathy created by these anemias can be performed
(Fig. 11C, D).

Suggested readings
Cassidy and Allanson. The Management of Genetic Syndromes.
Hennekam R, Allanson J, Krantz I. Gorlin Syndromes of the Head and
Neck. 6th edition.
Jones KL. Smiths Recognizable Patterns of Human Malformation.

Osteopetrosis
Gorlin Syndromes of the Head and Neck. p. 245.
Jones; Smiths recognizable Patterns of Human Malformation. p. 453e5.
Makarem, et al. Osteopetrosis: oral and maxillofacial manifestations.
Int J Head Neck Surg 2012;3(2):115e7.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:356e65.

Osteopathia striata with cranial sclerosis


Bass HN, Weiner JR, Goldman A, et al. Osteopathia striata syndrome:
clinical, genetic, and radiologic considerations. Clin Pediatr 1980;
19:369e73.
Gorlin Syndromes of the Head and Neck. p. 245.
Konig, et al. Osteopathia striata with cranial sclerosis. Am J Med Genet
1996;63:69e73.

Infantile cortical hyperostosis e Caffey Silverman


syndrome
Eversole SL Jr, Holman GH, Robinson RA. Hitherto undescribed
characteristics of the pathology of infantile cortical hyperostosis
(Caffeys disease). Bull Johns Hopkins Hosp 1957;101(2):80e99.
Gorlin Syndromes of the Head and Neck. 6th edition. p. 255.
Jones; Smiths Recognizable Patterns of Human Malformation.
Kamoun-Goldrat A, le Merrer M. Infantile cortical hyperostosis (Caffey
disease): a review. J Oral Maxillofac Surg 2008;66(10):2145e50.

Segmental regional odontomaxillary dysplasia


(SOD)
Danforth RA, Melrose RJ, Abrams AM, et al. Segmental odontomaxillary
dysplasia. Report of eight cases and comparison with

122
hemimaxillofacial dysplasia. Oral Surg Oral Med Oral Pathol 1990;
70(1):81e5.
Gorlin Syndromes of the Head and Neck. p. 1169.
Kuklani RM, Nair MK. Segmental odontomaxillary dysplasia: review of
the literature and case report. Int J Dent 2010;2010:837283.
Welsch MJ, Stein SL. A syndrome of hemimaxillary enlargement,
asymmetry of the face, tooth abnormalities, and skin findings
(HATS). Pediatr Dermatol 2004;21(4):448e51.

Cherubism
Carvalho SE, Carvalho Silva GC, Vieira TC. Cherubism: clinicoradiographic features, treatment, and long-term follow-up of 8 cases.
J Oral Maxillofac Surg 2007;65(3):517e22.
Gorlin Syndromes of the Head and Neck. p. 1218.

McCune Albright syndrome


Gorlin Syndromes of the Head and Neck. p. 392e7.
Jones; Smiths recognizable Patterns of Human Malformation. p. 594.
Lee JS, FitzGibbon EJ, Chen YR, et al. Clinical guidelines for the
management of craniofacial fibrous dysplasia. Orphanet J Rare Dis
2012;7(Suppl 1):S2. http://dx.doi.org/10.1186/1750-1172-7-S1-S2
[46(10):497e505].
Sachs S, Kleiman M, Psternak R. The surgical management of a facial
deformity secondary to craniofacial fibrous dysplasia: a case report.
J Oral Maxillofac Surg 1984;42(3):192e6.
Yeow VK, Chen YR. Orthognathic surgery in craniomaxillofacial fibrous
dysplasia. J Craniofac Surg 1999;10(2):155e9.

Osteogenesis imperfecta
Gorlin Syndromes of the Head and Neck. p. 219.
Jones; Smiths Recognizable Patterns of Human Malformation.
p. 562.

Sachs
Kindelan J, Tobin M, Roberts-Harry D, et al. Orthodontic and orthognathic management of a patient with osteogenesis imperfecta and
dentinogenesis imperfecta: a case report. J Orthod 2003;30(4):
291e6.

Marfan syndrome
Becker A, Lustmann J, Shteyer A. Cleidocranial dysplasia:
Part 1eGeneral principles of the orthodontic and surgical
treatment modality. Am J Orthod Dentofacial Orthop 1997;
111(1):28e33.
Beighton, et al. International nosology of heritable disorders of
connective tissue. Am J Med Genet 1988;29(3):581e94.
De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic
criteria for the Marfan syndrome. Am J Med Genet 1996;62(4):
417e26.
Gorlin Syndromes of the Head and Neck. p. 1283e9.
Jones; Smiths Recognizable Patterns of Human Malformation, chapter
546.
Marfan AB. Un Cas de Deformation Congenitales Desquatre, 1986-Paris.
Pyeritz RE. The Marfan syndrome. Annu Rev Med 2000;51:481.

Cleidocranial dysplasia (dysostosis)


Gorlin Syndromes of the Head and Neck. p. 333.
Jones; Smiths Recognizable Patterns of Human Malformation. p. 462e3.

Congenital hemolytic anemias


Drew SJ, Sachs SA. Management of the thalassemia-induced skeletal
facial deformity: case reports and review of the literature. J Oral
Maxillofac Surg 1997;55(11):1331e9.
Weissberg G, Epker B, Bordelon J. Correction of sickle gnathapathy
by total maxillary osteotomy. J Maxillofac Surg 1980;8(3):
187e94.

Metabolic and Autoimmune Syndromes


Victor Nannini, DDS a,b,*
KEYWORDS
 Fabry disease  Williams syndrome  Hurler syndrome  Hunter syndrome  Heerfordt syndrome  Sjo
gren syndrome
KEY POINTS
 Genetic alterations can cause physiologic responses resulting in systemic and metabolic complications.
 These complications can cause significant deficits, as in Hurler and Williams syndromes, which can lead to debilitating
disease and early death.
 These alterations may also lead to abnormal immune responses that affect significant organs and organ systems.

Fabry disease
Key points
 Fabry disease, also known as Anderson-Fabry disease, is
an inherited X-linked recessive disorder of lysosomal
storage.1e3
 Fabry disease is the second most prevalent lipid storage
disease after Gaucher disease and occurs from a deficient activity of lysosome hydrolase, alpha-galactosidase A.1e4

Genetics
The alpha-galactosidase A gene has been mapped to the region
q22.1 of the X chromosome.5e8 When mutated, a progressive
accumulation of a glycolipid called globotriaosylceramide
(Gb3) affects mainly endothelial and vascular smooth muscle
cells and causes damage to many major organs1 including renal
and cardiac insufficiency,2 and central nervous system disorders including cerebral infarction and skin and pulmonary
symptoms.1e4,9e11 It is mostly a male disease with the reported
incidence varying from 1 in 17,000 to 1 in 117,000 men in white
populations.12e14 However, this disease is probably unreported
because many of the manifestations are nonspecific, the disease is rare, and often the initial diagnosis is not accurate.4
Women can have the disease but usually have milder symptoms
that occur later in life.15e17 There are rare reports of women
being asymptomatic early in life, but then showing symptoms
as severe as those of men with the classic phenotype.15,16
The author has nothing to disclose.
a
Private Practice, Long Island Oral and Maxillofacial Surgery, P.C.,
134 Mineola Boulevard, Mineola, New York 11501, USA
b
Division of Oral and Maxillofacial Surgery, Nassau University Medical
Center, 2201 Hempstead Turnpike, East Meadow, New York 11554, USA
* Division of Oral and Maxillofacial Surgery, Nassau University Medical Center, 134 Mineola Boulevard, Mineola, NY 11590.
E-mail address: vnannini@hotmail.com
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 123134
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.005

Clinical features
Clinical manifestations of the disease often occur early in life,
caused by the increase in glycolipids, which causes inflammation and fibrosis.3 Therefore, severe neurologic pain in the
limbs, especially during times of stress, begins around the age
of 10 years.4 Renal dysfunction with proteinuria and polyuria,
often leading to renal failure, is one of the serious complications of the disease.3 Skin lesions are often present, including
hypohidrosis and angiokeratomas.4 The labial mucosa is often
involved with a maculopapular eruption (Fig. 1). Corneal
changes are usually an early sign with a whorl-like keratopathy
seen on a slit lamp examination (Fig. 2).11,18,19 As these patients age, central nervous system involvement often leads to
increased incidence of stroke.20,21 Cardiovascular effects
include hypertension and cardiomyopathy with eventual heart
failure.4,22 Oral and maxillofacial findings include increased
prevalence of maxillary cysts and maxillary prognathism.23
Thickening of the lips and a bulbous nose have been described
in many cases.4 Perioral linear telangiectases24 and cases of
granulomatous cheilitis and granulomatous gingivitis25e27 are
noted. Tinnitus is reported in approximately 40% of patients
with this disorder.4 Because of the severe major organ
dysfunction, most of these patients die at an early age secondary to stroke, end-stage renal failure, or cardiovascular
complications.

Differential diagnosis
Because this disorder is rare, it is often misdiagnosed because
of early nonspecific manifestations, including neurologic and
skin disorders. These disorders can include rheumatoid
arthritis, fibromyalgia, multiple sclerosis, and Meniere disease.4 The disorder is often discovered following more
serious complications such as stroke, cardiac insufficiency,
and renal failure.20e22,28e30 Because treatment with enzyme
replacement therapy has been shown to have positive results,
early diagnosis of Fabry disease is important. When suspected, serum assays of leukocyte alpha-galactosidase A
activity are effective in men; however, genetic testing
in women is recommended because of inclusive serum
results.4

oralmaxsurgeryatlas.theclinics.com

124

Fig. 1 Fabry disease. Note the pinpoint maculopapular lesions on


the lip. (From James WD, Berger TG, Elston DM. Andrews diseases
of the skin: clinical dermatology. 11th edition. Philadelphia:
Saunders, an imprint of Elsevier; 2011; with permission.)

Treatment considerations for the oral and


maxillofacial surgeon

Nannini

Fig. 2 Faint but extensive vortex keratopathy seen on retroillumination. (From Kanski J. Clinical diagnosis in ophthalmology.
Cornea. 1st edition. Philadelphia: Mosby, an imprint of Elsevier;
2006. Fig. 6.232; with permission; and Courtesy of W. Lisch, MD,
Hanau, Germany.)

prevalence of this mutation seems to be in the range of 1 in


7500 to 1 in 25,000 live births.16

Clinical features
Oral surgeons should be suspicious that any patient displaying
angiokeratomas of the face, cheilitis granulomatosa, or granulomatous gingivitis may have the potential for Fabry disease,
especially young men. With late-stage disease and renal, cardiac, and neurologic complications, treatment must be carefully administered with close consultation with the appropriate
specialists.

Williams syndrome
Key points
 Williams syndrome, also known as Williams-Beuren
syndrome, is a rare autosomal dominant neurodevelopmental disorder affecting men and women
equally.1e3
 Williams syndrome was first discovered in 1961 by J.C.P.
Williams, who found patients with supravalvar aortic
stenosis, facial anomalies, and mental retardation.4
 Independently in 1962, A.J. Beuren found similar phenomena in his patients but also certain dental characteristics and pulmonary artery stenosis.5

Genetics
Williams syndrome and its manifestations seem to result from a
1.5-Mb deletion on the number 7 chromosome pair at 7q11.23,
which includes 26 to 28 genes.6e11 This deletion significantly
affects the production of elastin, which leads to supravalvar
aortic stenosis and other cardiovascular disorders such as peripheral artery stenosis.6,12e14 The other characteristics of this
disease arise because adjacent genes responsible for facial and
neural development are located in the deletion.12,15 The

Williams syndrome is characterized by its elfin facial appearance,17,18 growth delays with low body weight,19,20 mental
retardation,16,17 cardiovascular disorders,1,4,5,21e28 sleep disorders,29 and transient hypercalcemia, usually as infants. These
patients tend to have intelligence quotients in the 50 to 60 range
and are overly friendly, extremely talkative, with severe bouts
of anxiety.12,16,17 The facial abnormalities (Fig. 3) include periorbital fullness, full upper and lower lips, long philtrum, flat
nasal bridge, micrognathia, and abnormal dentition (Fig. 4)
including hypocalcification of the enamel, short and narrow
primary teeth, and crowded permanent teeth.12,18,19,30e35
Hyperacusis has been noted to be present in most patients.36
Although it is been reported that there is an increase in gingival
height and width of these patients, there was no increase in loss
of attachment.31,32,37e39 There have been reports in the literature of keratoconus,40 multiple sclerosis,41 Crohns disease,42
and Burkitts lymphoma,43 but these are rare.

Differential diagnosis
Some of the symptoms of Williams syndrome are also found in
other disorders. Patients with Noonan syndrome have similar
facial appearances, including micrognathia, flat nasal
bridge,1,44 and leprechaunism (an endocrine disorder that
produces elfin facial features and growth retardation).45 Idiopathic infantile hypercalcemia not related to Williams syndrome has been reported.46 The definitive diagnostic test for
Williams syndrome is the fluorescence in-situ hybridization
test, which conclusively shows the gene deletion.16,47,48

Treatment considerations for the oral and


maxillofacial surgeon
Although there is no cure for Williams disease, treatment of
the underlying causes becomes paramount. Management of

Metabolic and Autoimmune Syndromes

125

Hurler syndrome
Key points
 Hurler syndrome is a rare autosomal recessive disease
that is classified in a group of disorders called mucopolysaccharidosis. It is also known as mucopolysaccharidosis type 1-H.
 First described by Dr Gertrud Hurler in 1919, Hurler
syndrome was discovered in 2 unrelated boys with
similar characteristics including mental impairment,
distortion of facial features, respiratory and cardiac
disease, hepatosplenomegaly, and corneal opacities.1e4
 It is the most severe form of mucopolysaccharidosis
and, without treatment, leads to early death before the
second decade of life.5

Genetics

Fig. 3 Characteristic facial appearance of Williams syndrome in


a 6-year-old boy with nonfamilial supravalvular aortic stenosis and
pulmonary artery stenosis. The patient was mentally retarded and
shows the typical large mouth with patulous lips, small chin, baggy
cheeks, blunt upturned nose, wide-set eyes, and malformed teeth.
(From Perloff JK. Clinical recognition of aortic stenosis. The
physical signs and differential diagnosis of the various forms of
obstruction to left ventricular outflow. Prog Cardiovasc Dis
1968;10:323. Fig. 1; with permission.)

these patients can be difficult because of their mental disorders, which often require sedation or general anesthesia for
treatment.46 As patients age, cardiovascular concerns along
with hypertension require close consultation with the appropriate medical practitioners.

Hurler syndrome occurs when there is a mutation in the alpha


6
L-iduronidase (IDUA) gene. IDUA is required for the degradation of heparan sulfate and dermatan sulfate in the lysosome.6
With the accumulation of these glycosaminoglycans in various
organs, multiple systemic effects begin to occur over a short
period of time.2,6 It seems that patients with the serious form
of the disease have nonsense mutations identified on both alleles.7 The incidence of Hurler syndrome is about 1 in 100,000
live births.2,8

Clinical features
Children with Hurler syndrome initially appear nearly normal at
birth but, because of accumulation of glycosaminoglycans,
progressive cell and tissue malfunction occurs, leading to
mental retardation, hepatosplenomegaly, corneal clouding,
with eventual cardiopulmonary failure.5,8,9 Clear cells (Hurler
cells) have been identified in infants within the myocardium.10
Affected individuals have short long bones and short and broad
digits consistent with dwarfism.5,11 Carpal tunnel syndrome
and limited mobility are common.12,13 Facial deformities
(Figs. 5 and 6) are prevalent, including an enlarged deformed
head with frontal bossing, a flattened nasal bridge, and
hypertelorism.11 The patients have thickened patulous lips
with a flattened philtrum.11,14e16 They have significant macroglossia that, over time, leads to an anterior open bite11 and,
combined with a short neck, leads to sleep apnea and significant complications from anesthesia.17,18 There are dental
anomalies, including short conical teeth, widely spaced
dentition, and supernumerary teeth in the mandibular
rami.19,20 There have been reports of increased dentigerous
cyst formation in the mandible.11

Differential diagnosis
Fig. 4 Williams syndrome: typical dental abnormality characterized by small, malformed, widely spaced teeth with malocclusion. (From Perloff JK. Congenital heart disease in adults. 3rd
edition. Philadelphia: Saunders, an imprint of Elsevier; 2008.
Fig. 20-14; with permission.)

At present 7 different types of mucopolysaccharidosis have


been identified.2 Of the mucopolysaccharidosis type 1 (MPS 1)
types, the phenotypes of each determines the specific syndrome. As mentioned earlier, Hurler syndrome (MPS 1-H), with
the most extensive symptoms, is distinguished from HurlerScheie syndrome (MPS 1-H/S), with intermediate symptoms (no

126

Nannini

Treatment considerations for the oral and


maxillofacial surgeon
A patient diagnosed with Hurler syndrome before the age of 2
years has shown considerable improvement of symptoms,
especially the neurologic defects, with hematopoietic stem
cell transplantation.2,5,7,8,17,21,24e27 However, there are significant risks, with increased morbidity and mortality.8 Enzyme
replacement therapy (ERT) with laronidase, which is a protein
analogous to human alpha iduronidase, is an alternative therapy.2 However, it does not cross the blood-brain barrier and
therefore shows no improvement in the neurologic deficits that
the syndrome displays. For the oral and maxillofacial surgeon,
these patients are extremely difficult to treat because of their
neurologic disorders, skeletal deformities, dental anomalies,
and anesthetic risks. Close consultation with the appropriate
specialists and probable palliative treatment is indicated.

Hunter syndrome
Key points
Fig. 5 Hurler syndrome. Coarse facial features, macrocephaly,
scaphocephalic skull, flattened nasal bridge, hypertelorism, short
neck, chest deformity, and protuberant abdomen in a girl with
Hurler syndrome (mucopolysaccharidosis I). (From Paller A,
Mancini AJ. Hurwitz clinical pediatric dermatology: a textbook of
skin disorders of childhood and adolescence. 4th edition. Philadelphia: Saunders, an imprint of Elsevier; 2011. Fig. 24.13; with
permission.)

cognitive disturbances), versus the Scheie syndrome (MPS 1-S),


with attenuated symptoms that occur later in life and progress
slowly.2 Because early diagnosis before the age of 2 years is
critical for the long-term survival of a patient with Hurler
syndrome, recognition becomes paramount. Early symptoms
such as rhinitis and hernia are vague, but radiographic features
can aid in the diagnosis.21e23 A decreased level of serum alpha21
L-iduronidase confirms the diagnosis.

 Hunter syndrome, also known as mucopolysaccharidosis


II, is a rare X-linked lysosomal storage disorder.1e7
 Hunter syndrome was first described by Dr Charles
Hunter8 in 1917, who described 2 brothers with significant skeletal deformities, including facial deformities
with hearing deficiencies.
 The syndrome causes a deficiency in the lysosomal
enzyme iduronate-2-sulphatase, which is responsible
for cleaving sulfate from the glycol aminoglycosides
dermatan sulfate and heparin sulfate.9 As a result,
gradual accumulation of these glycosaminoglycans results in multiple organ and systemic disorders.2

Genetics
The incidence of mucopolysaccharidosis II (MPS II) ranges from 1
in 110,000 to 1 in 135,500 live births.10 Because it is an X-linked
disease, most patients are male. There are some female cases
reported, which require either 2 pathologic alleles or a normal
inactivated allele.1,6,10 However, the female cases tend to have
attenuated symptoms.1,9 The gene that produces iduronate-2sulphatase is located on chromosome Xq28 with the exonic point
mutations G374sp comprising half of the mutations.11 Significant variability in the mutations is evident.12 It is thought that
this variance explains much of the difference between phenotypes and also the difficulty in treating patients with MPS II.11

Clinical features

Fig. 6 Facial coarseness in Hurler syndrome. (From Kanski J.


Clinical diagnosis in ophthalmology. 1st edition. Philadelphia:
Mosby, an imprint of Elsevier; 2006. Fig. 6.229; with permission.)

Similar to other patients with mucopolysaccharidosis, patients


with MPS II tend to appear normal at birth. Frequent upper
respiratory infections, umbilical hernias, and coarse facial
features are some of the early signs and symptoms.6,11 As the
increase in glycosaminoglycosides accumulate in organs, hepatosplenomegaly, skeletal and joint involvement with
decreased mobility, clubbed fingers, cardiac involvement, and
obstructive airway disease become prevalent.1,3,9,11,13,14
Facial features (Fig. 7) include frontal bossing, a wide nasal
bridge, a large skull, macroglossia often leading to an anterior

Metabolic and Autoimmune Syndromes

127

Differential diagnosis
Because there are significant differences in the expression of
this disorder, it can be difficult to distinguish this from other
forms of mucopolysaccharidosis. In the severe expression of
MPS II, there are many similar characteristics to Hurler syndrome, except without the corneal clouding.9,11,17 Other
lysosomal storage disorders that share similar features include
MPS VI (Maroteux-Lamy syndrome) and MPS VII (Sly syndrome).6
A preliminary test to confirm mucopolysaccharidosis is an increase in urinary glycosaminoglycans.6,25 Although this is not
specific to Hunter syndrome, further blood testing for deficiency of iduronate-2-sulfatase in leukocytes, serum, or
plasma will secure the diagnosis.1,6 A mnemonic screening tool
has been developed and has correctly identified 95% of patients
with no family history of Hunter syndrome.26

Treatment considerations for the oral and


maxillofacial surgeon

Fig. 7 Hunter syndrome. Note frontal bossing, wide nasal bridge,


macroglossia. (From Yoskovitch A, Tewfik TL, Brouillette RT, et al.
Acute airway obstruction in Hunter syndrome. Int J Pediatr Otorhinolaryngol 1998;44:273e8; with permission.)

open bite, and mandibular immobility.1,6,15e23 Non-tender,


irregularly shaped papules may be present on the skin of the
upper back (Fig. 8). Dental abnormalities have been reported,
including widely spaced teeth, enamel defects, carious teeth,
dentigerous cysts, and abscesses.16 In the most severe cases of
Hunter disease, central nervous system manifestations begin
between the ages of 2 and 4 years and are often expressed as
severe mental retardation.24 In these situations, death is usually expected before the third decade of life and usually as a
result of cardiac or obstructive respiratory failure.1,6,11 In the
milder forms, patients may have normal intellect and nearnormal stature with an increase in life expectancy.1,6,9

With many mucopolysaccharidosis disorders, early diagnosis is


critical because estrogen replacement therapy (ERT) with
idursulfase has been shown to be effective in delaying and
improving many of the symptoms associated with this disorder.4,9,13 However, this drug does not seem to cross the bloodbrain barrier and therefore has little effect on those patients
with severe central nervous system involvement.9 Unlike Hurler
syndrome (MPS 1-H), hematopoietic stem cell transplantation
does not seem to have any significant effect on neurologic
improvement.1,9 The oral and maxillofacial surgeon must be
cognizant that each individual with Hunter syndrome may present with a variety of symptoms. Anesthetic management and
risks associated with individual patients become paramount.

Heerfordt syndrome
Key points
 Heerfordt syndrome is a rare manifestation of systemic
sarcoidosis that includes fever, parotid swelling, uveitis, and facial nerve paralysis.1e5
 It was described by Danish ophthalmologist Christian
Heerfordt, who reported these traits without the
connection to sarcoidosis.6 That direct link was reported in 1937 by Dr Jan Waldenstrom.7
 The histology is classic for multiple noncaseating granulomas found in the parotid or salivary glands and
lacrimal glands.1
 Treatment of Heerfordt syndrome with long-term corticosteroids seems to have a good prognosis.2e4

Genetics

Fig. 8 Ivory-colored papules on the upper back in Hunter syndrome. (From Kliegman RM, Stanton BF, St Geme JW III, et al.
Nelson textbook of pediatrics. 19th edition. Philadelphia: Saunders, an imprint of Elsevier; 2011. Fig. 651-13; with permission.)

Sarcoidosis and therefore Heerfordt syndrome seems to be


more prevalent in women than in men, and in black Americans
versus white with 3 times the rate (36 per 100,000 vs 11 per
100,000) and also with more chronic and fatal disease.8 Most
patients show clinical signs between the ages of 20 and
40 years.3,4 Numbers vary around the world but it seems that
the frequency of Heerfordt disease is about 0.3% of patients
with sarcoidosis.9,10 Because sarcoidosis seems to have a

128

Nannini

genetic and environmental component, it is thought that


Heerfordt syndrome has similar findings.9 The human leucocyte
antigen (HLA) gene has been implicated in both sarcoidosis and
in Heerfordt syndrome but specifically the HLA-DRB1*04 allele
seems protective for sarcoidosis, but increases the risk for
ocular manifestations.9 Despite significant research the exact
cause has remained elusive and further genetic and immunologic studies are required.8,11e13

Clinical features
In patients with sarcoidosis, usually fever, followed by uveitis,
parotid gland swelling, and then facial nerve palsy are classic
for Heerfordt syndrome (Figs. 9 and 10).1e5 The parotid glands
usually enlarge bilaterally and are firm to the touch.14e21
Bilateral lacrimal gland enlargement is often seen with either
anterior or posterior uveitis, accompanied by blurred
vision.9,14,16 Although the facial nerve palsy is usually unilateral, bilateral deficits have been reported.22e24 Neurosensory
deficits of other cranial nerves, including the palate,18 have
been reported.

Differential diagnosis
The differential diagnosis for each of the components for
Heerfordt syndrome can be extensive. For example, bilateral
gren syndrome,
parotid swelling can be attributed to Sjo
tuberculosis, mumps, sialadenitis, and Mikulicz disease; however, none of these have uveitis. The definitive diagnosis is
made by histologic confirmation of sarcoidosis, which presents
as noncaseating granulomas.2,3 In cases in which tissue biopsy
is difficult, increased angiotensin converting enzyme levels in
combination with a positive 67 gallium scintigraphy have been
shown to have 99% accuracy.2

Fig. 10 Seventh nerve palsy may also form part of Heerfordt


syndrome. Also note granulomatous infiltration of the nose and
tracheostomy. (From Kanski J. Clinical diagnosis in ophthalmology.
1st edition. Philadelphia: Mosby, an imprint of Elsevier; 2006.
Fig. 10.76; with permission.)

Treatment considerations for the oral and


maxillofacial surgeon
Patients presenting with any of the symptoms of Heerfordt
syndrome should immediately be referred for the evaluation of
sarcoidosis. The treatment of this disorder is usually corticosteroids and occasionally azathioprine.3,4,16,22 Long-term
prednisone is often required.25 The long-term prognosis for
these patients is usually good, but a small number (less than
5%) die from sarcoidosis, usually as a result of pulmonary
fibrosis with respiratory failure.8

Sj
ogren syndrome

Key points

Fig. 9 Parotid enlargement typically occurs in Heerfordt syndrome, which also manifests fever and acute anterior uveitis.
(From Kanski J. Clinical diagnosis in ophthalmology. 1st edition.
Philadelphia: Mosby, an imprint of Elsevier; 2006. Fig. 10.75; with
permission.)

gren syndrome is a chronic autoimmune inflamma Sjo


tory disease that primarily affects the exocrine
glands.1,2 It was first described by Swedish ophthalgren in 1933.3,4
mologist Henrik Sjo
 The syndrome can manifest as a primary disorder usually within the lacrimal and salivary glands or have
systemic manifestations (most commonly rheumatoid
arthritis or systemic lupus erythematosus), and is
gren.2,5
defined therefore as secondary Sjo
 Although the exact cause is unknown, it seems that
genetic, environmental, and hormonal factors play a
significant role.2
 Patients with this disorder are at high risk for the
development of non-Hodgkin lymphoma.1,2,5
 Treatment of this disorder is mainly symptomatic, although immunologic therapies have shown some promise.5

Metabolic and Autoimmune Syndromes

129

Fig. 11 (A) Bilateral parotid and submandibular gland hypertrophy in a patient with Sjogren syndrome. (B) Bilateral sublingual gland
hypertrophy in a patient with Sjogren syndrome. (Courtesy of D DeLuke, DDS, MBA, Richmond, VA.)

Genetics
gren syndrome affects about 0.2% to 3% (200e3000 per
Sjo
100,000) of the population and has a significant female/male
ratio of 9:1.3,6 The important role of genetics in this disorder is
emphasized when siblings and relatives of patients with prigren syndrome have a significantly higher risk of also
mary Sjo
gren and other autoimmune dishaving the disease.7 With Sjo
orders, genetic factors are varied and complex.6 Variations
in human leucocyte antigen on chromosome 6 subunit DR
(HLA-DR) and human leucocyte anitgen on chromosome 6
subunit DQ (HLA-DQ), which are located within the major
histocompatibility complex class II genes, determine basic
gren synimmune response and have been implicated in Sjo
drome.1,6 Genes that affect production and proliferation of
T and B cells have also been studied.6,8,9 Multifactorial genetic
and immunologic events are involved in the expression of this
disorder.9e14

occurs along with hyaline deposits often described as epimyoepithelial sialoadenitis (Fig. 12).2

Differential diagnosis
Sarcoidosis with or without Heerfordt syndrome, multiple
sclerosis, and other neurologic disorders has been reported to
gren syndrome.25e27 Because exocrine dysfunction is
mimic Sjo
gren syndrome is often difficult to
the primary symptom, Sjo
diagnose. The American European consensus group established
gren syndrome.28 The patient
criteria for the diagnosis of Sjo
must have subjective symptoms of dry eyes and dry mouth,
objective ocular and salivary gland tests, histopathology

Clinical features
gren syndrome is classified primarily by lymphocytic infilSjo
tration of multiple exocrine glands, specifically the lacrimal
and salivary glands, resulting in keratoconjunctivitis sicca and
xerostomia. Because of lack of lacrimal secretions, corneal
abrasions, visual discomfort and impairment are possible.5
Xerostomia results in susceptibility to dental caries, periodontal disease, and difficulty in chewing and swallowing.15e19
There is often swelling of the parotid glands bilaterally
gren syndrome, extra(Fig. 11A and B).20 In secondary Sjo
glandular systemic involvement occurs (most likely rheumatoid arthritis or systemic lupus erythematous).1,2 Other clinical
features include fatigue21 and thyroid, liver, and kidney disease.22,23 There are reports of immune-mediated anemia and
gren syndrome.24 The most
thrombocytopenia secondary to Sjo
serious complication related to this disorder is the development of lymphoma; these patients have a 10 to 50 times higher
risk than normal individuals.2 On biopsy of the affected
glandular tissue, periductal infiltration with lymphocytes

Fig. 12 Photomicrograph of a lip biopsy in a patient with Sjogren


syndrome. Note the periductal lymphocytic infiltrate. (Courtesy of
J Burns, DDS, Phd, Richmond VA.)

130
usually by minor salivary gland biopsy, and the presence of
serum
autoantibodies
of
anti-Ro
and/or
anti-La
specificity.2,28e30

Treatment considerations for the oral and


maxillofacial surgeon
gren syndrome will have a significant impact on the ability
Sjo
of the oral and maxillofacial surgeon to treat head and neck
issues that might arise. Local secondary effects of the disease
may include xerostomia, rampant caries, periodontal disease,
and recurrent fungal infection. Systemic effects secondary to
treatment with steroids and other immunosuppressive drugs
must be considered, and consultation with multiple specialists
may be needed prior to surgery.

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Syndromes Affecting Skin and Mucosa


Ioannis G. Koutlas, DDS, MS
KEYWORDS
 Ehlers-Danlos syndromes  Parry-Romberg syndrome  Witkop syndrome  Ectodermal dysplasias
 Osler-Rendu-Weber syndrome  Ascher syndrome  Behcet syndrome  Felty syndrome
KEY POINTS
 Ehlers-Danlos syndromes are a heterogeneous group of disorders characterized by abnormal formation of collagen or
molecules related to collagen synthesis, abnormalities in the matrix glycoprotein tenascin, and probably fibronectin.
 Parry-Romberg (or Romberg) syndrome is, in most cases, a sporadic disorder characterized by slow progressive atrophy or
shrinkage of facial tissues including skeletal muscle, skin, eyes, hair, and frequently bone of, in most instances, half of the
face.
 Witkop syndrome, also known as tooth-nail or nail dysgenesisehypodontia syndrome, is an autosomal dominant type of
ectodermal dysplasia with an estimated incidence of 1 to 2 in 10,000.
 Ectodermal dysplasias are a group of heterogeneous inherited developmental disorders affecting structures that develop
directly from the ectoderm.
 Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber syndrome) is characterized by the presence of multiple arteriovenous malformations that lack intervening capillaries and result in direct connection between arteries and veins.
 Ascher syndrome is characterized by blepharochalasis, double lip, and nontoxic thyroid enlargement.
 Initially described as the combination of ocular inflammation and orogenital ulcerations, Behcet syndrome, or Behcet
disease, is a multisystem immunodysregulation disorder of unknown etiology, possibly triggered by environmental antigens,
including bacteria and viruses, and characterized by vasculitis of small and large arteries and veins.
 Felty syndrome occurs in patients who have a long history of seropositive rheumatoid arthritis, and is characterized by the
development of moderate to severe leukopenia, neutropenia, and, in most instances, splenomegaly.
 Reactive arthritis is a form of seronegative spondyloarthritis characterized by inflammatory back pain, additive or
migratory oligoarthritis and extra-articular symptoms that typically follow a gastrointestinal or urogenital infection by a
minimum of 1 to a maximum of 3 to 6 weeks.
 Stevens-Johnson syndrome and toxic epidermal necrolysis are conditions in the spectrum of severe cutaneous adverse
reactions affecting the skin and mucosal membranes.
 There is a range of diseases characterized by accelerating aging, such as Hutchinson-Gilford progeria syndrome, Werner
syndrome, Cockayne syndrome, trichothiodystrophy, and ataxia-telangiectasia.

Ehlers-Danlos syndromes

Clinical manifestations

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of


disorders characterized by abnormal formation of collagen or
molecules related to collagen synthesis, abnormalities in the
matrix glycoprotein tenascin, and probably fibronectin. According to the Villefranche Classification there are 7 major
types of EDS, 6 with subtypes that relate to specific collagen
defects and a seventh that represents a collection of all other
variants that are generally rare forms. For the purposes of this
article the most frequent types are presented, in addition to
forms with oral manifestations.

Classic EDS (EDS I and EDS II)


Eighty percent of patients with EDS have either EDS I (Gravis
type) or the more severe form EDS II (Mitis type). Both are
autosomal dominant and are characterized by mutations in the
COL5A1 that controls packing of collagen type 1 fibrils. Clinical
features include:

The author has nothing to disclose.


Division of Oral and Maxillofacial Pathology, School of Dentistry,
University of Minnesota, 515 Delaware Street SE #16-116B, Minneapolis,
MN 55455, USA
E-mail address: koutl001@umn.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 135151
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.06.001

1. Extreme joint hypermobility (Fig. 1) that can cause poor


joint stability and dislocations leading to premature
osteoarthritis
2. Hyperelastic velvety (Fig. 2) and friable skin that heals with
formation of often pigmented cigarette paperelike scars
(Fig. 3)
3. Connective tissue fragility associated with easy bruising
4. Oral mucosal fragility with delayed healing but without
scar formation, early periodontal disease (Fig. 4) because of
easily traumatized gingiva, subluxation of the temporomandibular joint (TMJ), and ability in 50% of patients to

oralmaxsurgeryatlas.theclinics.com

136

Koutlas

Fig. 1 Extreme joint hypermobility in a patient with EDS. (Courtesy of the collection of Robert J. Gorlin, DDS.)

touch their nose with the tongue (Gorlin sign; only seen in
the 8%e10% of the general population) (Fig. 5)
5. Dental abnormalities including hypoplastic enamel and
dentin, high cusps with deep occlusal fissures, and deformed
roots with pulp stones. Multiple keratocysts have been described in a patient with EDS II
6. Epicanthic folds, myopia, strabismus, eversion of the upper
eyelids, and, less often, blue sclera

Fig. 3 Pigmented cigarette paperelike scars in a patient with


EDS. (Courtesy of the collection of Robert J. Gorlin, DDS.)

7. Prolapse of mitral valve and (occasionally) tricuspid valve


Familial hypermobility EDS (EDS III)
This autosomal dominant type is seen in approximately 10% of
the patients, and in most patients is caused by mutations in
TNXB (tenascin-X), COL3A1, and, less often, COL1A2. Clinically
there is remarkable joint hypermobility while the skin properties are within normal limits. Peripheral neuropathy has been
described. Supernumerary teeth have been reported.
Vascular (ecchymotic) EDS (EDS IV and EDS V)
Six percent of patients with EDS have EDS IV, whereas EDS V
is very rare and is not discussed here. EDS IV can be a life-threating disorder because patients may suffer catastrophic
bleeding from arterial rupture (intracranial and renal artery

Fig. 2 Ehlers Danlos syndrome: Hyperelasticity of facial skin.


(From Neville BW, Damm DD, Allen CM, et al. Oral and maxillofacial pathology. 3rd edition. Philadelphia: Saunders, an Imprint of
Elsevier; 2009. Fig. 16-32; with permission.)

Fig. 4 Early periodontal disease as seen in EDS. (Courtesy of the


collection of Robert J. Gorlin, DDS.)

Syndromes Affecting Skin and Mucosa

137
EDS type VIII
EDS VIII is characterized by early-onset periodontal disease and
pretibial skin ecchymoses.

Differential diagnosis
The different types of EDS should be distinguished from
other inherited disorders that can present with hyperelastic
skin (cutis laxa syndromes), gerodermia osteodysplastica,
vascular fragility syndromes, and familial generalized articular hypermobility.

Treatment considerations for the oral and


maxillofacial surgeon

Fig. 5 The Gorlin sign in Ehlers-Danlos syndrome. (Courtesy of


the collection of Robert J. Gorlin, DDS.)

aneurysms) early in their lives, hence the shortened life span


encountered in most patients. Both autosomal dominant and
recessive modes of inheritance can occur, and multiple COL3A1
mutations have been described. Clinically, EDS IV is characterized by:
1. Thin translucent skin with visible veins, ecchymoses after
only minor trauma over knees and shins, and dark pigmented scars (Fig. 6)
2. Acrogeric facies (prominent eyes, protruding ears, pinched
nose, thin lips)
3. Early tooth loss attributable to periodontal destruction

Fig. 6 Ecchymoses caused by connective tissue fragility in EDS.


(Courtesy of the collection of Robert J. Gorlin, DDS.)

Patients with EDS experience low oral healtherelated quality


of life that includes muscle pain, hypermobility of the TMJ,
hematomas in the mouth, gingival fragility, and loss of periodontal support. Encouraging results have been reported with
placement of implants that lend periodontal support in patients with tooth loss. Arthroscopic surgery can alleviate EDSassociated temporomandibular disorders, especially in type III.

Parry-Romberg syndrome
Parry-Romberg (or Romberg) syndrome (PRS) is, in most cases,
a sporadic disorder characterized by slow progressive atrophy
or shrinkage of facial tissues including skeletal muscle, skin,
eyes, hair, and frequently bone of, in most instances, half of
the face (Fig. 7). It is accompanied very often by contralateral
Jacksonian epilepsy and trigeminal neuralgia. Bilateral manifestations occur in 5% to 10% of cases, and ipsilateral

Fig. 7 Hemifacial atrophy of the right side of the face as seen in


Parry-Romberg syndrome. (From Neville BW, Damm DD, Allen CM,
et al. Oral and maxillofacial pathology. 3rd edition. Philadelphia:
Saunders, an Imprint of Elsevier; 2009. Fig. 1-77; with permission.)

138

Koutlas

involvement of the rest of the body is rare. The cause is unknown; however, alterations in the peripheral trophic sympathetic system, cerebral disturbance of fat metabolism, trauma,
autoimmunity, and, recently, Borrelia spp infection have been
considered as possible causes. It is more common in females,
and in many studies the left side of the face seems to be more
frequently affected.

Clinical manifestations
PRS appears usually during the first decade, with the overlying
skin of the affected side becoming darkly pigmented. When the
facial bones are affected the disease starts earlier. The progression of the disease can be as long as 9 to 10 years, and it
becomes stationary for life. Hair involvement precedes that of
skin, with the affected side of the scalp characterized by focal
areas of complete alopecia, loss of eyelashes, and the median
portion of eyebrows. Some patients have a scar-like demarcation on the forehead near the midline known as linea
scleroderma or en coup de sabre (strike of the sword). Histopathologically there is atrophy of the epidermis, dermis, and
adnexal elements and vessels, in addition to inflammation.
These characteristics are also present in patients with linear
scleroderma.
Oral manifestations
Hemiatrophy of the tongue can be an early finding (Fig. 8).
Atrophy of half of the upper lip and tongue may lead to
exposure of maxillary teeth of the affected side. Delayed
eruption, root dilaceration, root hypoplasia (Fig. 9), and resorption are rarely described. Alteration in the development of
the mandible, which leads to malocclusion, is also reported
(Fig. 10).

Fig. 9 Root hypoplasia. (Courtesy of C. Whitt, DMD, Kansas


City, MO.)

seizures spreading from the distal limb to the face), followed


by cerebellar and cerebral hemiatrophy, calcifications, and,
less often, vascular abnormalities.

Differential diagnosis

Neurologic manifestations
Epileptic seizures are the most common neurologic manifestation, often of the Jacksonian type (motor cortexerelated

PRS should be differentiated from localized linear scleroderma


en coup de sabre (LSCS). There is considerable debate
regarding whether the 2 entities represent 2 distinct conditions
or if they are variations of the same disorder (ie, scleroderma).
The difficulty exists because both have the same age onset
and a slow progressive course, affect women more often, and
have common neurologic and ophthalmologic manifestations.
However, patients with PRS more often have central nervous
system manifestations. In PRS there is inflammation appreciated, which is not regarded as a feature in LSCS. Rasmussen
encephalitis presents neurologic manifestations essentially

Fig. 8 Hemiatrophy of the tongue in PRS. (Courtesy of the


collection of Robert J. Gorlin, DDS.)

Fig. 10 Malocclusion caused by alterations in the development


of the mandible as seen in PRS. (Courtesy of C. Whitt, DMD, Kansas
City, MO.)

Ophthalmologic manifestations
The most common manifestation is enophthalmos resulting
from loss of periorbital fat (Fig. 11). Loss of the underlying
bone may cause the outer canthus to be displaced downward.
Other ocular stigmata include atrophy of the eyelid, uveitis,
retinal vasculitis, glaucoma, and retinal pigmentations. The
contralateral eye may be also affected.

Syndromes Affecting Skin and Mucosa

139
Oral manifestations
There is hypodontia (Fig. 12), less often oligondontia, and in
rare extreme cases anodontia. The most frequently missing
teeth are the maxillary incisors, second molars, maxillary canines, and, less often, the premolars. The permanent dentition
is usually more severely affected. Moreover the tooth shape
varies, with teeth being conical and having narrow crowns.
Nail manifestations
Hypoplastic fingernails (Fig. 13) and/or toenails occur early in
life. Toenails are usually more severely affected than fingernails. Nails grow slowly, are spoon-shaped, and are prone to
fracture. The nail condition improves with age.

Differential diagnosis

Fig. 11 Parry-Romberg syndrome. Hemifacial atrophy without


induration of the overlying skin. (From Paller A, Mancini AJ. Hurwitz
clinical pediatric dermatology: a textbook of skin disorders of
childhood and adolescence. 4th edition. Philadelphia: Saunders, an
imprint of Elsevier; 2011. Fig. 22-49; with permission.)

similar to those of PRS. Congenital facial hypoplasia is diagnosed at birth, and there is diminution of the teeth of the
affected side. The oculo-auriculo-vertebral spectrum of malformations should also be included in the differential diagnosis. However, this group of conditions is related to anomalies
of the first and second branchial arches.

Treatment considerations for the oral and


maxillofacial surgeon
The main aim is to halt the disease and to improve symptoms
and facial appearance. Immunosuppressive medications have
been used for cerebellar involvement. After the condition is
stabilized, the restoration of the symmetry with corrective
esthetic surgery should be attempted, including facial recontouring with volumetric regeneration.

The differential diagnosis of WS includes X-linked and autosomal recessive hypohidrotic ED. However, patients with such
forms of ED have typical facies and decreased sweating, and
their nails are usually not dysplastic. Among those included are
Fried syndrome, DOOR (Deafness and OnychoOsteodystrophy
with Retardation) syndrome, and Curry-Hall syndrome. Of
these conditions, Fried syndrome closely resembles WS; however, it is autosomal recessive, and features sparseness and
thinness of hair and eyebrows as well as an everted lower lip.
Nails are not so severely affected. Curry-Hall syndrome also
features polydactyly.

Treatment considerations for the oral and


maxillofacial surgeon
A combined orthodontic/surgical treatment plan is recommended to address the dental concerns of patients. Dental
implants can be used.

Ectodermal dysplasia syndromes


EDs are a group of heterogeneous inherited developmental
disorders affecting structures that develop directly from the
ectoderm. However, mesodermal and endodermal derivatives
may be also affected because there are interactions between
the 3 germ layers. One should also note that abnormalities
identical to ED can occur in isolation. In this article only
hypohidrotic ectodermal dysplasia (HED), the most widely
known type of ED, is described. For those syndromes for which,

Witkop syndrome
Witkop syndrome (WS), also known as tooth-nail or nail dysgenesisehypodontia syndrome, is an autosomal dominant type
of ectodermal dysplasia (ED) with an estimated incidence of 1
to 2 in 10,000. It affects 2 ectodermal derivatives, namely
teeth and nails. It is caused by nonsense mutations of the MSX1
at 4p16.1. Isolated cases, without family history, have been
described.

Clinical manifestations
Teeth and nails are affected without involvement of sweat
glands and the characteristic facies seen in EDs. Most patients
report normal heat tolerance and normal sweating. Occasionally, hair may be thin and slow growing but without microscopic abnormalities.

Fig. 12 Hypodontia in Witkop syndrome. (Courtesy of the


collection of Carl J. Witkop, DDS.)

140

Fig. 13 Spoon-shaped nails as seen in Witkop syndrome.


(Courtesy of the collection of Carl J. Witkop, DDS.)

besides the ectodermal component, there are ocular and


skeletal anomalies, or for patients who present with clefting or
deafness, the reader is referred to the plethora of publications
covering such subjects.

Hypohidrotic ectodermal dysplasia


HED is usually inherited as an X-linked disorder with full
expression in males, and varying in females who may (1) not be
affected at all, (2) show only mild phenotype of HED (eg,
hypodontia), (3) express the condition in a less severe manner
than males, or (4) fully express the syndrome. The latter group
may have balanced X-linked/autosomal translocations. Autosomal recessive, and on rare occasion dominant forms, have
also been described. The X-linked type is mapped to Xq12q13.1, with the affected gene being EDA1 that encodes the
transmembrane protein Ectodysplasia A. The recessive and
dominant types are caused by mutations of the receptor of
EDA1, EDAR, which maps to 2q11-q13, and less often by mutations in EDARADD mapping in 1q42.2-q43. All of these types
produce the same phenotype. Autosomal recessive cases have
been also associated with mutations of WNT10A.

Koutlas

Fig. 14 Sweat ducts on the left are from normal skin;


decreased number and size of sweat ducts in a patient with
hypohidrotic ectodermal dysplasia (HED) on the right. (Courtesy
of the collection of Robert J. Gorlin, DDS.)

palatal and cranial base widths, small malar bones, and small
calvarial height.
Oral manifestations
Hemizygotes lack most deciduous and permanent teeth
(Fig. 16). The teeth that are rarely absent are central upper
incisors, upper and lower canines, and first molars. Upper incisors and canines have conical crowns. Taurodontism can also
be observed. The alveolar ridge is hypoplastic or undeveloped.

Clinical manifestations
The defining and major findings of the syndrome are hypohidrosis, hypotrichosis, and hypodontia.
Cutaneous manifestations
Hypohidrosis is the characteristic clinical presentation,
resulting from the severe reduction of sweat glands leading to
intolerance to heat (Fig. 14). Early in life and during the first
year, children with the disorder present with fever of unknown
etiology. Mild exertion can lead to hyperpyrexia. Sebaceous
glands are severely reduced to absent, causing severe dryness.
Patients can have hair, although it is usually fine and short.
Eyelashes and eyebrows are scant and occasionally missing.
Mammary glands are hypoplastic or absent. Nails are generally
normal.
Facial manifestations
In general, patients present with prominent frontal bossing and
a depressed nasal bridge (Fig. 15). There is loss of vertical
height owing to the absence of teeth. Cephalometric and
anthropometric studies feature smaller facial height, small

Fig. 15 Facial characteristics of a patient with HED. (From


Kurban M, Christiano AM. Inherited disorders of the hair. In: Rimoin
D, Korf B, editors. Emery and Rimoins principles and practice of
medical genetics. 6th edition. Philadelphia: Elsevier Ltd; 2013.
Fig. 152-5; with permission.)

Syndromes Affecting Skin and Mucosa

141
Table 1
(HHT)

Types of hereditary hemorrhagic telangiectasia

Type

Gene

Locus

Protein

HHT1

ENG

9q34.1

Endoglin

HHT2

ACVRL1

12q11eq14

Activin A receptor
type IIelike 1

HHT3

Unknown

5q31

Unknown

HHT4

Unknown

7p14

Unknown

JPHT

MADH4

18q21.1

SMAD4

Abbreviation: JPHT, juvenile polyposis hemorrhagic telangiectasia.

Fig. 16 Oligodontia and conical teeth. (Courtesy of the collection of Robert J. Gorlin, DDS.)

Patients have a dry mouth because of diminished or absent


salivary glands. The lack of saliva can lead to caries.
Other findings
Glands along the respiratory tract are diminished or absent,
resulting in tissue dryness and infections. Patients can present
with various otologic abnormalities that range from auricular
anomalies to hearing loss. Most patients develop allergic disorders, especially eczema and asthma.
Differential diagnosis
The list of disorders to be considered in the differential diagnosis of HED is large, among which there are a few that should
be known. For example, abnormalities affecting hair and teeth
are encountered in trichodental dysplasia. However, such patients generally do not have hypohidrosis and are not lacking as
many teeth as in HED. Hair and nails without hypohidrosis and
hypodontia are seen in autosomal recessive ED pure hair and
nail type. Clouston syndrome is another form of ED without
dental and sweat-gland abnormalities. However, patients
present with sparse hair, severe nail dystrophy, palmoplantar
hyperkeratosis, and hyperpigmentation of the skin, especially
over joints.

observed in HHT cause disturbance in the transforming growth


factor (TGF)-b signaling pathway, which is important in cell
proliferation, differentiation, adhesion, and migration. Specifically, ENG and ACVRL1 are important in the development
and maintenance of arteriovenous identity and smooth-muscle
recruitment to developing vessels. SMAD4 participates in the
TGF-b signaling transmission to the cell nucleus.

Clinical manifestations
In general, patients can present with epistaxis, hemoptysis,
hematemesis, and hematuria. Although all lesions can be seen
in patients with both HHT1 and HHT2 types, pulmonary and
possibly cerebral AVMs are more common in patients with ENG
mutations, and hepatic AVMs are more common in patients
with ACVRL1 mutations. However, pulmonary hypertension in
the absence of severe vascular shunting is almost exclusive to
ACVRL1 mutations.
Table 2 highlights the various clinical features of HHT. The
oral manifestations are described separately in more detail.
Oral manifestations
The lips and tongue dorsum and tip are more frequently
affected (Figs. 17 and 18) than the buccal mucosa, gingiva, and
palate. Recognition of oral lesions has led many times to the
establishment of the diagnosis, and this has been undoubtedly
the experience of this author. The clinician should differentiate

Treatment considerations for the oral and maxillofacial


surgeon
The oligodontia can be addressed with implant-based oral
rehabilitation after thorough radiographic 3-dimensional reconstruction and cephalometric evaluation. Bone grafts should
be used for ridge augmentation if there is significant bone
hypoplasia.

Osler-Rendu-Weber syndrome (hereditary


hemorrhagic telangiectasia)
Hereditary hemorrhagic telangiectasia (HHT; Osler-RenduWeber syndrome) is characterized by the presence of multiple
arteriovenous malformations (AVMs) that lack intervening
capillaries and result in direct connection between arteries
and veins. It is a heterogeneous autosomal dominant condition
with 5 different types identified. The causative gene is known
in 3 of these types (Table 1).
The most common types are HHT1 and HHT2. Mutations in
MADH4 seen in juvenile polyposis hemorrhagic telangiectasia
are de novo and not inherited. The heterogeneous mutations

Fig. 17 Telangiectasias of hereditary hemorrhagic telangiectasia. Multiple telangiectasias on the nose and lips. (From Wilcox
CM. Atlas of clinical gastrointestinal endoscopy. Philadelphia: WB
Saunders; 1995. p. 123; with permission.)

142
Table 2

Koutlas
Clinical features of HHT

Clinical
presentation

Frequency Diagnostic
(%)
procedure

Potential
complications

Epistaxis

90

Evident

Anemia
Massive acute
hemorrhage

Telangiectasias
of the lip, oral
mucosa, nose,
fingertips,
other mucous
membranes
(bladder,
uterus, vagina)

80

Evident

Cosmetic
Hemorrhage

Gastrointestinal
telangiectasia

15e30

Endoscopy

Hemorrhage
Anemia

Pulmonary AVMs

50

CT scan
C-Echo

Asymptomatic
Hypoxemia
1. Stroke
2. Brain abscess
3. Migraine
Hemorrhage
1. Hemoptysis
2. Hemothorax

Cerebral vascular
malformations

10e20

MRI
Hemorrhage
Angiography Headache
Epilepsy
Cardiac failure
in children

Hepatic vascular
malformations

Spinal AVMs

30e70

Rare

Doppler
Asymptomatic
ultrasono- Pulmonary
graphy
hypertension
CT
Portal
hypertension
Biliary ischemia
MRI

Hemorrhage
Paraplegia
Pain

Abbreviations: AVM, arteriovenous malformation; CT, computed


tomography; MRI, magnetic resonance imaging.

the lesions of HHT from petechiae seen in disorders presenting


with hemorrhagic diathesis. Bleeding from the mouth is second
in frequency to epistaxis.

Fig. 18 Small telangiectatic lesions in the lip and the tongue.


These lesions were misdiagnosed for years as petechiae.

experience bleeding even with tooth brushing. Dental prophylaxis can cause bleeding from labial telangiectasias, and
scaling and root planing should be carried out with great care
and even avoided in some instances. To control epistaxis,

Table 3 Conditions presenting with telangiectasias and


vascular anomalies in oral and perioral tissues
Condition
Small cutaneous and
mucosal vascular
anomalies

Very common in normal individuals;


increase with age

Sublingual
phlebectases

Common; increase with age

Cherry angiomas

Very common in individuals >40 y

Fabry syndrome

Angiokeratomas; genitals; oral


mucosa can be affected; tongue
not affected; involvement of nasal
mucosa infrequent

Maffuci syndrome

Hemangiomas in the mouth; skeletal


lesions

Hereditary benign
telangiectasia

No oral lesions; no bleeding

Blue rubber bleb


syndrome

Larger vascular lesions; rare oral


involvement

CREST syndrome

Nonhereditary; older women; oral


telangiectasias present but no
oral lesions

Differential diagnosis
The telangiectasias seen in patients with HHT should be
differentiated from telangiectasias and other vascular lesions
seen in normal patients that generally develop after the age of
40 years. Conditions presenting with telangiectasias and
vascular anomalies in oral and perioral tissues are listed in
Table 3.

Treatment considerations for the oral and


maxillofacial surgeon
Every dentist and dental specialist should be aware of the risk
of oral hemorrhage in patients with HHT. Patients may

Characteristics and distribution


of lesions

Abbreviation: CREST, Calcinosis/Raynaud phenomenon/Esophageal


dysmotility/Sclerodactyly/Telangiectasia.

Syndromes Affecting Skin and Mucosa

143

sclerotherapy and laser have been used besides hormones,


tamoxifen, thalidomide, and nonsteroidal anti-inflammatory
drugs (NSAIDs). Recently, injections with bevacizumab have
been shown to substantially decrease bleeding episodes. Oral
lesions have been also successfully treated with sclerotherapy
and laser. To avoid bacteremia, besides daily optimal dental
hygiene, patients with HHT undergoing surgical procedures
should be prescribed antibiotics prophylactically.

Ascher syndrome
Ascher syndrome (AS) is characterized by blepharochalasis,
double lip, and nontoxic thyroid enlargement. Thyroid enlargement is not necessary for the diagnosis. Most cases are
sporadic, although an autosomal dominant trait has been
established in some patients.

Clinical manifestations
Labial manifestations
There is tissue duplication (Fig. 19) occurring between the pars
glabrosa and the pars villosa that can exist from childhood,
which is not evident when the lips are closed but becomes
striking when patients smile. Hyperplastic salivary glands,
increased vascularity, and occasional inflammation are appreciated microscopically.
Ocular manifestations
There is prominent shagging of the eyelids (Fig. 20), most
frequently the upper, which is caused by relaxation of the
tarsal fold. The eyelid itself is atrophic. In many instances this
occurs after multiple episodes of angioedema-like episodes.
Patients initially experience swollen lids, and the initiation of
this swelling coincides with enlargement of the lip. Histologically there may be enlargement of the lacrimal glands.
Thyroid
Euthyroid goiter develops in some patients with AS. However,
rare examples of hypothyroidism and myxedema are reported.

Differential diagnosis
Blepharochalasis and double lip can be encountered as isolated
anomalies. Specifically, acquired double lip is frequently the
result of habitual trauma. Congenital double lower lip has been
described in association with blepharochalasis, broad nose

Fig. 19 Double lip in Ascher syndrome. (Courtesy of the


collection of Robert J. Gorlin, DDS.)

Fig. 20 Remarkable bilateral blepharochalasis with sagging of


the eyelids at the lateral canthus. (From Kamran A. Ascher syndrome: a case report and review of the literature. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2007;103(2):e26e8. Fig. 5; with
permission.)

with broad tip, highly arched palate, and bilateral third finger
clinodactyly.

Treatment considerations for the oral and


maxillofacial surgeon
Surgical excision of the excess tissue should be attempted for
aesthetic purposes.

Behcet syndrome
Initially described as the combination of ocular inflammation
and orogenital ulcerations, Behcet syndrome (BeS), or Behcet
disease, is a multisystem immunodysregulation disorder, of
unknown etiology, possibly triggered by environmental antigens, including bacteria and viruses, and characterized by
vasculitis of small and large arteries and veins. Although not
hereditary, an autosomal recessive mode of inheritance is
proposed in pediatric patients who present, less frequently,
with genital and eye disease. Interleukin-10 (anti-inflammatory
cytokine) gene mutations have also been described.

Clinical manifestations
BeS affects men and women approximately equally, usually in
their third decade. Men can present with a more severe course.
BeS is more frequent in countries along the Silk Road where
the prevalence of the HLA-B51 is also relatively high in comparison with the rest of the world. The highest rate of BeS is
observed in Turkey, with 1 in 250 people affected. Other
countries with a high incidence include Iran, Israel, North
Africa, Japan, and China. In the United States a rate of 5.2 per
100,000 population was calculated in Olmsted County, Minnesota. BeS is very infrequent in the United Kingdom.
The International Society for BeS (ISBD) has established
criteria for the diagnosis, which have 91% sensitivity and 96%
specificity. Oral ulcers are a cardinal finding. Two other findings among a list of signs must additionally be present. The list
includes genital ulcers, eye disease, skin lesions, and a positive
pathergy test, which refers to development of papules and
pustules 48 hours after inserting 20-gauge needles in a vertical

144
or oblique way through the superficial aspect of the skin. The
area to be tested for the pathergy test is the hairless area of
the forearm, which should be cleaned with alcohol (but not
with a surgical cleaning solution) before insertion. The ISBD
criteria do not include intestinal, central nervous system,
or pulmonary vascular disease occasionally seen in patients
with BeS.
Oral manifestations
Recurrent aphthous stomatitis (RAS) occurs in 97% to 100% of
patients (Fig. 21). Recurrent oral ulcerations with 3 episodes in
1 year are a mandatory criterion for the diagnosis of BeS. All
types of RAS can occur, namely minor, major, and herpetiform,
with minor aphthae more commonly seen in men and major
aphthae more frequently seen in women. Ulcers affect predominantly the nonmasticatory mucosa, covered by white to
yellowish pseudomembrane and surrounded by a red halo.
Deeper lesions last longer. In one study a positive intraoral
pathergy test was seen in 85% of participating patients. Low
frequency in RAS has been observed in smokers with BeS.
Genital manifestations
Genital ulcers are also a cardinal finding in BeS (Fig. 22). These
ulcers are painful and, similarly to RAS, are covered by pseudomembrane, feature swelling in the periphery, and, if larger
than 1 cm, frequently heal with scarring. Male patients develop
ulcers usually in the scrotum and the inguinal area. Penile
lesions are rare (Fig. 23) and urethritis is not observed. The
ulcers in women affect the labia majora and femoral/inguinal
regions. These ulcers can cause scar formation, which does not
occur in the labia minora and vestibule. Vaginal and cervical
ulcers are rare.
Cutaneous manifestations
 Erythema nodosum characterized by red painful nodules
is observed in approximately 50% of patients, more commonly females, and affects primarily the lower extremities in the areas of the pretibial surface in a symmetric
pattern. The lesions heal with pigmentation. Arms and
thighs can also be involved.
 Superficial thrombophlebitis is appreciated more frequently in males. It presents as red nodules in the area of
the tibia and follows the course of the great saphenous
vein. As older lesions heal, new ones appear with areas of
hyperpigmentation. There is increased risk for deep vein
thrombosis.
 Acneiform papulopustular lesions can develop on the
back, chest, shoulders, and, less frequently, the face,

Koutlas
which is the area of predilection for acne vulgaris.
Acneiform lesions in postadolescent patients not on systemic steroids should be interpreted as a sign of BeS.
Ocular manifestations
Eye involvement is observed in half of the patients. Chronic
and relapsing bilateral uveitis is usually observed, with hypopyon uveitis seen in approximately 20% of the patients, signifying severe retinal disease. Patients also develop keratitis,
conjunctivitis (Fig. 24), corneal ulcerations, and papilledema.
Musculoskeletal manifestations
Approximately half of the patients develop nondeforming
monoarthritis or oligoarthritis, usually in the knees, followed in
frequency by ankles, wrists, and elbows.
Vascular and cardiac manifestations
Approximately 30% of patients develop thrombophlebitis.
Thromboses of the superior and inferior vena cava are also
seen. Budd-Chiari syndrome is rare but carries high mortality.
Arterial involvement is less frequent, but when it occurs
can cause death. Myocarditis, pericarditis, and intracardial
thrombus formation have been infrequently reported.
Central nervous system manifestations
Parenchymal and, less often, nonparenchymal brain disease
can develop in approximately 10% of the patients, who
present with pyramidal, cerebellar, and sensory manifestations, and intracranial hypertension caused by dural
sinus thrombosis. Parenchymal disease has a more serious
prognosis.
Other manifestations
Gastrointestinal involvement occurs in about 30% of Japanese patients, but is less common in patients from the
Mediterranean. Pleural pericardial effusions, mediastinal
lymphadenopathy, glomerulonephritis, secondary amyloidosis, epididymitis, and bladder involvement have been
described in the literature.

Differential diagnosis
The differential diagnosis includes inflammatory bowel disease
(IBD), reactive arthritis and autoimmune bullous disorders.
Aphthous-like lesions, erythema nodosum, and nonerosive
arthropathy can accompany IBD. However, genital ulcers and a
positive pathergy confirm the diagnosis of BeS as they are not
seen in IBD.

Fig. 21 Bechet syndrome: (A) Deep crater-like ulcers consistent with recurrent aphthous stomatitis (RAS) major type. (B) Shallow ulcers
consistent with RAS minor type. Courtesy of the collection of Robert J. Gorlin, DDS.)

Syndromes Affecting Skin and Mucosa

Fig. 22 Ulcers on the scrotum of patient depicted in Fig. 21A.


(Courtesy of the collection of Robert J. Gorlin, DDS.)

Treatment considerations for the oral and


maxillofacial surgeon

145

Fig. 24 Keratoconjunctivitis in Bechet syndrome. (Courtesy of


the collection of Robert J. Gorlin, DDS.)

Oral manifestations
Nonspecific ulcers, candidiasis, and periodontal disease may
develop in some patients.

Topical steroids and systemic corticosteroids are the first line


of treatment for oral and genital ulcers. Systemic corticosteroids are used in patients with eye involvement. Colchicine
should be given to patients with predominantly genital ulcers
and erythema nodosum. Azathioprine, cyclosporine, cyclophosphamide, tumor necrosis factor (TNF) antagonists, and
interferon-a have been used with or without corticosteroids in
refractory cases.

Differential diagnosis

Felty syndrome

Treatment considerations for the oral and


maxillofacial surgeon

Felty syndrome (FS) occurs in patients who have long history of


seropositive rheumatoid arthritis (RA), and is characterized by
the development of moderate to severe leukopenia (<4000
white blood cells/mL), neutropenia (<1500 neutrophils/mL),
and, in most instances, splenomegaly.

Clinical manifestations
Because of leukopenia/neutropenia, patients have an
increased risk of serious infections, and often present with
persistent ulcers of the lower extremities caused by rheumatoid vasculitis. Moreover, 30% of patients can develop large
granular lymphocytic leukemia.

Fig. 23 Penile shallow ulcers in patient depicted in Fig. 21A.


(Courtesy of the collection of Robert J. Gorlin, DDS.)

Most patients with FS are known to have RA. In the absence of


RA there are conditions that may resemble FS, including lymphoproliferative and myeloproliferative disorders, systemic
lupus erythematosus, antieTNF-induced lupus, human immunodeficiency virus and cytomegalovirus infections, sarcoidosis,
amyloidosis, and cirrhosis.

The surgeon should be aware of the treatment and its side


effects. Treatment of the underlying RA is essential, and is
accomplished with weekly doses of methotrexate. Other
anti-RA medications collectively known as DMARDs (DiseaseModifying Antirheumatic Drugs) that include, besides methotrexate, sulfasalazine, hydroxychloroquine, leflunomide,
azathioprine, and cyclosporine, may be used. Splenectomy is
performed in patients with complications of neutropenia who
do not respond to DMARD treatment. However, the results are
not always long-lasting, and there is recurrence of
neutropenia.

Reactive arthritis
Disclaimer: Hans Conrad Julius Reiter (1881e1969) was the
fourth person to describe what has been known in the literature as Reiter syndrome. His patient, a soldier, presented with
large joint oligoarthritis, urogenital tract infection, and uveitis. Reiter was a Nazi criminal. For these 2 reasons the
designation Reiter syndrome is avoided in the following
paragraphs. Readers are encouraged to avoid such designation. The condition has been renamed as reactive arthritis.
Reiter syndrome is only a clinical subtype of this disease. Also,
some consider the condition as a syndrome of psoriasis
because, histopathologically, it features psoriasiform dermatitis and mucositis.
Reactive arthritis (ReA) is a form of seronegative spondyloarthritis characterized by inflammatory back pain, additive
or migratory oligoarthritis, and extra-articular symptoms that
typically follow a gastrointestinal (most frequently Yersinia,

146

Koutlas

Salmonella, Shigella, Campylobacter) or urogenital (most frequently Chlamydia trachomatis, Neisseria gonorrhoeae,
Mycoplasma genitalium) infection by a minimum of 1 to a
maximum of 3 to 6 weeks. It commonly affects young Caucasian adults carrying the HLA-B27 allele. Ocular, skin, and heart
involvement are not uncommon and can vary in severity. ReA
affects males and females equally. However, when related to
Chlamydia trachomatis, males are more frequently affected.
The arthritis is not caused by the microbial agent itself but by a
CD4 T-cell response to the invading bacteria that triggers
articular inflammation, along with a CD8 response. The altered
immune response leads to the unbalanced production of
T-helper 2 cytokines, and this further helps the poor elimination
of the antigen by the host. The HLA-B27 haplotype perpetuates
the chronicity of the process. The average duration of acute
ReA is 3 to 5 months. If the arthritis lasts more than 6 months it
is regarded as a sign of development of chronicity.

Clinical manifestations
The patients initially present with history of gastrointestinal or
genitourinary infection. The typical patient with ReA features:
 Asymmetric oligoarthritis of the lower extremities and,
less frequently, the upper extremities including small
joints (dactylitis)
 Enthesitis (Achilles tendon) or bursitis
 Acute inflammatory back pain that worsens in the night,
radiating to the buttocks
Ocular manifestations
 Conjunctivitis and anterior uveitis leading to redness,
pain, irritation, and blurred vision (Fig. 25)
Skin manifestations
 Balanitis circinata (Fig. 26) characterized by well-circumscribed erythematous erosions on the glans penis that
frequently resemble the lesions of migratory stomatitis.
These lesions are seen in 20% to 39% of patients
 Keratoderma blennorrhagicum on the soles and, less
frequently, palms
Oral manifestations
 Occasional transient painless ulcerative lesions similar to
migratory stomatitis (Fig. 27) present in less than 20% of
patients

Fig. 25 Conjunctivitis occurring in a patient with ReA. (Courtesy


of the collection of Robert J. Gorlin, DDS.)

Fig. 26 Balanitis circinata in a patient with ReA. (Courtesy of


the collection of Robert J. Gorlin, DDS.)

 Arthritis of the TMJ in 30% of patients, with erosion of the


condylar head
Cardiac manifestations
In 10% of patients, especially those with prolonged disease,
aortic regurgitation, heart conduction disturbances, and pericarditis can be encountered.

Differential diagnosis
Other forms of arthritis may be considered in the differential
diagnosis of patients with similar symptoms and signs. Obtaining
a good medical history can point toward the correct diagnosis.

Treatment considerations for the oral and


maxillofacial surgeon
It is imperative that patients are completely treated for the
triggering infection. The bacterial infections are treated with

Fig. 27 Oral lesions in ReA are indistinguishable from migratory


stomatitis. (Courtesy of the collection of Robert J. Gorlin, DDS.)

Syndromes Affecting Skin and Mucosa

147

azithromycin, tetracyclines, or a combination of the 2. NSAIDs


and glucocorticoid injections are used for the monoarticular or
oligoarticular disease. In severe cases, immunosuppressive
drugs such as methotrexate and sulfasalazine are prescribed.

Stevens-Johnson syndrome/toxic epidermal


necrolysis
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN) are conditions in the spectrum of severe cutaneous
adverse reactions that affect the skin and mucosal membranes.
Traditionally, SJS was classified as a worse form of erythema
multiforme with mucosal involvement (EMM). EMM is characterized by ulcerative lesions of the mucous membranes and
scattered, well-defined targetoid lesions of the skin. However,
in 1993 a consensus was reached separating EMM from SJS and
TEN. Specifically, SJS is characterized by confluent purpuric
cutaneous macules and blisters with limited skin detachment
(body surface area <10%). TEN requires more than 30% of the
skin to be detached. Patients having between 10% and 30% skin
detachment are classified as having an SJS/TEN overlap.
Moreover, in both SJS/TEN, although atypical targetoid lesions
may be seen, the typical targetoid lesions of EMM are not
evident. Table 4 summarizes the clinical manifestations of SJS
and TEN.
The cause in approximately 75% of the patients with SJS and
TEN is a medication, while in the remaining 25%, in whom no
drug can be determined, infection has been suggested as the
culprit in many but not all of the patients. The cause in some
patients remains unknown.
Medications that have been associated with high and
moderate risk for the development of SJS/TEN are listed in
Table 5.
The clinician should also be aware of common medications without increased risk for SJS/TEN, which include
b-blockers, angiotensin-converting enzyme inhibitors, calcium-channel blockers, thiazide diuretics, sulfonylurea,
antidiabetics, insulin, and NSAIDs of the propionic acid type
(eg, ibuprofen).
SJS/TEN is a T-cell mediated response with CD8 T cells,
natural killer cells, and the cytolytic protein granulysin, which
is produced by CD8 T cells, participating in the destruction of
epidermal cells. Certain genetic predisposition is also observed
in many patients, especially in Asia, where in allopurinolinduced cases of SJS/TEN a 100% association with HLA-B*58:01
was demonstrated.

Table 4

Clinical manifestations
An acute and a late phase are recognized. The initial symptoms
of the acute phase include fever, stinging eyes, and discomfort
in swallowing. These symptoms precede mucocutaneous lesions by a few days.
Acute phase: mucocutaneous manifestations
Erythematous to livid confluent purpuric macules develop
initially in the presternal region of the trunk, face, palms, and
soles, which expand throughout the body in a matter of days
(Fig. 28). There is concomitant development of erythematous
lesions, erosions, and ulcers in the mucous membranes that
include the mouth (see later discussion), genitals (balanitis and
colpitis), eyes (severe conjunctivitis and blepharitis), and the
upper aerodigestive tract (Fig. 29). There is a positive Nikolsky
sign on the skin. Skin detachment when limited defines SJS.
However, expansion of the detachment, depending on the
percentage of the body surface affected, signifies progression
toward SJS/TEN overlap and TEN (Fig. 30).
Oral manifestations
Typical hemorrhagic erosions covered by crusts (Fig. 31) are
observed on the lips while the erythematous and ulcerative
lesions are distributed throughout the oral mucosa (Fig. 32),
sometimes including the masticatory mucosa.
Late phase and sequelae
Hyperpigmentation and hypopigmentation, pruritus, hyperhidrosis, xeroderma, nail dystrophies, atrophic or hypertrophic
scars, conjunctival keratinization, keratoconjunctivitis sicca,
depapillation of the tongue, lack of sensation, and loss of taste
are observed.

Differential diagnosis
The differential diagnosis may vary based on the skin detachment. In early stages of the disease, maculopapular drug or
viral eruptions should be considered. However, such processes
do not present with the hemorrhagic and erosive lesions seen in
SJS. Typical target lesions are a feature of EMM, so the
distinction can be made. In later stages of SJS/TEN, when
blisters and skin detachment are prevalent, a Tzanck test or
cryostat histology are necessary to exclude the diagnosis of
staphylococcal scalded-skin syndrome. Targetoid lesions are
not present in staphylococcal scalded-skin syndrome, and

Clinical manifestations of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
SJS

SJS/TEN overlap

TEN

Primary lesions

Erythematous lesions
Atypical targetoid lesions

Erythematous lesions
Atypical targetoid lesions

Erythematous lesions
Epidermal detachment, spontaneous
or by friction
Atypical targetoid lesions

Distribution

Isolated lesions
Confluence on face and trunk

Isolated lesions
More confluence on face and trunk

Diffuse lesions throughout the body

Mucosal
involvement

Yes

Yes

Yes

Systemic
symptoms

Usually

Always

Always

Detachment (%)

<10

10e30

>30

148

Koutlas

Table 5 Medications associated with high and moderate risk


for the development of SJS/TEN
High risk

Moderate risk

Allopurinol

Cephalosporins

Carbamazepine

Macrolides

Cotrimoxazole: sulfonamides
and sulfasalazine

Quinolones

Lamotrigine

Tetracyclines

NSAIDs: oxicam type


(eg, meloxicam)

NSAIDs: acetic acid type


(eg, diclofenac)

Phenobarbital
Phenytoin
Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.

mucosal involvement is rare. Other conditions that should be


included in the differential diagnosis are pemphigus vulgaris
and bullous pemphigoid, bullous phototoxic reactions, and
generalized bullous fixed drug eruption. However, for the
latter, patients usually have a history of fixed drug eruption.

Treatment considerations for the oral and


maxillofacial surgeon
The causative medication should be withdrawn as soon as
possible because patients exposed for a prolonged time to such
medication, especially with a long half-life, have an increased
risk of dying. Highly specialized dermatology units are the
preferable treatment units for patients with SJS/TEN, but if
not available, transfer to a burn unit or an intensive care ward
with daily dermatologic consultation seems to be the best

Fig. 28 Macular lesions expanding on the trunk. (Courtesy of the


collection of Robert J. Gorlin, DDS.)

Fig. 29 Multiple erosive and ulcerative lesions on the skin of the


face. Note eye and labial lesions.

alternative options. Patients, depending on the severity of


their lesions, can be treated with systemic corticosteroids and
intravenous immunoglobulins. Oral lesions tend to respond in
the same manner as cutaneous lesions. Special attention
should be paid to the prevention of ocular complications, with
this being the concern of a specialized ophthalmologist.

Progeria
There is a range of diseases characterized by accelerating
aging, such as Hutchinson-Gilford progeria syndrome (HGPS),
Werner syndrome, Cockayne syndrome, trichothiodystrophy,
and ataxia-telangiectasia, of which HGPS stands out. HGPS is
characterized by premature signs of aging at a very early age
and death before the age of 20 years caused by cardiovascular
or cerebrovascular disease. The incidence is 1 in 4 million, with
approximately 100 patients known to be alive in the world
according to the Progeria Research Foundation. Although it is
very rare, the disease has stirred a tremendous interest in the
pathobiology of aging. Initially the disorder was thought to be
autosomal recessive, but recent evidence suggests a single
nucleotide mutation with autosomal dominant expression
affecting the lamin A gene (LMNA), which is located in chromosome 1q. The mutated LMNA is called progerin, and in patients with HGPS there is production of normal lamin A as well
as progerin.

Fig. 30 Extensive lesions with areas of necrosis in the patient


depicted in Fig. 29. Progression to toxic epidermal necrolysis.

Syndromes Affecting Skin and Mucosa

149

Fig. 31 Characteristic labial lesions in SJS. (Courtesy of the


collection of Robert J. Gorlin, DDS.)

Clinical manifestations
Growth
Growth is normal for the first 9 to 12 months, when it plateaus
until about 10 years of age. At this age patients have the size of
a normal 3-year-old child, rarely exceeding 110 cm in height
and 15 kg in weight, and the appearance is that of a diminutive, wasted-looking older person. There is no sexual maturation and the voice is high-pitched and squeaky. Intelligence is
normal.
Craniofacial manifestations
The face is small in comparison with the cranial vault (Fig. 33).
Alopecia starts developing around age 2 years, with eyebrows
and eyelashes also generally lost. Frontal and parietal bossing
is evident early, and scalp veins become prominent. Ears are
small without ear lobes and the nose is beak-like. There is
mandibular hypoplasia leading to micrognathia and increased
mandibular angle.
Oral manifestations
Circumoral cyanosis is noted. Dental manifestations vary, with
most patients featuring hypodontia, microdontia, and teeth
with variations in shape. There is delay in eruption. Only a few
patients have normal teeth; however, there is crowding caused
by micrognathia.

Fig. 33 The radiograph features a smaller face in comparison


with the cranial vault. Note also the micrognathia. (Courtesy of
the collection of Robert J. Gorlin, DDS.)

Skin manifestations
There is significant loss of subcutaneous fat that results in thin,
tight skin. Scleroderma-like changes are also seen in some
patients. The veins over the thighs and scalp become prominent (Fig. 34).
Musculoskeletal manifestations
The chest is narrow and the abdomen protuberant. Although
bone maturation is normal, bones are osteoporotic, and joints
feature limited extension and degenerative changes including
hip dislocation. A horse-riding stance is observed early.
Osteolytic changes are seen radiographically, and are most
prominent in the terminal phalanges and clavicles. The
calvaria is thin and the anterior fontanel open. Frontal sinuses
are frequently absent.
Cardiovascular manifestations
Accelerated cardiovascular and cerebrovascular diseases result
in death between the ages of 7 and 20 years. Major events are
preceded by severe atherosclerosis leading to congestive heart
failure, ischemic attacks, and diastolic hypertension. Multiple
other organs seem to be unaffected by this disease, including
the liver, kidney, lung, gastrointestinal tract, bone marrow,
and brain.

Differential diagnosis

Fig. 32 Multiple ulcerative lesions on the buccal mucosa in the


early stage of EMM or SJS. (Courtesy of the collection of Robert J.
Gorlin, DDS.)

The differential diagnosis includes, among others, Werner


syndrome, Cockayne syndrome, Hallerman-Streiff syndrome,
Bloom syndrome, mandibuloacral dysplasia, EDS. Werner
syndrome is a condition of premature aging caused by mutations in Werner syndrome adenosine triphosphateedependent
helicase. However, progeric changes start at 10 to 20 years of
age. Patients present with short stature, bilateral cataracts,

150

Koutlas
Memarpour M, Shafiei F. Witkop tooth and nail syndrome: a report of
three cases in a family. Pediatr Dermatol 2011;28:281e5.

Ectodermal dysplasia syndromes


Bergendal B. Orodental manifestations in ectodermal dysplasia e a
review. Am J Med Genet A 2014;9999:1e7.
Itin PH. Ectodermal dysplasia: thoughts and practical concepts concerning disease classification e the role of functional pathways in
the molecular genetic diagnosis. Dermatology 2013;226:111e4.
The ectodermal dysplasias. In: Hennekam RC, Krantz ID, Allanson JE,
editors. Gorlins syndromes of the head and neck. 5th edition.
New York: Oxford University Press; 2010. p. 627e33.

Osler-Rendu-Weber syndrome (hereditary


hemorrhagic telangiectasia)

Fig. 34 Prominent veins resulting from absence of fat. (From


James WD, Berger TG, Elston DM. Andrews diseases of the skin:
clinical dermatology. 11th edition. Philadelphia: Elsevier/Saunders; 2011. Fig. 27-43; with permission.)

Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber syndrome).


In: Hennekam RC, Krantz ID, Allanson JE, editors. Gorlins syndromes of the head and neck. 5th edition. New York: Oxford
University Press; 2010. p. 684e8.
McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic
telangiectasia: An overview of diagnosis, management, and pathogenesis. Genet Med 2011;13:607e16.
Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology,
diagnosis and treatment. Blood Rev 2010;24:203e19.

Ascher syndrome
graying hair, and early hair loss and scleroderma-like
changes. Patients also present with osteoporosis, diabetes,
atherosclerosis, and neoplasms. The median age of death is
54 years.

Treatment considerations for the oral and


maxillofacial surgeon
A phase 2 trial using farnesyltransferase inhibitors, pravastatin,
and zoledronic acid is ongoing.

Recommended readings
Ehlers-Danlos syndromes
Ehlers-Danlos syndromes. In: Hennekam RC, Krantz ID, Allanson JE,
editors. Gorlins syndromes of the head and neck. 5th edition.
New York: Oxford University Press; 2010. p. 594e610.
Jensen JL, Storhaug K. Dental implants in patients with Ehlers-Danlos
syndrome: a case series study. Int J Prosthodont 2012;25:60e2.
Jerjes W, Upile T, Shah P, et al. TMJ arthroscopy in patients with
Ehlers-Danlos syndrome: case series. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2010;110:e12e20.

Ali K. Ascher syndrome: a case report and review of the literature. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e26e8.
do AA, de Pochat VD, Barreto TF, et al. Management of an
de Figuere
unusual presentation of Ascher syndrome. J Craniofac Surg 2012;23:
e570e1.
Gomez-Duaso AJ, Seoane J, Vazquez-Garcia J, et al. Ascher syndrome:
report of two cases. J Oral Maxillofac Surg 1997;55:88e90.

Behcet syndrome
Hatemi G, Yazici Y, Yazici H. Behcets syndrome. Rheum Dis Clin North
Am 2013;39:245e61.
Mat C, Yurdacul S, Devim A, et al. Behcets syndrome: facts and controversies. Clin Dermatol 2013;31:352e61.

Felty syndrome
Feltys syndrome. In: Kasper DL, Braunwald E, Fauci AS, et al, editors.
Harrisons principles of internal medicine. 16th edition. New York:
McGraw Hill; 2005. p. 1972.
Feltys syndrome. In: Hoffbrand AV, Pettit JE, Vyas P, editors. Color
atlas of clinical hematology. 4th edition. Philadelphia: Mosby
Elsevier; 2010. p. 485.

Parry-Romberg syndrome

Reactive arthritis

El-Kehdy J, Abbas O, Rubeiz N. A review of Parry-Romberg syndrome. J


Am Acad Dermatol 2012;67:769e84.
Romberg syndrome. In: Hennekam RC, Krantz ID, Allanson JE, editors.
Gorlins syndromes of the head and neck. 5th edition. New York:
Oxford University Press; 2010. p. 1131e4.

Hannu T. Reactive arthritis. Best Pract Res Clin Rheumatol 2011;25:


347e57.
Selmi C, Gerschwin ME. Diagnosis and classification of reactive
arthritis. Autoimmun Rev 2014;13:546e9.

Witkop syndrome

Stevens-Johnson syndrome/toxic epidermal


necrolysis

Altug-Atac AT, Iseri H. Witkop tooth and nail syndrome and orthodontics. Angle Orthod 2008;78:370e80.

Cao ZH, Wei ZY, Zhu QY, et al. HLA-B*58:01 allele is associated with
augmented risk for both mild and severe cutaneous adverse

Syndromes Affecting Skin and Mucosa


reactions induced by allopurinol in Han Chinese. Pharmacogenomics
2012;13(10):1193e201.
Harr T, French LE. Severe cutaneous adverse reactions: acute
generalized exanthematous pustulosis, toxic epidermal necrolysis
and Stevens-Johnson syndrome. Med Clin North Am 2010;94:
727e42.
Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol
2011;7:803e15.

151

Progeria
Burtner CR, Kennedy BK. Progeria syndromes and ageing: what is the
connection? Nat Rev Mol Cell Biol 2010;11:567e78.
Kieran MW, Gordon L, Kleinman M. New approaches to progeria.
Pediatrics 2007;120:834e41.
Progeria (Hutchinson-Gilforn syndrome). In: Hennekam RC, Krantz ID,
Allanson JE, editors. Gorlins syndromes of the head and neck.
5th edition. New York: Oxford University Press; 2010. p. 447e51.

Hamartoneoplastic Syndromes
David M. Shafer, DMD*, Lisa Marie Di Pasquale, DDS
KEYWORDS
 Hamartoma  Gorlin-Goltz  Peutz-Jeghers  Gardner syndrome  Multiple endocrine neoplasia  Sturge-Weber
 Neurofibromatosis  Tuberous sclerosis
KEY POINTS
 Hamartomas are benign malformations presenting as an excess of normal tissue within the tissue of origin.
 Although some syndromes show a clear genetic transmission, the underlying reasons for many of these abnormalities are
not fully understood.
 The hamartomatous syndromes are usually associated with other neural, cutaneous, skeletal, or developmental
malformations.
 The orofacial signs and symptoms often precede systemic displays of the syndromes. Thus, oral and maxillofacial surgeons
are in a unique position to identify and aid in diagnosing many of the hamartoneoplastic syndromes.

Gorlin syndrome (nevoid basal cell carcinoma


syndrome)
 Genetics
 Nevoid basal cell carcinoma syndrome (NBCCS) includes
more than 100 signs and symptoms involving the skin,
central nervous system, and skeletal system. The inheritance pattern is autosomal dominant. It is caused
by a chromosome 9q22 microdeletion. Forty percent of
new mutations arise spontaneously and the trait has
complete penetrance with a widely varied expressivity.1 In general, this syndrome and many others are
noted to support the double-hit theory, the first hit
being genetics and the second hit being some environmental insult.2
 Clinical features
 Also known as Gorlin-Goltz syndrome, NBCCS includes
multiple symptoms of the skeletal system, central
nervous system, and skin. Manifestations commonly
include nevoid basal cell carcinomas, odontogenic
keratocysts (OKCs), skeletal anomalies, and bifid ribs.1
 People affected with NBCCS tend to be very tall, and
70% of patients have a characteristic facies caused by
enlarged occipitofrontal circumference. Ocular hypertelorism is also, along with prominent supraorbital
ridges, a broad nasal base, and mandibular prognathism. Cleft lip and/or palate occur in about 5% of
cases. Congenital blindness may also occur.1,3
 Skin involvement includes nevoid basal cell carcinomas.
In contrast with classic basal cell carcinomas, these
The author has nothing to disclose.
Division of Oral and Maxillofacial Surgery, University of Connecticut
School of Dental Medicine, 263 Farmington Avenue, Farmington, CT
06030, USA
* Corresponding author.
E-mail address: dshafer@uchc.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 153166
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.04.002




lesions tend to appear at an early age (before 35 years


old), in multiples, and on areas of skin not exposed to the
sun. Palmar/planar pits present along the ventral surfaces of hands and feet in more than half of cases, with a
higher frequency among elderly affected individuals.4
Reproductive system abnormalities can occur, such as
bilateral calcifying ovarian fibromas or ovarian
fibrosarcoma.1
Calcification of the falx cerebri and tentorium cerebelli
is common, as well as calcification of the dura and the
pia mater and the choroid plexus. Although neurologic
abnormalities are frequent, the incidence of intellectual disability is around 3%.1,4
Common skeletal abnormalities include bifid, missing,
splayed, fused, or hypoplastic ribs. Kyphoscoliosis may
be present along with spinal bifida occulta. Lytic pseudocystic bone lesions are usually seen in the bones of the
feet and hands. They can also affect the arms, legs,
pelvis, and skull.1
As mentioned earlier, odontogenic keratocysts of the
jaw are often the first clinically detected feature, and
85% of cases are affected before the third decade of
life. Originating from the remnants of the dental lamina, the OKCs are large, expansile, and generally
asymptomatic. However, the cysts may be associated
with an unerupted tooth causing cortical expansion,
tooth mobility, and displacement and invasion of nearby
structures. The mandible is 3 times more likely to be
affected than the maxilla, but OKCs can occur in both
jaws simultaneously. The posterior molar/ramus area is
the most common site to be affected in the mandible
and the second molar region is the most common site of
the maxilla. OKCs may present as multilocular or unilocular lesions, and the recurrence rate after surgical
treatment is high, ranging from 30% to 60%.1e4
Diagnosis of the OKC is normally done from a histologic
sample of the lining. Two types of stratified squamous
epithelium can line OKCs: parakeratinized or, more

oralmaxsurgeryatlas.theclinics.com

154
rarely, the orthokeratinized type. Also typically displayed are a well-defined basal epithelial layer, palisaded nuclei, no rete ridges, and prominent epithelial
rests. Inflammatory cells are commonly found in the
underlying connective tissue. Syndromic OKCs have a
higher rate of satellite cysts. Ameloblastoma and squamous cell carcinomas of the jaw can, rarely, arise from
OKCs.2,4
 Differential diagnosis
 Diffuse osteoma cutis, basaloid follicular hamartomas
(associated with myasthenia gravis), Bazex syndrome,
Rombo syndrome, multiple seborrheic keratoses in patients with adenocarcinoma. Multiple jaw cysts may be
mistaken for dentigerous cysts or isolated OKCs. Severe
calcifications of many organs may also suggest
pseudohypoparathyroidism.1
 Treatment considerations for the oral and maxillofacial
surgeon
 OKCs are typically the first presenting feature of the
syndrome so radiographic examination of skull and
jaws is indicated. Biopsy of the skin lesions confirms
clinical presentation of nevoid basal cell carcinomas,
whereas OKCs may be distinguished histologically.
OKCs associated with NBCCS tend to develop multiple
new cysts and may be confused with recurrence of
previous lesions. Because syndromic OKCs present at
an earlier age than sporadic cysts, with the multiplicity of lesions and potential for recurrence, management by the maxillofacial surgeon continues into
adulthood because lifelong follow-up is anticipated
(Figs. 1 and 2).2e4

Gardner syndrome
 Genetics
 Gardner syndrome (GS) has been found to be associated
with the extracolonic manifestations of adenomatous

Fig. 1 (A, B) Panoramic radiographs of siblings with multiple


OKCs as seen in Gorlin-Goltz syndrome.

Shafer & Di Pasquale

Fig. 2 Multiple basal cell nevi in a patient with Gorlin syndrome.


(Courtesy of D. DeLuke, DDS, MBA, Richmond, VA.)

polyposis of the colon (APC). The germline mutation


associated with GS is localized to a gene on the long
arm of chromosome 5. GS is present with APC with an
incidence of 1 in 4000 to 1 in 12,000. Although the wide
spectrum of extracolonic manifestations depicts the
variable expressivity of the genotypic abnormality, GS
represents a more complete phenotypic expression of
the APC genotype.5 Spontaneous mutations can arise,
because 30% of cases occur because of a new dominant
mutation.1
 Clinical features
 The classic presentation of GS is a collection of multiple
intestinal polyps (adenomatosis), widespread osteomas
and abnormalities of the facial skeleton, epidermoid
cysts, and desmoid soft tissue tumors. Extracolonic
features typically precede the intestinal polyposis.6
Although the early symptoms of APC are not well
defined, soft tissue and other benign tumors in a child
or adolescent may indicate the possible onset of GS
followed by adenomas in the colorectal region.7
 Osteomas of the jaw are most often found throughout
the facial bones and are slow growing and reach a
limited size. Appearing with well-developed haversian
systems on radiograph,1 the enostotic lesions may
coalesce with other lesions. Other bones, such as the
radius, ulna, and tibia, may be affected, and lesions
appear as small osteomas with cortical hyperostosis.5
 Approximately 58% to 88% of all individuals affected by
ACP-GS have characteristic bilateral lesions of the
retina, known as congenital hypertrophy of the retinal
pigment epithelium.8
 Skin lesions include epidermoid cysts, desmoid tumors,
and fibrous hyperplasia. Epidermoid cysts are generally
small, always benign, and occur in about half of cases
of GS. They occur most often on the extremities, face,
and scalp, typically manifesting in adolescence, and
they precede the intestinal polyposis. Often unnoticed
by patients, development of skin cysts may serve as an
indication for further investigation for intestinal abnormalities. Desmoid tumors appear in 3.5% to 5.7% of
patients,9 typically near other surgical sites such as the
abdominal cavity. Desmoid tumors are rare in the general population, so discovery in a patient should lead to
an investigation of the colon for other signs of GS.10
 Gastrointestinal system manifestations are required for
diagnosis, and these multiple intestinal adenomatous

Hamartoneoplastic Syndromes
polyps are at high risk for malignant transformation. By
30 years of age, 50% of patients show malignancy of a
polyp, and as age advances the likelihood of malignancy
is expected to reach 100%.1
 Beside multiple osteomas, other dental-osseous abnormalities occur in w17% of patients and include supernumerary teeth and impacted teeth, hypercementosis,
root resorption, dentigerous cysts, and multiple complex odontomas. Odontomas tend to be in both the
mandible and the maxilla, most frequently in the incisalpremolar area.9
 Differential diagnosis:
 Multiple polyps of the colon can raise suspicion for juvenile polyposis of the colon, Turcot syndrome, PeutzJeghers syndrome (PJS), Cronkite-Canada syndrome,
Torre-Muir syndrome, Cowden syndrome (CS), and
Bannayan-Riley-Ruvalcaba syndrome.1
 Treatment considerations for the oral and maxillofacial
surgeon
 The role of the oral and maxillofacial surgeon is for
early detection of GS. Extraintestinal manifestations
are common, and 70% of all affected individuals have
significant abnormalities detectable on a dental
panoramic radiograph.8 Because intestinal lesion
polyposis is often a late sequela, multiple facial bone
and dental abnormalities should prompt further
investigation for predictive testing of at-risk individuals to predict and identify children who may
have inherited the GS or APC gene.7 Computed tomography images provide the necessary details of the
osteomas, and are the preferred radiologic examination for the assessment of bone abnormalities. Osteomas that restrict mandibular function or affect
cosmesis may require resection with risk for recurrence. Necessary exodontia should be approached
with care because increased density of alveolar bone
and possible loss of the periodontal space caused by
hypercementosis may complicate the procedure
(Fig. 3).9

155

Klippel-Tr
enaunay-Weber syndrome
 Genetics
naunay
 First reported in France in 1900, Klippel-Tre
syndrome (KTS) is a rare congenital disorder characterized by multiple large venous varicosities and malformations, capillary malformations, and cutaneous
nevi and lymphatic abnormalities with hard and soft
tissue hypertrophy. The diagnosis can be made by
identification of two of the fundamental features of
varicose veins, capillary malformation and hypertrophy
of the affected limb.11 Although a genetic basis is suggested because of cases being reported occurring
within particular families, the cause of this syndrome
remains unknown. There are no direct hereditary factors, suggesting an inheritance on a multifactorial
basis.11 One hypothesis states that the syndrome could
result from a lethal gene that survives by mosaicism.12
The presumed disorder suggested is a developmental
derangement of mesoderm, lending to arteriovenous
malformations, intrauterine injury to the sympathetic
ganglia and intermediolateral tract, and resultant
dilation of microscopic arteriovenous anastomoses.12
 Clinical features
 The classic presentation of KTS is a triad of abnormalities that includes varicose veins, capillary malformations, and hypertrophy of affected limbs. In addition,
malformations of the venous valves may be seen.11 The
vascular irregularities typically occur in the lower extremities because gravity assists venous drainage from
the head and neck. These deep vein abnormalities can
result in obstruction of normal venous flow and can lead
to venous hypertension, development of varices, and
hypertrophy of the limb.12
 Capillary malformations typically present as port-wine
stains (PWSs). They are usually purple, macular, endothelium-lined vascular channels located in the superficial dermis. These lesions are nonproliferative, do not
blanch, and typically do not resolve.12

Fig. 3 (A) Panoramic radiograph of multiple odontomas of the jaws. (B) Large bilateral osteomas in a patient with Garner syndrome. (C)
Dense, compact bone from an osteoma of the mandible in a patient with Garner syndrome. (Courtesy of [A] O. Erdo
gan, DDS, PhD, Adana,
Turkey; and [B] L. Eisenbud, DDS.)

156
 Limb hypertrophy in KTS is always associated with
limb elongation leading to limb discrepancy. Excessive
limb growth is both in length and girth, with hard
tissue and soft tissue hypertrophy, and the growth rate
is unpredictable, without regular rate or form. The
soft tissues include increases in vascular tissue, muscle, and skin.11 Associated with the soft tissue hypertrophy is vascular hyperplasia and arteriovenous
malformations.13
 Approximately 5% of KTS anomalies affect the head and
neck14 and appear as orofacial anomalies with hard and
soft tissue hypertrophy. As with the hypertrophy of the
extremities, the tissues appear to be increased unilaterally and may spread throughout the maxilla,
mandible, tongue, lips, cheek, and palate.13
 The excessively large varicosities seen in KTS are
congenital lesions, and appear earlier than usual varicose veins, typically being seen when patients begin to
ambulate. These abnormalities may be painful and
tender, and can lead to fatigue, heaviness, and ulcerations. Aneurysms of deep veins may occur as a result of
high pressure or vessel wall fragility.12 Other vascular
deformities such as aplasia, phlebitis, and valvular
incompetence can manifest.
 Patients may have lymphatic abnormalities such as
aplasia, hypoplasia, and extremity edema from congestion of the lymphatic system. Associated additional
findings such as abdominal hemangioma, heart defects,
syndactyly, polydactyly, oligodactyly, and macrodactyly have been reported in the literature.13 Complications from KTS can include cellulitis, thrombosis,
emboli, disseminated intravascular coagulation, and
neurologic disease.15
 Differential diagnosis
 KTS should be distinguished from other congenital
vascular anomalies like Parkes Weber syndrome, which
is limb enlargement with a malformation and arteriovenous fistula.
 Sturge-Weber syndrome (SWS) commonly presents with
facial hemangiomas along with focal seizures, sensory
and motor paralysis, calcifications of vessel walls, and
visual field defects. Also included are neurofibromatosis, Beckwith-Wiedemann syndrome, and Maffucci
syndrome.1
 Treatment considerations for the oral and maxillofacial
surgeon
 Addressing the facial asymmetry and esthetics is the
main goal for the oral and maxillofacial surgeon. Lesions associated with KTS are associated with capillary
fragility and tend to bleed easily.13 Prolonged
bleeding may be expected, and significant preoperative hematological testing should be performed in
patients with KTS to avoid possible postoperative
bleeding problems.16 Lesions of KTS occur in the head
and neck as unilateral enlargement, and may disrupt
the dentoalveolar segment presenting as displaced
teeth with malocclusion. Beyond the abnormal blood
vessels, the literature also suggests defects in platelets, coagulation factors, and fibrin degradation
products (FDP) contributing as systemic causes of
bleeding.13 Thus, the preoperative tests requested
should include FDP, antithrombin III, and specific
factor XIII assay before performing any oral surgical
procedures (Figs. 4 and 5).13

Shafer & Di Pasquale

Fig. 4 Exophytic pedunculated growth arising from the gingiva


on buccal side of the upper right molar teeth. (From Bathi RJ,
Agarwal N, Burde KN. Klippel-Trenaunay syndrome (angio osteohypertrophy syndrome): a report of 3 cases. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2002;93(3):276e80; with permission.)

Sturge-Weber syndrome
 Genetics (including inheritance patterns and frequency)
 Sturge-Weber Syndrome (SWS) is a neurocutaneous
syndrome characterized by port-wine staining (PWS) in
the skin of the face and leptomeningeal angiomatosis.17
SWS is generally proposed to be a result of genetic
mosaicism; therefore, it arises spontaneously without
family history. Precise population-based data do not
exist for the prevalence or incidence of SWS, but the

Fig. 5 Cutaneous and subcutaneous hemangioma of the lower


third of the face with swelling of the lower lip and increased lower
facial height. (From Bathi RJ, Agarwal N, Burde KN. Klippel-Trenaunay syndrome (angio osteohypertrophy syndrome): a report of
3 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2002;93(3):276e80; with permission.)

Hamartoneoplastic Syndromes
incidence of a PWS is estimated to be 0.3% in newborns,
without evidence of a sex predilection. SWS is an
embryologic anomaly and arises in utero when a
vascular plexus fails to regress from the portion of
neural tube that is destined to become facial skin,
thereby causing angiomatosis of the leptomeninges.1
 Clinical features (including histology if relevant)
 Dermal capillarovenous malformations, called PWSs,
are made up of postcapillary venules within the dermis.
They appear at birth on the face in 90% of patients, but
may spread to neck, chest, and back. They start out as
pink macules, but tend to darken and increase in
thickness with age.18 As a disruption in the development of cephalic neuroectoderm, a distribution among
the trigeminal nerve is seen, particularly the ophthalmic (V1) division. These cutaneous abnormalities
never regress spontaneously.
 Congenital glaucoma is the most common presentation in
a patient with a PWS with V1 division involvement.19 Other
ocular abnormalities include strabismus and choroidal
vascular lesions.20 They show angiomatosis vascular hyperplasia, blanch with pressure, and can present in the
oral cavity affecting the buccal mucosa, lips, and even
the alveolar process, which can result in changes to the
eruption pattern of teeth and malocclusion.
 The characteristic angioma of the leptomeninges
generally affects the temporal, parietal, or occipital
areas and even possible involvement of the cerebral
vascular system.1 If cutaneous lesions are lacking, the
diagnosis of SWS is made from radiologic findings,
including intracranial calcifications, which are likely to
be caused by decreased blood flow in areas of pial
angiomatosis.21
 Progressive neurologic deficits are present in 40% of
patients. The presence of calcifications, atrophy, or
seizures may suggest cognitive decline and need for
surgical intervention.21 Other symptoms associated
with SWS include hemiparesis, hemiplegia, cerebral
atrophy, and angiomatosis of various other organs.19
 Differential diagnosis
 KTS often occurs with SWS, suggesting a similar underlying disorder.1
 Coats disease involves telangiectasias of the retinal
blood vessels and may involve other areas of the face.
Congenital hemangiomas typically do not present as
large as the PWS. A rare, hereditary form of vascular

157
malformation presenting intraorally is the Osler-WeberRendu syndrome.22 Neurofibromatosis, Bannayan-RileyRuvalcaba syndrome, and Beckwith-Wiedemann
syndrome should also be considered in a differential
diagnosis.
 Treatment considerations for the oral and maxillofacial
surgeon
 The most commonly accepted treatment of PWS is
accomplished with the use of a pulsed dye laser using
wavelengths of 577 nm and 585 nm. The lesions typically do not cause functional problems with bleeding
and treatment is directed toward improving cosmesis.
Before initiating treatment it is important to distinguish
PWS lesions from other lesions that may have a greater
blood flow and therefore an increased risk of bleeding.
Hemangiomas may not become clinically evident until
the patient is older, whereas vascular malformations
are almost always noticed at birth and continue to grow
with the patient.22 If the lesion is purely dermal or
submucosal, and the underlying bone is not affected,
bony surgery including osteotomies for orthognathic
surgery can be performed without fear of excessive
bleeding.22
 Spontaneous expansion of a vascular malformation or
bleeding secondary to trauma or infection may cause
the patient to present with acute painful swelling.16
Pyogenic granulomas frequently develop within PWSs,
particularly in the mouth.1 These patients should be
evaluated hematologically, including prothrombin
time, partial thromboplastin time, fibrin split products,
and fibrinogen and platelet levels. Surgical intervention
can then be planned in the absence of coagulopathy
(Fig. 6).21

Peutz-Jeghers syndrome
 Genetics
 Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder that typically manifests in childhood and
early adulthood and is characterized by orofacial
melanosis and intestinal polyposis with an increased
risk of gastrointestinal and other cancers.23
 The inheritance pattern is autosomal dominant, and PJS
is the most common hereditary hamartomatous
gastrointestinal polyposis syndrome.24 The mutated

Fig. 6 (A) Capillary malformation with cobblestone appearance in an adult with SWS. (B) Angiomatous lesion of the left mandible in a
patient with SWS. (Courtesy of [B] D. DeLuke, DDS, MBA, Richmond, VA.)

158
gene on chromosome 19 seems to serve as a tumor
suppressor gene that encodes for serine threonine kinase (STK11).23 A truncation in the protein and loss of
its expression causes a reduced kinase activity and loss
of function to control growth in intestinal cells.24 With a
high degree of penetrance, the estimated incidence of
PJS is between 1 in 50,000 and 1 in 200,000 with no
evident gender or racial predilection.1
 Clinical features
 Gastrointestinal manifestations are the most important
component of this syndrome. The intestinal polyps are
usually found in the small bowel and the colon,1 but
they may be found anywhere along the gastrointestinal
tract and at even extraintestinal sites.25 Presenting
signs and symptoms, such as abdominal pain, anemia
secondary to bleeding, and intestinal obstruction
caused by intussusception occur early in life, with more
than 30% of patients presenting with symptoms in the
first decade, and 60% by age 20 years.26
 The correlation between PJS and cancer remains
controversial. Many sources suggest that the intestinal
polyps found in PJS are at an increased risk of
cancer through the hamartomas-adenoma-carcinoma
pathway.26 Other malignancies have been shown to be
related to PJS, including cancers of the breast, lung,
ovary, uterus, cervix, testicle, and pancreas. Ovarian
malignancies in particular occur in 10% to 14% of female
patients with PJS. In addition, gynecomastia can
develop in men by hormonal imbalance caused by
calcified Sertoli cell testicular tumors.26
 Mucocutaneous hyperpigmentation is an early manifestation of PJS and occurs in 95% of patients.23 Characteristic bluish-black spots appear at birth, and are
concentrated around the vermillion of the lips, palate,
buccal mucosa, and tongue, as well as the anus, genitals, and periorbital region.24 Variable in intensity,
these lesions tend to fade after puberty but remain on
the palate and buccal mucosa, thus being helpful in
diagnosis.1 On histology, the macules appear as
increased melanin in basal cells, and an increased
number of melanocytes at the dermoepidermal
junction.24
 Differential diagnosis
 Familial juvenile polyposis, hereditary mixed polyposis,
CS, Cronkhite-Canada syndrome, familial adenomatous
polyposis syndrome, Bannayan-Ruvalcaba-Riley syndrome, and basal cell nevus syndrome should all be
considered in the differential diagnosis. The pigmented
lesions differential includes Leopard syndrome, Laugier-Hunziker syndrome, and Carney complex.24 Toxins
such as lead, arsenic, and bismuth are known to cause
diffuse pigmentation of the gingiva. Other metabolic
disorders associated with hyperpigmentation are
chronic nutritional deficiencies, including pellagra,
celiac sprue, and anorexia nervosa.27
 Treatment considerations for the oral and maxillofacial
surgeon
 The diagnosis of PJS remains primarily a clinical process. Because the oral lesions present before the onset
of gastrointestinal disease, oral health care providers
have a unique role for surveillance of the oral cavity
with frequent recall for presenting signs and symptoms.24 Any mucocutaneous features and family history
should direct the clinician toward the diagnosis and the

Shafer & Di Pasquale


patient should be sent for further genetic testing and
screening.
 Patients may present with a history of short bowel
syndrome after multiple surgical resections, with
possible related malabsorption and iron deficiency
anemia. Subsequent oral manifestations such as atrophic glossitis can be detected clinically.24 If surgery is
planned, obtain complete blood count with differential, metabolic panel, platelet count, and electrolytes,
and the patient should be transfused as indicated.
There is no current standard treatment of the mucocutaneous lesions that present with PJS. Treatment
modalities for removal of these lesions include cryosurgery, dermabrasion, and various laser ablation
techniques.25 Thus, diffuse oral macular pigmentation,
when confirmatory signs and symptoms indicating systemic disorders are present, contraindicate a biopsy of
corresponding oral lesions because melanoma is unlikely (Fig. 7).28

Cowden syndrome
 Genetics
 Cowden syndrome (CS), also known as multiple
hamartomas syndrome, is a dermatosis characterized
by multiple hamartomatous papules and nodules of the
face, oral cavity, and skin.29 CS has an autosomal
dominant inheritance and complete penetrance of
equal frequency in both sexes. CS is rare, with prevalence of 1 in 200,000, often manifesting in the second
or third decade with the obvious signs being lesions of
the skin and oral mucosa.30 However, a variable penetrance does exist among patients.31 CS shows a race
predilection and tends to be more common in white
people.32
 The causative genetic abnormality is reported to be a
germline mutation in chromosome 10q23. A mutated
tumor suppressor gene PTEN (phosphatase and tensin
homolog) has a loss of function in regulating cell growth
with an inability to check the protein tyrosine kinase.31
 Clinical features
 The distinguishing lesions of CS are mucocutaneous
hamartomas. The hamartomas arise as alterations of
ectodermal, endodermal, and mesenchymal origin and
can affect multiple organs systems.32
 The facial lesions generally arise first, and the papules
or nodules can be found over facial skin, mucosal

Fig. 7 Oral melanotic macules in PJS. (From Cohen BA. Pediatric


dermatology. 3rd edition. Philadelphia: Elsevier, 2005; with
permission.)

Hamartoneoplastic Syndromes
surfaces, lips, and neck, as well as hyperkeratosis on
extremities and palmoplantar surfaces.1
 Lesions appear as papillomatous formations with features of hair follicles, thus giving the histology of tricholemmomas, composed of epithelial cells with
abundant glycogen surrounded by smaller palisading
cells.1 Oral fibromas and papillomas can also be seen.33
Lesions may coalesce to form a cobblestone
appearance.
 These hamartomatous lesions may progress to cancer,
specifically tumors of the breast, thyroid, polyposis of
the gastrointestinal tract, and malignancy of the female reproductive tract. Although breast cancer is the
most serious complication of CS, the female reproductive tract may show symptoms such as irregular menses,
ovarian cysts, and uterine leiomyomas.30 Other benign
lesions may develop, such as thyroglossal duct cysts,
fibrocystic breast disease, and multinodular thyroid
goiter.1
 Multiple gastrointestinal polyps are also common. They
may be seen throughout the gastrointestinal tract,
although the incidence of malignant transformation of
the gastrointestinal polyps is unknown.30
 Skeletal abnormalities such as scoliosis have been
documented and progressive macrocephaly seems to be
an important early marker of CS in young children.1 A
hypoplastic mandible and maxilla, microstomia, higharched palate, and malocclusion may accompany the
large head circumference.29
 Differential diagnosis
 Byars-Jurkiewicz syndrome presents with fibroadenomas of the breast, scoliosis, and gingival fibromatosis.
 The cutaneous lesions may resemble epidermodysplasia, Darier disease, Torre-Muir syndrome, and the
multiple oral fibromas in tuberous sclerosis.
 Similarities exist between the intraoral lesions and
polyposis of the intestines in CS, multiple endocrine
neoplasia (MEN) type 2B, and neurofibromatosis.1
 Multiple traumatic fibromas, multiple verruca vulgaris,
and Sipple syndrome.33
 Treatment considerations for the oral and maxillofacial
surgeon
 Extensive papules, papillomas, and oral lesions should
suggest CS and are often the first presenting sign. Early
recognition of this syndrome is important in view of the
high risk for the development of such malignant tumors.
In patients with CS, follow-up at 6-month intervals has
been recommended.34
The oral lesions may interfere with function and prosthetic treatment plans and their surgical removal is
then indicated using electrocautery.
At extreme risk for caries, the patients should also
maintain strict oral hygiene (Figs. 8 and 9).32

159

Fig. 8 Clinical view showing multiple oral papules over the


alveolar ridge. (From Gilbert HD, Plezia RA, Pietruk T. Cowdens
disease (multiple hamartoma syndrome). J Oral Maxillofac Surg
1985;43(6):457e60.)

divided into MEN 2A and MEN 2B. Patients with MEN 2A


have an increased risk of parathyroid adenoma or hyperplasia. MEN 2B, also known as mucosal neuroma
syndrome, describes patients with an abnormal
phenotype characterized by a marfanoid habitus,
mucosal neuromas of the lips and tongue, and ganglioneuromatosis of the gastrointestinal tract. Thyroid
carcinoma typically occurs in early childhood in MEN 2B
and early adulthood in MEN 2A.36
MEN 2B has an autosomal dominant inheritance pattern
with a high degree of penetrance.35 Germline

Multiple Endocrine Neoplasia syndromes


 Genetics
 Three types of Multiple Endocrine Neoplasia (MEN) have
been described. The first type presents with tumors of
the pituitary, parathyroids, and pancreas and is called
MEN type 1 (MEN 1). Another type, defined by the
presence of medullary thyroid carcinoma and pheochromocytoma, is designated MEN 2.35 MEN 2 is further

Fig. 9 The typical distribution of facial papules around the


mouth and nose common to multiple hamartomas syndrome.
(From Gilbert HD, Plezia RA, Pietruk T. Cowdens disease (multiple
hamartoma syndrome). J Oral Maxillofac Surg 1985;43(6):457e60.)

160
mutations to the RET proto-oncogene on chromosome
10 are thought to be responsible, because RET transduces the growth and differentiation of developing
tissues including those derived from the neural crest.37
Although nearly 100% of patients with MEN 2A have familial genetic abnormalities, patients with MEN 2B
often do not have a family history of the disease and
50% of cases are caused by spontaneous germline mutations.38 The overall frequency of MEN 2 in the United
States is 1 in 50,000 cases. MEN 2A is slightly more
common than MEN 2B.39
 Clinical features
 MEN 2B is the rarest of the 3 MEN syndromes, clinically
presenting as neoplastic changes to the endocrine
glands with a cluster of phenotypic changes.
 General appearance is often a marfanoid habitus with
other musculoskeletal anomalies occurring in at least
75% of cases.35 These anomalies include pes cavus,
slipped capital femoral epiphysis, kyphosis, scoliosis,
lordosis, increased joint laxity, and extremity
weakness.30
 The distinctive orofacial features of MEN 2B are often
the first features to be expressed and are considered
reliable markers of the disease.36 Multiple mucosal
neuromas are present, which are hamartomatous proliferations of nerve cells presenting as nodules on the
face, gingiva, palate, anterior portion of the tongue,
and the buccal mucosa.35,36 Skeletal facial features
such as a broadened nasal bridge, a high-arched palate,
and a prognathic mandible contribute to an overall
dolichofacial profile.35 Lip enlargement is classically
seen and is caused by diffuse angioneuromatosis. The
oral lesions are generally asymptomatic and benign.36
Ocular signs include dry eyes present in childhood with
children unable to cry tears. Prominent corneal nerves
are observed in all cases, as well as neuromas of the
tarsal plate with characteristic lid margin thickening.40
Childhood onset of chronic constipation is a common
complaint. Diffuse intestinal ganglioneuromatosis is
present in approximately 40% of cases and can occur
anywhere along the gastrointestinal tract.37 Chronic
diarrhea may also occur and may be related to the
medullary thyroid carcinoma.35
 Differential diagnosis
 Pheochromocytoma can also occur with neurofibromatosis, or as an isolated tumor, or in von Hippel-Lindau
syndrome presenting with certain brain tumors.
Pheochromocytoma with medullary thyroid carcinoma
occurs in MEN IIA and Sipple syndrome. Hyperparathyroidism may have genetic inheritance or be secondary
to hyperplasia or adenomas of the parathyroids.
Duodenal carcinoid or Hirschsprung disease may also be
confused with the intestinal ganglioneuromatosis of
MEN 2B.1
 Treatment considerations for the oral and maxillofacial
surgeon
 Oral health care providers are likely to encounter patients with this syndrome for evaluation of orofacial
lesions, malocclusion, generalized spacing between
teeth, anterior open bite, and facial asymmetry.36 MEN
2B, with distinctive oral characteristics, should be
considered by the oral and maxillofacial surgeon who
may be the first practitioner to diagnose the syndrome
and refer for appropriate treatment35

Shafer & Di Pasquale


 A panoramic dental radiograph may reveal shortened
roots of the lower incisors, spacing of the anterior teeth
in both jaws, and thickened inferior alveolar nerve
canal.36
 Pheochromocytoma may cause complications during
general anesthesia. Presenting symptoms may include
profuse sweating, palpitations, tachycardia, nausea,
vomiting, headaches, angina, and dyspnea.36 Pertinent
tests for screening of medullary thyroid cancer include
serum calcitonin levels after appropriate stimulation
and low values of serum calcium. The treatment of
intraosseous lesions of hyperparathyroidism seems to
be conservative. Besides biopsy, no active surgical
intervention is indicated in the treatment of primary
hyperparathyroid lesions of the jaws (Figs. 10 and 11).41

Proteus syndrome
 Genetics
 Proteus syndrome (PS) is a rare hamartomatous disorder
affecting multiple tissues including bone, soft tissue,
vascular structures, and skin.42,43 The term PS was suggested by Wiedemann and colleagues42 after the Greek
god Proteus who was able to change his shape at will.
 The cause and genetic basis of PS is not yet known, and
no sex predilection is associated.44 A postzygotic mutation has been postulated because of clinical discordance in identical twins, the mosaic distribution of the
lesions, and because all cases have been sporadic.42
The frequency of PS is also difficult to determine,
because fewer than 200 published cases fulfilling diagnostic criteria worldwide.43 The PTEN gene has been
implicated because of its role in other hamartomatous
syndromes.45 However, there is no clear phenotypic
distinction between PS with and without PTEN mutations, and both may fulfill the diagnostic criteria.42 The
clinical features of PS probably represent a second hit
in specific tissues or at a specific stage of embryologic
development in patients with inherited PTEN mutation.
Thus, PS is a phenotypic diagnosis and can result from
mutations in several different genes.45
 Clinical features
 Wiedemann and colleagues42 proposed diagnostic
criteria: gigantism of the hands and/or feet, pigmented

Fig. 10 Appearance of the tongue showing lumps on the


anterior margin and a midline cleft. (From Schenberg ME, Zajac JD,
Lim-Tio S, et al. Multiple endocrine neoplasia syndrome type 2b.
Case report and review. Int J Oral Maxillofac Surg 1992;21(2):
110e4; with permission.)

Hamartoneoplastic Syndromes

Fig. 11 Patient with MEN 2b showing long and thin extremities.


(From Schenberg ME, Zajac JD, Lim-Tio S, et al. Multiple endocrine
neoplasia syndrome type 2b. Case report and review. Int J Oral
Maxillofac Surg 1992;21(2):110e4; with permission.)

nevus, hemihypertrophy, subcutaneous tumors, skull


anomalies, accelerated growth, and visceral abnormalities. Diagnosis is made by evidence of 3 mandatory
criteria, including sporadic occurrence, mosaic distribution of lesions, and a progressive course.
 Skeletal and soft tissue overgrowth may affect the
face, limbs, and the trunk.46 Skeletal abnormalities
include macrocephaly, exostoses, kyphosis, scoliosis,
and spinal canal stenosis. Ocular problems such as
enlarged eyes, nystagmus, epibulbar tumors, and
retinal detachment have been reported. Mental retardation may be associated with cranial abnormalities.46
 The cerebriform connective tissue nevus (CCTN) is one
of the most characteristic skin findings. It commonly
occurs on the soles of the feet, and is frequently a
cause of pain, pruritus, infection, bleeding, exudation,
and walking impairment. CCTN slowly spreads and
grows thicker, forming skin masses that fold on each
other resembling sulci, leading to the designation as
cerebriform.43 On histology, CCTN appear with decreased fibroblasts, variable thick collagen bundles in a
disorganized pattern, sparse fragmented elastic fibrils,
and increased fat and sweat glands in the reticular
dermis. Other skin findings have patterns consistent
with mosaicism, including linear verrucous epidermal
nevi and vascular malformations such as PWSs,
angiomas, and cavernous lymphangiomas.43,46,47 In
addition, hyperpigmented/hypopigmented macules,
localized hypertrichosis, and areas of lighter-colored
scalp hair can occur.
 Dysregulated fat overgrowth is another common
feature of PS. Lipomas and/or lipohypoplasia are usually absent at birth and occur in early life. Patients with

161
PS may develop unusual tumors such as testicular,
ovarian, and central nervous system tumors.42
 Differential diagnosis
 PS is thought to be part of a spectrum of hamartomatous
neurocutaneous syndromes.48 CS, Bannayan-RileyRuvalcaba syndrome, and proteuslike syndrome have
germline PTEN mutations, as does a VATER-like disorder
with hydrocephalus and macrocephaly with autism.42 PS
must also be differentiated from neurofibromatosis,
naunay-Weber syndrome, enchondromatosis,
Klippel-Tre
and Maffucci syndrome.49
 Treatment considerations for the oral and maxillofacial
surgeon
 In roughly 30% of the cases reported, facial anomalies
occur, including malformed ears, high-arched palate,
malocclusion, mandibular prognathism, and depressed
nasal bridge.50 There is also an increased risk of
development of a malignancy, deep venous thrombosis,
and pulmonary embolism. Although vascular malformations and epidermal nevi may be among patients
cosmetic concerns, surgical removal of the vascular
tumors is discouraged because of the formation of unsightly scars, keloids, and tissue overgrowth.48 However,
when undertaken, excisions of subcutaneous tumors is
difficult because abnormal tissue may be left and the
planes of dissection are vascular. Many stages are usually required and postoperative morbidity is increased
and complex, because leakage from residual lymphatic
channels is expected. It is frequently necessary to
anticipate secondary deformities. Families should be
made aware that, with patience and multiple procedures, a satisfactory outcome might be expected
(Fig. 12).50

Neurofibromatosis
 Genetics
 Neurofibromatosis type 1 (NF1), also known as von
Recklinghausen disease, is an autosomal dominant,
multisystem disorder affecting approximately 1 in 3500
people.1 The NF1 gene, located on chromosome
17q11.2, encodes for the tumor suppressor neurofibromin, expressed in neural and glial cells, Schwann
cells, and melanocytes.51 NF1 has one of the highest
rates of spontaneous mutations, and loss of function
leads to unregulated cell growth in these tissues.
Penetrance is 100%, thus patients with the mutation
manifest tumors clinically, although expressivity is
highly variable.51 NF2 results from a mutation in the
NF2 gene and is characterized by bilateral vestibular
schwannomas and various other tumors.52
 Clinical features
 The diagnosis of NF1 is based on clinical findings. There
are definite diagnostic criteria for NF1 that satisfy any 2
-au-lait macules, 2 or
of the following: 6 or more cafe
more neurofibromas or 1 plexiform neurofibroma, axillary or groin freckling, optic glioma, 2 or more Lisch
nodules, a distinctive bony lesion, dysplasia of the
sphenoid bone or of long bone cortex, and a first-degree
relative with NF1.53
-au-lait macules has smooth
 The classic lesion of cafe
borders (coast of California) and homogeneous color
-au-lait. NF1 becomes evident in
close to that of cafe

162

Shafer & Di Pasquale

Fig. 12 (A) Connective tissue nevi on feet of patient with PS who also has overgrowth of the right foot. (B) Supraorbital osseous protuberances, more pronounced on the left side, and dolichocephaly in a patient with PS. (From [A] Twede JV, Turner JT, Biesecker LG,
et al. Evolution of skin lesions in Proteus syndrome. J Am Acad Dermatol 2005;52(5):834e8; and [B] Raboudi T, Bouchoucha S, Hamdi B,
et al. Soft-tissue necrosis complicating tibial osteotomy in a child with Proteus syndrome. Orthop Traumatol Surg Res 2014;100(2):247e50;
with permission.)

-au-lait spots
the first few years of life when cafe
develop.53,54
The hallmark neurofibroma is a benign peripheral nerve
sheath tumor. In the maxillofacial region, severe facial
disfigurement is almost always caused by a plexiform
neurofibroma of the trigeminal nerve and may invade
both the cheek and oral cavity.52 Cutaneous neurofibromas usually do not become apparent until puberty,
and then may continue to increase in size and number
throughout adulthood.55 Although these neurofibromas
do not progress to malignant neoplasms, studies have
shown that 1% to 2% of patients with NF1 develop malignant peripheral nerve sheath tumors.54,56
Skin fold freckling (Crowe sign) is the most specific of
the cardinal criteria for NF1, and is considered nearly
pathognomonic. It generally occurs around 5 years of
age in either the axillae, groin, neck, circumoral area,
or the trunk area.53
Bony abnormalities are variable and include scoliosis,
sphenoid wing or long bone dysplasia, and osteopenia.
Primary defects may include scalloping of vertebrae,
congenital bowing of long bones, and osteolytic lesions,
and secondary erosive defects caused by invasive
tumors.54
Lisch nodules are small, hyperpigmented macules of
the iris. They occur in about 20% of children by 6 years
of age and 95% of adults with NF.54 The slow-growing
optic glioma is a tumor of the optic nerve and is present
in approximately 20% of patients. It presents as eye
proptosis and decreased visual acuity associated with
precocious puberty.53
Neurologic complications have been observed in 55% of
patients. These complications may include neurophysiologic disorders, and 1 in 200 present with cognitive
defects and learning difficulties.54
Patients with NF2 may present with acoustic neuromas,
tumors of Schwann cell origin, and multiple neurofi-au-lait
bromas in the absence of Lisch nodules and cafe
spots.52

 Differential diagnosis
 An important disorder to distinguish from NF1 is NF1-au-lait
like syndrome. This syndrome consists of cafe
macules, axillary freckling, and macrocephaly, and is
negative for an NF1 gene mutation.51
 Syndromes associated with multiple mucosal neuroma
are MEN IIb, KTS, Jaffe-Campanacci syndrome, and
McCune-Albright syndrome.1
 Treatment considerations for the oral and maxillofacial
surgeon
 Abnormalities of dentition might be the first clinical
sign to allow correct diagnosis of NF1. Impacted, displaced, or missing teeth with enlargement of the
alveolar ridge are oral manifestations of NF1. Radiological findings include widening of mandibular canal
and mental foramen.52,57
 Management often involves multiple specialties because there is no specific medical management available.54 Pigmented lesions are generally not treated and
darken in response to sunlight, and tend to fade with
time to become less noticeable. Symptomatic neurofibromas that compromise function are candidates for
surgical removal; however, multiple lesions and plexiform neurofibromas may be tangled with normal tissue,
causing difficulty in removal while preventing neurologic deficits.52,54 Despite the solitary nature of the
tumor, the vascularization is dense and vascular
malformations are common. Intraosseous neurofibromas often require large resections of the mandible
(Figs. 13 and 14).52,55

Tuberous sclerosis
 Genetics
 Tuberous sclerosis complex (TSC) is an autosomal
dominant, systemic disorder characterized by the formation of hamartomas in multiple organ systems, most
commonly the brain, skin, kidney, and eye. Eighty

Hamartoneoplastic Syndromes

Fig. 13

Intraoral view of palatal neurofibroma.

percent of the cases seem to be sporadic, and the


incidence of TSC is estimated to be 1 in 6000.58,59
Approximately two-thirds of patients have no parental
history of TSC, which signifies a high rate of spontaneous mutation. Two separate tumor suppressor genes
may produce tuberous sclerosis: TSC1 on chromosome
9q34 and TSC2 on chromosome 16p13.3.59 The clinical
spectrum in TSC is widely variable even among members of the same family, ranging from a single asymptomatic cutaneous hamartoma to involvement of
multiple organ systems.60
 Clinical features
 Because of the highly variable tuberous sclerosis
phenotype, diagnostic features may be present at birth
and others develop later in life.61 About 85% of children
and adolescents with tuberous sclerosis have central
nervous system complications, including epilepsy,
cognitive impairment, and autism.62 The prevalence of
mental retardation in TSC is up to 70%. Patients have
bimodal distributed intelligence quotients (IQs), with
55% of patients in normal range, 14% showing mild to
severe impairment, and 30.5% with profound mental

163
retardation.62 Cognitive impairment in TSC is thought to
result directly from cortical tubers, seizures, or both.
 The most common brain lesions include abnormal
neuronal and glial elements, cortical and white matter
tubers, and giant cell astrocytomas. Other findings such
as cerebral atrophy, cerebral infarct, cerebral aneurysm, and arachnoid cysts may be present.59
 Hypomelanotic macules may be the first cutaneous
manifestation and are reliably detected in patients
with tuberous sclerosis during infancy.63 Lesions may
appear as ash leaf spots, confection macules, thumbprint macules, or angiofibromas. Facial angiofibromas
occur in up to 90% of patients, typically presenting in
preschool years and occurring as bilateral and symmetric, small, telangiectatic papules on the cheeks,
chin, and nose.59,63 Approximately 50% of patient have
eye problems, including retinal hamartomas.62 Nontraumatic ungual fibromas are among the major diagnostic criteria for the diagnosis of TSC and a major
concern to patients because of pain and distortion of
the nail; they have a frequency of 15% to 52%.64
 Oral lesions have been reported in about 11% of patients.58 These lesions consist mainly of fibrous growths
affecting the oral mucosa of the anterior gingiva, lips,
tongue, and palate. Pitted enamel hypoplasia is
another characteristic oral manifestation of the disease
found in 58% of patients.60
 Between 50% and 80% of patients with TSC have renal
lesions like angiomyolipomas, renal cysts, nephrolithiasis, and renal tumors.61
 Diagnosis of tuberous sclerosis is difficult because no
single symptom is present in all patients, and none are
absolutely pathognomonic.64
 Differential diagnosis
 Several familial tumor syndromes can present with
multiple facial and oral papules, including TSC, CS, BirtHogg-Dube syndrome, and MEN type I. Moreover, facial
angiofibromas have also been reported to occur in patients with MEN type 1 and neurofibromatosis.1

-au-lait spots (arrow). (B) Nonencapsulated neural elements typical of neuroFig. 14 (A) Patient with typical neurofibromas and cafe
fibroma are seen in this palatal excision in a patient with neurofibromatosis. ([A] From Reynolds RM, Browning GG, Nawroz I, et al. Von
Recklinghausens neurofibromatosis: neurofibromatosis type 1. Lancet 2003;361(9368):1552e4, with permission; and [B] Courtesy of
D. DeLuke, DDS, MBA, Richmond, VA.)

164

Shafer & Di Pasquale

Fig. 15 Clinical and histologic features of oral lesions in one patient with tuberous sclerosis complex. Biopsy specimen of dome-shaped
fibroma on hard palate (A) revealed haphazard array of collagen with several thin-walled vascular channels underlying thickened
epithelium (B). Biopsy specimen of fibroma at angular commissure (C) revealed vessels and fibrous bands of collagen (D). (B and D, Hematoxylin-eosin stain; bar Z 65 _m; original magnification 3100.) (From Sparling JD, Hong CH, Brahim JS, et al. Oral findings in 58 adults
with tuberous sclerosis complex. J Am Acad Dermatol 2007;56(5):786e90; with permission.)

 Treatment considerations for the oral and maxillofacial


surgeon
 Tuberous sclerosis is a neurocutaneous condition known to
have manifestations in the head and neck, including rare
reports of solitary odontogenic tumors such as calcifying
epithelial odontogenic tumor and central odontogenic
fibromas.65 Examination for oral fibromas may therefore
reveal an abnormality in an apparently unaffected relative of a patient with tuberous sclerosis and identify
unsuspected carriers within families with obvious transmission.58 TSC is an important condition to identify
because it can be inherited genetically and patients may
have morbidity related to the seizure disorder or renal and
lung lesions. Renal angiomyolipomas, subependymal
giant cell tumors, pulmonary complications, and cardiac
complications are the major causes of shortened life
expectancy.61 Spontaneous hemorrhage of an angiomyolipoma has been reported as a leading cause of death in
the TSC population. Follow-up over time with interval
panoramic radiographic examination is a valuable tool to
accompany an oral health clinical screening evaluation
of patients with TSC. Once diagnosis is made, scrupulous,
regular, age-dependent screening for behavioral,
cognitive, and neurodevelopmental dysfunction is
strongly recommended (Fig. 15).64

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Branchial Arch Syndromes


David Al, DDS, MD a,*, Din Lam, DMD, MD b, Jaime Gateno, DDS, MD a
KEYWORDS
 Branchial arch syndrome  Treacher Collins syndrome  Pharyngeal arch  Mandibulofacial dysostosis
 Oculoauriculovertebral dysplasia  Goldenhar syndrome  Mo
bius syndrome  Congenital facial palsy
KEY POINTS






Branchial arch syndromes present with variable expressivity.


Management necessitates a multidisciplinary approach.
Features corroborate a disorder with first and second branchial arch derivatives.
Treatment should be performed early for vital functional impairments and delayed for esthetic concerns.
bius syndrome is a rare congenital palsy of the sixth and seventh cranial nerves.
Mo

Treacher Collins syndrome


Genetics (including inheritance patterns and
frequency)
 Autosomal dominant inheritance pattern (a small percentage has autosomal recessive inheritance)
 Affects 1 in 50,000 live births
 Up to 60% of cases result from new or sporadic mutations
 There are 3 recognized gene mutations:
 TCOF1 and POLR1D: autosomal dominant
 POLRIC: autosomal recessive
 The result of these mutations is an aberrant production of
ribosomal RNA that is important in the structural development of the face, and more specifically the first and
second branchial arches

Clinical features
The clinical features of Treacher Collin syndrome (TCS) consist
of bilaterally symmetric, abnormal development of the structures arising from the first and second branchial arches. This
abnormal development contributes to deficient generation of
the lower two-thirds of the face (Fig. 1).
The first branchial arch is involved with the growth of the
mandible and the zygomaticomaxillary complex and the second arch or hyoid arch is involved with development of the
middle ear. The classically presented patient accordingly has a
convex facial profile with gross hypoplasia or incomplete formation of the zygoma, maxilla, and mandible in all 3 dimensions. These individuals also have normal intelligence.
These facial features are summarized in Table 1.
The authors have nothing to disclose.
Department of Oral & Maxillofacial Surgery, Houston Methodist
Specialty Physician Group, Weill Medical College Cornell University,
New York, 6560 Fannin Suite 1280, Houston, TX 77030, USA
b
Oral and Maxillofacial Surgery, Virginia Commonwealth University,
Richmond, VA, USA
* Corresponding author.
E-mail address: dmalfi@houstonmethodist.org
a

Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 167173


1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.04.003

Differential diagnosis:
 Craniofacial microsomia: features are asymmetric and
usually unilateral
 Pierre Robin sequence: children born with severe hypoplasia of the mandible, high arching cleft palate, and a
relative macroglossia
 Stickler syndrome comprises a group of hereditary conditions involving eye, ear, and joint deformities plus
Pierre Robin sequence
 Nager syndrome includes malformed upper limbs as well
as cleft palate and severe palatal hypoplasia

Treatment considerations for the oral and


maxillofacial surgeon
The treatment strategy for patients should prioritize procedures that result in functional improvement while delaying
those with cosmetic goals until growth maturity. The following
functional categories may necessitate early intervention:
airway, feeding, hearing, speech, vision, and socialization.
Airway
Maxillary and mandibular hypoplasia can contribute to a compromised airway. Choanal atresia or stenosis can compound this problem, which may require immediate intervention ranging from
observation with pulse oximetry and positioning to mandibular
advancement with distraction osteogenesis, or tracheotomy (Fig. 2).
Feeding
An incompetent lip seal or cleft lip and or palate may
compromise adequate nutrition. Considerations to cleft
treatment algorithms or G-tube placement may be necessary.
Hearing
Pediatric otolaryngology consultation and formal audiology
testing is required early in order to establish successful hearing.
Vision
Pediatric ophthalmologist should be consulted to evaluate for
any extra ocular muscle (EOM) dysfunction or deficits in visual
acuity. When the lateral and inferior orbital supporting

oralmaxsurgeryatlas.theclinics.com

168

Alfi et al.

Fig. 1 A 6-year-old girl with TCS. Note the facial features of TCS: colobomata, lower lid hypoplasia, downward slanting of palpebral
fissures, prominent nasal dorsum, malar and zygomatic hypoplasia, mandibular hypoplasia, microgenia, Angle class 2 open bite. (Courtesy
of Dr. Sidney Eisig.)

structures are hypoplastic or missing the corneas are unprotected, which may necessitate earlier reconstruction of the
orbital and zygomatic structures.
Table 1

TCS facial features

Eyes

Downward slanting of palpebral fissures


Colobomata
Lower lid hypoplasia and partial absence
of eyelid cilia
Dystopia

Ears

Microtia or absent external ear


Middle ear or ossicle hypoplasia
Conductive deafness
Atresia

Nose

Prominent nasal dorsum


Choanal atresia or stenosis

Mouth

Cleft palate  lip


Malocclusion (Angel class II, anterior open
bite, steep clockwise rotation of the
maxillomandibular complex)
Dental abnormalities (enamel opacities,
dental agenesis, eruption disturbances)

Musculoskeletal

Skeleton

Muscles
Joint

Mandibular hypoplasia
Microgenia
Hypoplastic glenoid fossa
Maxillary hypoplasia
Muscular hypoplasia (muscles of
mastication)
Absent, hypoplastic, or deformed
TMJ

Abbreviation: TMJ, temporomandibular joint.

Speech
Correction of a cleft palate should follow the standard cleft
treatment recommendations.
Secondary treatment strategy should take place at the end
of skeletal maturity and include orthognathic surgery and
zygomatic-orbital reconstruction.
Malar and orbital reconstruction uses a full-thickness
calvarium bone graft through a coronal incision and exposure.
It is recommended that this procedure be performed after the
age of 6 years, for skeletal maturity of the midface, as well as
the ability to reconstruct the donor calvarium site with a local
split-thickness calvarium graft.
Maxillomandibular reconstruction is best approached with
traditional orthognathic surgery at 13 to 15 years of age, at the
time of early skeletal maturity. Le Fort I and rami osteotomies
with sliding genioplasty are usually indicated.
When the deformity results in absent ramus, condyle, or
glenoid fossa, then reconstruction may be performed at the
time of malar and orbital reconstruction. The use of costochondral bone graft to reconstruct the ramus-condyle is advocated. A second reconstruction with conventional osteotomies
is almost certain to be warranted after skeletal maturity.
As with conventional orthognathic surgery, nasal reconstruction should be performed as the final reconstructive procedure when indicated.

Goldenhar syndrome
Hemifacial microsomia (HFM), Goldenhar syndrome, and oculoauriculovertebral dysplasia have been used interchangeably.

Branchial Arch Syndromes

169

Fig. 2 A patient before (A) and after (B) mandibular distraction. (From Gateno J, Teichgraeber FJ, Aguilar E. Computer planning for
distraction osteogenesis. Plast Reconstr Surg 2000;105(3):873e82; with permission.)

The findings are usually unilateral, and, if bilateral, are always


asymmetric. For this reason many clinicians prefer the term
craniofacial microsomia. Most reserve the term Goldenhar
syndrome for when the complex includes epibulbar dermoids
and cervical spine anomalies.

Table 2

Genetics (including inheritance patterns and


frequency)
 Usually acquired sporadically; however, both autosomal
recessive and autosomal dominant transmission has been
implicated
 The incidence has been reported as between 1 in 3500 and
1 in 26,000 births
 Gene mapping has indicated a link to a region on chromosome 14q32.
 Pathogenesis has been theorized to involve a vascular
disruption to the developing first and second branchial
arches. The stapedial artery has been implicated.

Goldenhar syndrome associated features

Skin

Preauricular skin tags

Eyes

Epibulbar dermoid cysts


Dystopia

Ears

Microtia or absent external ear


Atresia

Nose

Prominent nasal dorsum


Choanal atresia or stenosis

Mouth

Macrostomia: clefting of the oral commissure


Cleft palate  lip
Malocclusion (cross bite, open bite,
asymmetry, occlusal plane cant with
ipsilateral shortening)

Musculoskeletal

Skeleton

Clinical features
Goldenhar syndrome shares phenotypic manifestations of first
and second branchial arch derivative malformations. The
findings can be viewed as similar to those of TCS, but usually
these findings are unilateral, causing gross facial asymmetry.
Hallmark features include microtia, hemifacial microsomia, epibulbar dermoids, and preauricular skin tags. A
constellation of other findings may be present and are listed in
the following table (Table 2). The OMENS classification system
was developed to indicate the 5 major manifestations of HFM
(Table 3).

Muscles
Joint

Mandibular hypoplasia
Microgenia
Hypoplastic glenoid fossa
Maxillary hypoplasia
Malar hypoplasia
Orbital hypoplasia
Muscular hypoplasia (muscles of
mastication)
Absent, hypoplastic, or deformed
TMJ

Neurologic

VII nerve palsy

Other

Vertebral anomalies, cardiac malformations,


genitourinary anomalies, central nervous
system involvement

Note: features are usually unilateral.

170
Table 3

Alfi et al.
OMENS

Orbit

Abnormal orbital size, position, or both

Mandible

Abnormal ramus, condyle, and TMJ: hypoplasia,


abnormal shape, or missing unit

Ear

Abnormal ear canal, lobule, or middle structures:


hypoplasia, atresia, malposition, or absence

Facial
nerve

Facial nerve weakness: upper facial nerve, lower


facial nerves, or both

Soft tissue

Subcutaneous and muscular hypoplasia

Differential diagnosis:
 VACTERL is an acronym for vertebral anomalies, anal
atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies, and limb anomalies.
 Nager syndrome: downward palpebral fissures, midface
hypoplasia, micrognathia, and upper limb (radial) deformities. Features are usually bilateral.
 TCS: bilateral midface and mandibular hypoplasia,
microtia, and coloboma.

Treatment considerations for the oral and


maxillofacial surgeon
Controversy exists regarding the time of intervention for repair
of the jaw deformity with surgery. Some evidence suggests that

Fig. 3

the degree of deformity remains stable during growth and that


mandibular asymmetry is not progressive. Contrary to this
viewpoint, other series suggest progressive canting and asymmetry. However, the question of progression versus nonprogression may not be the most important. The timing of
surgery should be determined individually. Whether there is an
advantage for a particular patient to undergo early surgery (ie,
when the final outcome will be better with early surgery) needs
to be determined (Figs. 3 and 4).
As with many facial reconstructive procedures, treatment
should be delayed until skeletal maturity. However, in some
cases early surgical intervention is advantageous, such as a
compromised airway, psychosocial problems, or when early
surgery will improve final surgical outcomes.
Malar and orbital reconstruction uses a full-thickness
calvarium bone graft through a coronal incision and exposure.
It is recommended that this procedure be performed after the
age of 6 years.
Maxillomandibular reconstruction is best approached with
traditional orthognathic surgery at 13 to 15 years of age at the
time of early skeletal maturity. The condyle-ramus reconstruction may necessitate costochondral grafting.
Correction of complex maxillofacial deformities, especially those with three-dimensional asymmetries, such as in
patients with HFM, was particularly challenging with conventional treatment planning. The advent of computer-aided
surgical simulation has improved the outcomes of orthognathic surgery.

A patient followed from infancy to teenage years shows a stable left hemifacial deformity.

Branchial Arch Syndromes

171

Fig. 4 The patient from Fig. 3 with three-dimensional reconstruction and computer-simulated surgery. It was decided in this case that
early mandibular surgery, at age 12 years, would allow for alveolar growth of the left posterior mandible. This allows for a more predictable and symmetric final orthognathic surgery after skeletal maturity with use of Le Fort 1, bilateral sagittal split osteotomy, and
genioplasty.

Often the deformities are severe enough to warrant early


mandibular surgery with either a rib graft or distraction
osteogenesis. Early intervention should be realized as stage I
with anticipation for corrective stage II orthognathic surgery at
skeletal maturity.

Table 4

bius syndrome facial features


Mo

Eyes

Abducens nerve palsy


Ocular hypertelorism
Small palpebral fissures
Epicanthal folds
Inferior scleral show

M
obius syndrome

Ears

External ear deformities


Hearing loss

bius syndrome is a congenital, nonprogressive, and bilateral


Mo
facial and abducens nerve palsy, often accompanied by other
cranial nerve palsies and limb deformities.

Nose

Flattened nasal bridge

Mouth

Maxillary constriction
Cleft palate
Bifid uvula
Malocclusion (excessive overjet, anterior
open bite)
Lip incompetence and open mouth posture
Dental abnormalities (dental agenesis,
oligodontia)

Musculoskeletal

Skeleton

Micrognathia
Retrognathia

Muscles

Muscular hypoplasia
(associated with affected
nerves)

Genetics (including inheritance patterns and


frequency)
 Most cases are thought to be sporadic in nature
 Few familial studies suggest an autosomal dominant
transmission
 The responsible gene is located at chromosome 13q12.2-q13
 Pathogenesis has been theorized as vascular insufficiency or obstruction of basilar and vertebral arteries
during development leading to necrosis of brain stem
nuclei with resulting hypoplasia of affected cranial
nerves
 Other studies have described more peripheral or distal
pathogenesis with normal-appearing nuclei

Neurologic

VI and VII nerve palsy


Other cranial nerve palsies

Other

Limb deformities

172

Alfi et al.

bius syndrome, before surgery. Note the thin upper lip. (B) After surgery, with bilateral reduced latissimus dorsi muscle
Fig. 5 (A) Mo
powered by the masseteric branch of the seventh nerve. Upper lip augmented with lipodermal graft. (From Harrison DH. The treatment of
unilateral and bilateral facial palsy using free muscle transfers. Clin Plastic Surg 2002;29:539e49; with permission)

Clinical features
bius syndrome are described as having maskPatients with Mo
like faces. The facial weakness associated with cranial nerve
VII and VI palsies leaves children with expressionless faces with
the inability to abduct the eye. The expressivity is variable and
patients may also have additional cranial nerve palsies, limb
deformities, and other manifestations.
Commonly associated clinical features are listed in Table 4.
Differential diagnosis:
 Hereditary congenital facial paralysis: shares similar
findings; however, this syndrome is limited to palsy of the
facial nerve only.

Treatment considerations for the oral and


maxillofacial surgeon
Social development is profoundly handicapped by the inability
to express feelings. Treatment should therefore be planned to
limit social and psychological maladaptation. This planning
requires a multidisciplinary team approach in order to
normalize faces to form and function.
Facial expression is managed by surgeons familiar with
microsurgical facial reanimation (Fig. 5). Nerve transplantation and free muscle transplantation are used to provide
facial movement. Nerve donors must be tailored to the individual, because additional cranial nerve involvement limits
which nerves can be used for transplantation. Furthermore,
the bilateral nature prevents cross-nerve transplantation.
Cranial nerves V, XI, and XII have been used. Muscle donors
commonly used for reanimation are the gracilis, pectoralis
minor, and latissimus dorsi.
Recognizing and coordinating care for dental caries and
periodontal disease is paramount, because patients have

increased risk for dental disease. The lack of facial muscle


movement, and often masticatory function, contributes to
poor self-cleansing, trapped food, and poor salivary function.
Orthognathic surgery to address the multiple facial skeletal
deformities is advocated.
At the time of orthognathic surgery, it is important to
consider associated soft tissue deformities. It may be necessary to perform a vestibuloplasty to correct a hypoplastic and
short lip and shallow vestibule.

Further readings
Behrents RG, McNamara JA, Avery JK. Prenatal mandibulofacial
dysostosis (Treacher Collins syndrome). Cleft Palate J 1977;
14:13.
Bergmann C, Zerres K, Peschgens T, et al. Overlap between VACTERL
and hemifacial microsomia illustrating a spectrum of malformations
seen in axial mesodermal dysplasia complex (AMDC). Am J Med
Genet A 2003;121:151e5. http://dx.doi.org/10.1002/ajmg.a.20167.
Bianchi B, Copelli C, Ferrari A, et al. Facial animation in children with
Moebius and Moebius like syndromes. J Pediatr Surg 2009;44:
2236e42.
Bianchi B, Ferri A, Brevi B, et al. Orthognathic surgery for the complete
rehabilitation of Moebius patients: principles, timing and our
experience. J Craniomaxillofac Surg 2013;41(1):e1e4.
Gateno J, Teichgraeber JF, Xia JJ. Three-dimensional surgical planning
for maxillary and midface distraction osteogenesis. J Craniofac Surg
2003;14:833e9.
Gateno J, Xia J, Teichgraeber JF, et al. The precision of computergenerated surgical splints. J Oral Maxillofac Surg 2003;61:
814e7.
Gateno J, Xia JJ, Teichgraber JF. Three-dimensional computer-aided
surgical simulation for maxillofacial surgery. Atlas Oral Maxillofac Surg
Clin North Am 2005;13(1):25e39. http://dx.doi.org/10.1016/j.cxom.
2004.10.004.
Gateno J, Xia JJ, Teichgraber JF, et al. Clinical feasibility of computeraided surgical simulation (CASS) in the treatment of complex

Branchial Arch Syndromes


cranio-maxillofacial deformities. J Oral Maxillofac Surg 2007;65(4):
728e34.
Gorlin RJ, Cohen MM Jr, Levin LS. Syndromes of the head and
neck. Oxford (United Kingdom): Oxford University Press; 1990.
p. 666e72.
ndez-Alfaro F. Management of maxillofacial
Guijarro-Martnez R, Herna
hard and soft tissue discrepancy in Mobius sequence: clinical report
and review of the literature. J Craniomaxillofac Surg 2012;40(1):
e11e6.
Guzelmansur BY, Daplan T, et al. Prenatal diagnosis of Goldenhar
syndrome with unusual features by 3D ultrasonography. Genet
Couns 2013;24(3):319e25.
Ha H, Messieh Z. Management of a patient with Mobius syndrome: a
case report. Spec Care Dentist 2003;23(3):111e6.
Kaban LB, Moses ML, Mulliken JB. Surgical correction of hemifacial
microsomia in the growing child. Plast Reconstr Surg 1980;82:
9e19.
Kaban LB, Padwa BL, Mulliken JB. Surgical Correction of mandibular
hypoplasia in hemifacial microsomia: the case for treatment in
early childhood. J Oral Maxillofac Surg 1998;56(5):628e38.
Manoha DJ. Congenital midface abnormalities. Neuroimaging Clin N Am
2011;21:563e84.

173
Posnick JC, Ruiz R, Tiwana P. Treacher Collins syndrome: comprehensive evaluation and treatment. Oral Maxillofac Surg Clin North Am
2004;16:503e23.
Posnick JC. Treacher Collins syndrome: evaluation and treatment.
Orthognathc surgery principles and practice. Elsevier. 2014, Ch 27:
1059e1094.
Posnick JC. Hemifacial microsomia: evaluation and treatment.
Orthognathc surgery principles and practice. Elsevier. 2014, Ch 27:
1095e1158.
Poswillo D. The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis). Br J Oral Surg 1975;13:1e26.
Poswillo DE. The pathogenesis of the first and second branchial arch
syndrome. Oral Surg Oral Med Oral Pathol 1973;35:302e28.
Rune B, Selvik G, Sarnas KV, et al. Growth in hemifacial microsomia
studied with the aid of roentgen stereophotogrammetry and
metallic implants. Cleft Palate J 1981;18:128.
Terzis JK, Noah EM. Mobius and Mobius like patients: etiology, diagnosis, and treatment options. Clin Plast Surg 2002;29:497e514.
Venramini-Pittoli S, Kokitsu-Nakatya NM. Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal
dominant inheritance and review of the literature. Clin Dysmorphol
2009;18:67e77.

Clefting Syndromes
Stephanie J. Drew, DMD
KEYWORDS
 Clefting syndromes  Clefting disorders  Pierre-Robin  Velocardiofacial syndrome
 Van der Woude syndrome  Stickler syndrome  CHARGE syndrome
KEY POINTS
 There are over 500 syndromes with clefting as part of the phenotype.
 An understanding of sequence is needed to effectively manage patients with clefting disorders.
 Various treatments are available for the wide variety of clefting disorders.

Introduction
The process of lip and palate morphogenesis depends on
complex molecular signaling pathways to enable cellular proliferation, differentiation, and apoptosis. Both genetic and
environmental factors may be responsible for dysregulating
these pathways, leading to development of cleft lip or palate.
Cleft lip with or without cleft palate is a distinct entity from cleft
palate only. Palate closure occurs between weeks 8 and 12 in
utero, and lip formation is concluded by week 7. During these
periods of development, dysregulation of different pathways
leads to cleft of the lip, palate, or both (Figs. 1 and 2).
Cleft lip and palate, when it occurs as the only malformation (anomaly), is considered nonsyndromic. Seventy percent
of all cases of cleft lip and palate are nonsyndromic. Cases of
cleft palate only are different in that they are nonsyndromic
50% of the time.
However, when cleft lip and palate or cleft palate alone is
associated with other clinical features (anomalies), it is
considered syndromic. Thus, cleft lip and palate occurs as
syndromic 30% of the time. Cleft palate only occurs as syndromic 50% of the time. The diagnosis of a syndrome is made
from the overall pattern of anomalies present. The more
anomalies noted, the easier it is to diagnose. However, sometimes, some of these features may not be fully expressed and
are more difficult to diagnose.
More than 500 syndromes are identified with cleft lip and
palate as part of the phenotype. The most common mechanisms related to syndromic cleft lip and palate are either single
gene mutations or chromosome abnormalities. Of note are the
findings in some syndromes of trisomy chromosomes (13, 18,
and 21), partial deletions, and duplications. Therefore, several
genomic regions containing loci either excessive or insufficient
can lead to cleft lip and palate. There are both autosomal
dominant inheritance patterns and autosomal-recessive
The author has nothing to disclose.
Hofstra School of Medicine, Hempstead, New York, USA
Stony Brook University Medical Center, 101 Nicolls Road, Stony
Brook, NY 11794, USA
Private Practice, The New York Center for Orthognathic and Maxillofacial Surgery, 474 Montauk Highway, West Islip, NY 11795, USA
E-mail address: DrDrew@nycoms.com
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 175181
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.001

IRF6 (interferon regulator


factor 6)

Van der Woude syndrome (VWS)/


popliteal pterygium syndrome

FGFR2 (fibroblast growth


factor receptor 2)

Cruzon and Apert syndromes

FGFR1

Kallmann syndrome

COL2A1, COL11A1,
COL11A2

Stickler syndrome types 1, 2 and 3

SOX9

Pierre Robin

TBX1

DiGeorge/velocardiofacial
syndromes: 22q11 deletion

patterns of inheritance of syndromic clefting. A few syndromes


also have an X-linked inheritance pattern (Fig. 3).
Multiple genes have been identified over recent years that
are responsible for different aspects of syndromic cleft lip and
palate formation:
Genes have also been identified in nonsyndromic cleft lip
and palate:
IRF6
8q24 locus
Vax1
Other genes studied with a likely association with nonsyndromic cleft lip and palate include:
MSX1
FOXE1
MYH9
MAFB
ABCA4
17q22 locus
BMP4
FGFR2
Research is still ongoing to prove the relationships between
these genes and clefting disorders.
For a complete listing of all genes/syndromes identified thus
far, refer to the National Institutes of Health Web site OMIM
(Online Mendelian Inheritance in Man): http://www.ncbi.nlm.
nih.gov/omim.

oralmaxsurgeryatlas.theclinics.com

176

Drew

Fig. 1

Left unilateral cleft lip and palate.

Treatment considerations
For the oral and maxillofacial surgeon, understanding the
significance of syndrome-related clefting is necessary to plan
surgery throughout the patients lifetime as well as manage
associated potential complications of the syndrome-related
anomalies. Some of these anomalies may include major organ
issues from deformations, to malformations, disruptions, and
dysplasias. Of course, these anomalies may affect anesthesia
management, behavior and compliance, wound healing,
and the overall treatment planning and long-term predictability of the surgical procedures. Some of the more common
syndromes are discussed in the following sections. However,
in general, treatment follows a practical protocol based on
developmental, functional, and social/aesthetic goals of
treatment.

Basic timeline for all cleft lip and palate disorders


Lip closure
In infancy, the child has to be well enough to withstand
anesthesia and blood loss for an elective procedure. Various

Fig. 3

Chromosome.

orthopedic appliances are used along with taping to shape the


nasal cartilages and bend the alveolar components, bringing
the soft tissues of the lip closer before closing the primary lip
(Fig. 4).

Palate closure
The soft palate is typically closed before the hard palate during
the first 2 years. However, there are several teams who close
both the hard and soft palate simultaneously at this time.
Closure of the hard palate depends on team protocols: some
perform this procedure at around 2 years, whereas others
delay and place pinned prostheses during infancy to let soft
tissues hypertrophy to make closure easier and also so that
skeletal growth is less restricted. The hard palate is then
closed at around age 5 years before the child starts school
(Figs. 5 and 6).

Myringotomy
This surgery is usually combined with palatal surgery once
hearing deficits are confirmed.

Fig. 2

Bilateral cleft lip and alveolus.

Fig. 4 Gentle pressure is applied by adjusting the wire and the


acrylic bulb to lift the nasal rim and shape the cartilage before
repair.

Clefting Syndromes

177

Fig. 7 Pharyngeal flap with mucosa of pharyngeal wall attached


to soft palate. Note lateral portals. These flaps may present a
challenge for the anesthesia team during intubation.

When velopharyngeal insufficiency (VPI) is a problem, this flap


is one of the methods used to decrease hypernasal speech.
However, with newer techniques of palatal lengthening, this
flap seems to be used less as a first line of defense and is more
used as a salvage procedure. There is a risk that some children
may develop obstructive sleep apnea syndrome when this
procedure is performed (Fig. 7).

palate can be widened. This procedure may also be necessary


to provide access before alveolar bone grafting. Timing is
based on need.
Second, if there is an anterior-posterior hypoplasia, the
maxilla may be protracted with orthopedic forces and head gear
or an inverted Herbst-type appliance. More recently, attempts
have been made to gain advancement with skeletal anchorage,
with some success with minor deficiencies. However, major
deficiencies should be addressed with formal surgery via
orthognathic surgery or distraction or a combination of both.
Third is the need to organize the dentition and set up the
occlusion for prosthetic rehabilitation or surgery.

Rhinoplasty

Bone grafting

Initial attempts during primary closure are made to make the


nose as aesthetic and functional as possible in these children.
However, multiple revisions are usually performed throughout
childhood (eg, before entering middle school or high school).
Often, these procedures are performed in conjunction with
other surgeries such as lip and scar revisions.

Bone grafting is performed to create alveolar continuity and


close any remaining alveolar and nasal fistulae. Timing is based
on the developing dentition in the cleft site. These children
may be missing the permanent lateral incisor, and grafting can
be delayed until the canine is about 50% to 75% formed.
Because of the variation between somatic and dental age, the
use of dental radiographs is critical in timing surgery for these
children.

Fig. 5

Isolated cleft palate in an infant.

Pharyngeal flap

Orthodontic care
Orthodontic intervention is needed for several reasons. First, if
there is maxillary hypoplasia in a transverse dimension, the

Orthognathic surgery
This surgery is performed at the cessation of growth, if
needed. Many children with cleft palate have maxillary skeletal deficiency and subsequent functional malocclusions.
Often, these skeletal problems are masked with both cosmetic
surgical procedures and orthodontic compensation. Studies
vary as to the frequency of need for corrective jaw surgery in
patients with cleft palate; frequencies from 25% to 75% have
been reported in the literature.
Special consideration when planning for these children is
given to the amount of movement needed and scar tissue
resistance. Vascular anomalies may also be present in some
syndromic children.

Distraction

Fig. 6 Pinned palatal prosthesis. Note screws in acylic, securing


it to maxilla.

In the child with cleft palate who needs corrective jaw surgery,
if the maxillary skeletal deficiency is greater than 12 mm, it is
often difficult to achieve a stable result with standard
orthognathic surgery, because of the enormous strain placed at
the scarred regions of the palatal tissues. Distraction should be

178
considered in these cases to slowly advance the maxilla and
stretch these tissues.
Distraction surgery has also been used in infants with
mandibular hypoplasia and cleft palate who are in airway
distress, in order to open the airway and to either prevent tracheostomy or to allow for decannulation. Conservative therapy
is first attempted with these children. The palatal tissues need
to be closed in these hypoplastic patients. The airway is further
compromised if the mandible is the cause of the obstruction.

Tooth replacement
A missing lateral incisor is the most common tooth that needs
replacement in the cleft site. There are several syndromic
clefting disorders that have multiple missing teeth as part of
the syndrome. The same basic guidelines for tooth replacement
in children are used for children with cleft palate. Prosthetic
rehabilitation should be geared toward the most aesthetic
outcome. It is often difficult to adequately reconstruct both
bone and soft tissue for dental implants; for some patients,
conventional crown and bridge work may be a reasonable option. Working hand in hand with the patient, restoring dentist,
and orthodontist is essential to achieve realistic goals.

Anesthesia
Oral anomalies challenge the anesthesia team, with possible
issues related to airway malformation, previous surgery
(especially pharyngeal flap surgery), and possible range of
motion issues associated with other syndromic clefting disorders that have concurrent temporomandibular joint anomalies.
Cardiac issues in some syndromic clefting disorders may also
need to be addressed as part of the anesthesia management.

Compliance
Younger patients may not be compliant after surgery, which
can lead to wound breakdown and poor wound healing.
If distraction is considered, the child needs to allow you to
turn the distractors to achieve the needed results. The parents
are often challenged with this task and may not be able to
accomplish it, and thus, the patient may need to see the surgeon daily during the distraction period.

Drew
have primary pulmonary dysgenesis. Other anomalies reported
are inguinal hernia or umbilical hernias. These patients often
have mental retardation and learning disabilities, as well as
behavioral issues. Metabolic issues include hypocalcemia in
infancy. These children may also be at increased risk for infections as a result of T-lymphocyte dysfunction.

Genetics
There is a defect in chromosome 22 with a microdeletion
(1.5e3.0 Mb) on the long arm of chromosome 22 (del22q11
syndrome).

Inheritance pattern
The inheritance pattern is autosomal dominant.

Frequency
This syndrome occurs in 1 in 2000 to 7000 live births.

Differential diagnosis
About 10% of patients with velocardiofacial syndrome (Fig. 8)
have DiGeorge syndrome, which consists of at least 2 of the
following features:
 Conotruncal cardiac anomaly
 Hypoparathyroidism, hypocalcemia
 Thymic aplasia, immune deficiency

Treatment considerations for the oral and


maxillofacial surgeon
These patients may have had cardiac surgery to repair various
anomalies, and there may be residual problems that might

Velocardiofacial syndrome (Shprintzen


syndrome)
Facial anomalies include cleft palate only with VPI. The Pierre
Robin sequence may be seen with this syndrome. As many as
15% to 20% of patients have Pierre Robin syndrome, which includes small jaw, U-shaped cleft palate, and glossoptosis. The
nasal tip is typically bulbous. Other anomalies include narrow
palpebral fissures, malar deficiency, vertical maxillary excess,
long face, retruded chin and malocclusion; microencephaly is
found in 40% to 50% of cases. These patients have growth
anomalies and are short in stature, with slender hands and
digits. Hypotonia occurs in infancy.
Major organ anomalies are present. Approximately 85% of
patients have congenital heart anomalies, possibly including
ventricular septal defect or tetralogy of Fallot. There may be
right aortic arch, aberrant left subclavian vein, and carotid
artery abnormalities. Some patients have been reported to

Fig. 8 Patient with typical phenotype features of velocardiofacial syndrome. Note long face, broad nasal bridge, and
epicanthal folds.

Clefting Syndromes
indicate a need for antibiotic coverage and/or specialized
anesthesia management during surgery. Also, any anomalous
carotid vessels may need to be documented preoperatively,
prior to any surgical dissection in the palatopharyngeal
region.

Van Der Woude syndrome 1 and 2


Facial anomalies may include lower lip pits (Fig. 9), cleft lip,
cleft palate, cleft uvula, and hypodontia.

179
opening. There is high penetrance with this genetic mutation,
and families should be counseled.

Pierre Robin sequence


Once believed to be a specific syndrome, the occurrence of 3
anomalies (cleft palate, micrognathia, and glossoptosis) is
referred to as the Pierre Robin sequence (Fig. 10). These
anomalies are often found together in multiple syndromes.
Clinically, neonatal airway obstruction and feeding problems
may be encountered, leading to failure to thrive.

Genetics
Genetics
Most reported cases of Van Der Woude syndrome (VWS) have
been linked to chromosome 1q32-q41 (VWS1) and are caused
by mutation in the IRF6 gene.
VWS2 has been mapped to chromosome 1p34 and a mutation
identified in the WDR65 gene.

This condition can be monogenic, chromosomal, or teratogenically induced. There are also several cases with unknown
genesis.

Inheritance pattern
Inheritance pattern
The inheritance pattern is autosomal dominant.

There are autosomal dominant as well as autosomal-recessive


patterns, and also an X-linked form and forms associated with
trisomy 18 and other syndromes.

Frequency
Frequency
This syndrome is the most frequent form of syndromic clefting,
accounting for 2% of all cases of cleft lip and palate. The
prevalence ranges from 1:100,000 to 1:40,000 stillborn or live
births.

Differential diagnosis
Lip pitting may also be present in Popliteal Pterygium Syndrome, a closely related inherited syndrome.These patients
have unilateral cleft lip and palate, ankyloblepharon,
paramedian lip pits, unilateral renal aplasia, and coronal
hypospadias.

Treatment considerations for the oral and


maxillofacial surgeon
These patients often have multiple surgical procedures to treat
the unaesthetic aspects of the lip pitting. This situation often
leaves them with unaesthetic scarring and decreased oral

Fig. 9

The frequency depends on the associated syndrome.

Differential diagnosis
The differential diagnosis includes Stickler syndrome (Fig. 11)
and fetal alcohol syndrome.

Treatment considerations for the oral and


maxillofacial surgeon
The dilemma in treatment is in making an accurate diagnosis of
the cause of the micrognathia and cleft palate. If the syndrome
is identified, then planning can be more precise. Treatment of
these children is performed in stages. The first priority is to
secure a safe airway. If acutely unstable, tracheostomy may be
necessary. Otherwise, consideration is given to advancing the
mandible with distraction osteogenesis, after securing the
airway with intubation.

(A) Patient with VWS after revision of animation of lip pits. (B) Unrepaired lip pits in a patient with VWS.

180

Drew

Fig. 10 (A) Child with Pierre Robin sequence and normal condyles. Micrognathia and microgenia evident. (B) This patient with PierreRobin sequence has agenesis of both mandibular condyles.

Once the skeletal and soft tissue of the tongue is advanced,


and the airway is open, then the palatal tissues can be repaired
and closed, with less chance of creating further airway
compromise. The patient should be evaluated for lower airway
anomalies of the larynx or trachea, which may also contribute
to the airway obstruction. Also, neurologic issues, especially
centrally induced sleep apnea, should be considered in the
differential diagnosis of poor airway in the neonate.
The second consideration for the oral and maxillofacial
surgeon is growth of the facial skeleton after distraction. In a
patient with an anomalous condyle, it is difficult to predict
development of the condylar processes. If this development
cannot be predicted, at what point should corrective jaw
surgery, further distraction, or condyle replacement be
necessary? These decisions are clinically and functionally
determined. If further airway compromise occurs during
childhood because of lack of growth of the mandible, then

Fig. 11

reopening the airway and getting rid of the apneas is important


to the overall health of the child.
Tooth buds may be in the line of osteotomy during initial
distraction surgery and may need to be removed because of
anomalous formation or development of impaction.

Other common clefting syndromes


CHARGE syndrome
Anomalies: coloboma, heart defect, atresia choanae, retarded
growth and development, or central nervous system anomalies, genital hypoplasia, and ear anomalies or deafness
Occurrence: 1 in 10,000 births
Genetics: mutation in CHD7 gene on long arm of chromosome 8
Autosomal dominant

(A, B) Stickler syndrome. Note long philtrum, prominent eyes, and small chin.

Clefting Syndromes

181

Stickler syndrome

Internet resources

Anomalies: Robin sequence, myopia, glaucoma, cataracts,


retinal detachment, hearing loss, skeletal abnormalities with
loose hypermobile joints, leading to arthritis with age

Available at: http://www.Genome.gov. Accessed 30 June, 2014.


Available at: http://www.omim.org (online Mendelian inheritance in man).
Accessed 30 June, 2014.
Baek RM, Koo YT, Kim SJ, et al. Internal carotid artery variations in
velocardiofacial syndrome patients and its implications for surgery.
Plast Reconstr Surg 2013;132(5):806e10.
Brito LA, Miera JG, Kobayashi GS, et al. Genetics and management of
the patient with orofacial cleft. Plastic Surg Int 2012;2012:782821.
Available at: http://www.hindawi.com.
Chinnaduri S, Goudy S. Understanding velocardiofacial syndrome: how
recent discoveries can help you improve patient outcomes. Curr
Opin Otolaryngol Head Neck Surg 2012;20(6):502e6.
Cohen MM. Syndromes with cleft lip and cleft palate. Cleft Palate J
1978;15(4):306e28.
Dixon MJ, Marazita ML, Beaty TH, et al. Cleft lip and palate: synthesizing genetic and environmental influences. Nat Rev Genet 2011;
12(3):167e78.
Gangopadhyay N, Mendonca DA, Woo AS. Pierre Robin sequence. Semin
Plast Surg 2012;26:76e82.
Leslie EJ, Marazita ML. Genetics of cleft lip and palate. Am J Med
Genet C Semin Med Genet 2013;163C:246e58.
NIH (National Institutes of Health). www.nih.gov.
Papangeli I, Scambler P. The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1. Wiley Interdiscip
Rev Dev Biol 2013;2:393e403. http://dx.doi.org/10.1002/wdev.
75.
Rajion ZA, Alwi Z. Genetics of cleft lip and palate: a review. Malays J
Med Sci 2007;14(1):4e9.

Occurrence: 1 in 7500 to 9000 newborns


Genes: COL2A1, COL11A1, COL11A2, COL9A1, and COL9A2
Autosomal dominant for COL2A1, Col11A1, and COL11A2
Autosomal recessive for COL9A1 and COL9A2
Other syndromes that may show variable clefting of the lip
or palate are addressed elsewhere in this issue, including:
Apert syndrome
Cruzon syndrome
Treacher Collins syndrome
Hemifacial microsomia

Recommended resources
Texts
Benum of anesthesia and uncommon diseases. 6th edition. Philadelphia: Saunders; 2012.
Gorlin syndromes of the head and neck. 5th edition. New York: Oxford
Publisher; 2010.

Syndromes Affecting the Central Nervous


System
David W. Lui, DMD, MD a,b,*, Roman G. Meyliker, DMD a,b, Samir Singh, DMD a,b
KEYWORDS
 Lesch-Nyhan syndrome  Marcus Gunn syndrome  Cavernous sinus syndrome  Superior orbital fissure syndrome
 Trotter syndrome  Horner syndrome  Frey syndrome  Ramsay-Hunt syndrome
KEY POINTS
 Many syndromes affecting the central nervous system (CNS) demonstrate both intraoral signs as well as head and neck
manifestations.
 Their causes include, but are not limited to, genetics, infection, trauma, neoplasm, postsurgery, and idiopathy.
 Various treatment methods are available and must be considered when working with patients who present with syndromes
affecting the CNS.

Lesch-Nyhan syndrome
 Genetics
 Extremely rare, present in only 1 in 380,000 live births.1
 Lesch-Nyhan syndrome (LNS) is an X-linked recessive
disorder of purine metabolism; however, up to 30% of
patients carry de novo mutations.2,3 It is caused by the
deficiency of hypoxanthine guanine phosphoribosyl
transferase (HPRT), which is a purine salvage enzyme
responsible for recycling purine bases into purine
nucelotides.4 Specifically, it converts hypoxanthine and
guanine into their respective 50 -mononucleotides.5
 The gene for HPRT (HPRT1) is encoded on the long arm
of the X chromosome at Xq26-Xq27.2 This enzyme is
present in all tissues with the highest levels in the basal
ganglia, which accounts for the extrapyramidal effects
seen in this syndrome.4
 Because it is an X-linked disorder, male patients are almost
exclusively affected. Female patients may be carriers.5
 A phenotypic spectrum exists, which is thought to be
based on variability in HPRT levels and activity.4,5
Classic LNS is correlated with severe or complete HPRT
deficiency. Patients with partial HPRT deficiency may
present with hyperuricemia with or without neurologic
and/or behavioral symptoms.4,5
Funding Sources: None.
Conflict of Interest: None.
a
Department of Oral and Maxillofacial Surgery, Virginia Commonwealth University School of Dentistry, 521 North 11th Street, Room 311,
Richmond, VA 23298-0566, USA
b
Division of Oral and Maxillofacial Surgery, Department of Surgery,
Medical College of Virginia Medical Center, 521 North 11th Street,
Room 311, Richmond, VA 23298-0566, USA
* Corresponding author. Department of Oral and Maxillofacial
Surgery, Virginia Commonwealth University School of Dentistry, 521
North 11th Street, Room 311, Richmond, VA 23298-0566.
E-mail address: dlui@vcu.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 183195
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.002

 Clinical features
 Often, children have a normal prenatal and perinatal
course with development of symptoms within the first 3
to 6 months.1
 LNS has a spectrum of phenotypic presentations. However, classic LNS is characterized by aggressive and
self-mutilating behavior (most commonly persistent lip,
tongue, and finger biting resulting in severe avulsion
injury to perioral tissues and amputation of digits),
hyperuricemia, and involuntary movements with severe
dystonia (Fig. 1A, B).2,6,7
 Other features that may be present include developmental delay, megaloblastic anemia, nephropathy, and
gout or tophi.2,4
 The first sign is the appearance of an orange or reddish
sandy material in the diapers of newborns due to uric
acid crystalluria and microhematuria.2,3 Additional
early findings, within the first year of life, include
episodic opisthotonus and the inability of a child to sit
in a chair unless secured with chest or waist restraints
(see Fig. 1C).1,2,7
 Differential diagnosis
 Diagnosis is made based on phenotypic presentation,
elevated serum uric acid levels (greater than 4e5 mg/dL
in children), and HPRT enzyme assays.2,4
 A wide array of disorders of purine metabolism exist
that exhibit features of LNS such as gout, Arts syndrome, ribosephosphate diphosphokinase, hyperactivity, and adenylosuccinate lyase deficiency.1
 From a cognitive and neurobehavioral standpoint, LNS
may mimic dyskinetic or athetoid type cerebral palsy,
autism, Rett syndrome, Cornelia de Lange syndrome, or
Down syndrome.8
 Treatment considerations for the oral and maxillofacial
surgeon
 Treatment has largely been aimed at controlling the
presenting symptoms and prevention of severe injury
from self-mutilation.

oralmaxsurgeryatlas.theclinics.com

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Fig. 1 Self-injury in Lesch-Nyhan syndrome. (A) Injury from persistent lip biting. (B) Finger amputation from self-mutilating behavior. (C)
r PR, Jinnah HA. Lesch-Nyhan disease and the basal
Patient in protective physical restraints and wheelchair device. (From Visser JE, Ba
ganglia. Brain Res Brain Res Rev 2000;32(2e3):467; with permission.)

 Allopurinol has been used to decrease the overproduction of uric acid.4 This, in turn, delays the
development of renal failure.6 Allopurinol, however,
has no effect on behavioral, neurologic, and cerebral
manifestations of the syndrome.4,6 Dystonia and spasticity have been managed with GABA agonists (eg,
benzodiazepines and baclofen), dopamine replacement
therapy (eg, L-dopa), and deep brain stimulation to the
globus pallidus.4,6 Control of self-injurious behavior has
been sought with benzodiazepines, neuroleptics, antiepileptics, and chloral hydrate.6 Recent studies have
demonstrated that the limitation of self-mutilating
behavior includes a combined approach using physical
restraints, behavioral treatment, and pharmacologic
therapy.6
 In the event that self-mutilating behavior is refractory
to medical management, alternative therapies have
been proposed. Some have advocated extraction of
front teeth or all remaining teeth.6 To avoid this invasive treatment, other investigators have advocated oral
protective devices such as lip bumpers or shields,
tongue shields, and occlusal bite plates or splints,
which have shown some success.6
 A recent study by Chen and colleagues4 demonstrated
regression in aggressive and self-injurious behavior and
to a lesser extent dystonia with oral supplementation of
S-adenosylmethionine based on its therapeutic potential to replenish the nucleotide pool in the brain.

Marcus Gunn syndrome


 Genetics
 Marcus Gunn syndrome is the most common congenital
synkinetic eyelid disorder, with a prevalence of 4% to
6% among patients with congenital ptosis.9
 Several studies have reported that patients have a
higher likelihood to have the left eye affected.10,11 The

syndrome was also found to exhibit equal sex


predilection.9
 Patients with Marcus Gunn syndrome may also have
other eye disturbances such as amblyopia, vertical
strabismus, and double elevator palsy. These eye disturbances should be addressed before any corrective
ptosis surgery.9
 Clinical features
 Marcus Gunn syndrome, or trigemino-oculomotor synkinesis, occurs due to an aberrant connection between
the motor branches of the third division of trigeminal
nerve innervating the pterygoid muscle and the fibers
of the superior division of the oculomotor nerve that
innervate the levator palpebrae superioris.12
 It is clinically characterized as a ptotic eyelid that is
rapidly elevated on lateral excursions, opening of
the mandible, whistling, sucking, blowing, smiling,
speaking, and tongue movements (Fig. 2).13,14
 Differential diagnosis
 A differential diagnosis to consider is Marin-Amat syndrome. This synkinetic eyelid disorder is characterized
as involuntary eyelid closure on jaw opening. It occurs
due to an aberrant connection between the facial nerve
and the trigeminal nerve.15
 Treatment considerations for the oral and maxillofacial
surgeon
 Eye shields or eye protection should be used during
dental or oral and maxillofacial surgery procedures
because the eye will open when the mouth opens.13
 In a mild case that is not bothersome to the patient, no
intervention can be elected.
 In a case in which there is moderate-to-severe ptosis, or
if the patient has esthetic concerns, a surgical intervention can be considered.
 Several corrective procedures exist, including the
Fasanella-Servat procedure, bilateral levator muscle
excision followed by bilateral fascia lata brow suspension, or bilateral frontalis suspension with levator

Syndromes Affecting the Central Nervous System

185

Fig. 2 (A) Child with Marcus Gunn jaw-winking phenomenon demonstrating unilateral left upper eyelid ptosis. (B) Ptosis is resolved by
ska-Pawelec G, et al. Marcus Gunn
synkinetic upper eyelid elevation with concomitant jaw opening. (From Bartkowski SB, Zapala J, Wyszyn
jaw-winking phenomenon: management and results of treatment in 19 patients. J Craniomaxillofac Surg 1999;27(1):26; with permission.)

excision on the affected side.16e18 Other surgical procedures exist; however, it is beyond the scope of this
article to describe all methods.

Cavernous sinus syndrome


 Genetics
 Cavernous sinus syndrome has no genetic basis; however, multiple causes for the syndrome exist and many
of these have underlying genetic causes. Discussion of
each is beyond the scope of this article.
 A study done by Keane19 investigated the most common
causes of cavernous sinus syndrome. He found that,
among 151 subjects (45 subjects, 30%), tumors were the
most frequent cause of this syndrome. The second-most
common cause (36 subjects, 24%) was trauma. Selflimited inflammation was the third-most frequent cause
(34 subjects, 23%). Carotid aneurysms and fistulas,
infection, and other causes composed the remaining
12%.
 Clinical features
 The cavernous sinus is a paired structure that lies on
either side of the sella turcica and lateral to the pituitary gland.20 The contents include an extradural plexus
surrounded by a dural fold and the internal carotid artery with associated sympathetic plexus (Fig. 3).21 The
abducens nerve runs lateral to the internal carotid artery but medial to the oculomotor nerve (see Fig. 3).21
Within the lateral dural border of the cavernous sinus
lie the oculomotor nerve, trochlear nerve, ophthalmic
division of trigeminal nerve and maxillary division of the
trigeminal nerve (superior to inferior) (see Fig. 3).21
Venous drainage is from the superior and inferior orbital
veins.20
 The main symptoms of cavernous sinus syndrome are
ophthalmoplegia, sensory loss of the ophthalmic and
maxillary divisions of the trigeminal nerve distribution,
with or without the presence of lid ptosis, anhidrosis,
and miosis on the affected side (Fig. 4).20e22
 Other symptoms may include orbital congestion and
proptosis and periorbital edema, depending on the
cause of the syndrome.20,21

 Differential diagnosis
 The differential diagnosis for cavernous sinus syndrome
includes superior orbital fissure syndrome, orbital apex
syndrome, Horner syndrome, carotid canal syndrome,
and Tolosa-Hunt syndrome.20,21
 Treatment considerations for the oral and maxillofacial
surgeon
 Treatment of this syndrome is aimed at identifying and
managing the underlying condition.
 Broad categories of diseases resulting in the clinical
presentation of cavernous sinus syndrome include bacterial and fungal infection, noninfectious inflammation,
vascular lesions, and neoplasms.21
 Several infectious processes may result in the development of cavernous sinus thrombosis. Infections of the
midface (ie, nasal furuncles) can enter the facial vein
and pterygoid plexus and be carried to the cavernous
sinus.23 Staphylococcus aureus is the most common
microbe in this setting.23 Acute or chronic sphenoid and
ethmoid sinusitis may result in cavernous sinus thrombosis. Common pathogens include Staphylococcus
aureus and Streptococcus pneumoniae, as well as other

Fig. 3 Coronal section through the cavernous sinus. Meningeal


layer in orange, periosteal layer in green. Car. A., carotid artery; CN,
cranial nerve; Pit., pituitary; Sphen., sphenoid; V1, V2, V3, cranial
nerves V1, V2, V3. (From Campero A, Campero AA, Martins C, et al.
Surgical Anatomy of the dural walls of the cavernous sinus. J Clin
Neurosci 2010;17(6):747; with permission.)

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Fig. 4 (A) Patient presented with a left intracavernous internal carotid aneurysm (ICICA) occupying the posterior third of the cavernous
sinus, demonstrating left-globe proptosis, abducens nerve palsy, and sympathetic nerve impairment with partial Horner syndrome. (B)
Patient presented with a right ICICA occupying the anterior third of the cavernous sinus, demonstrating partial right eyelid ptosis and
restricted upward gaze of right globe significant for isolated right oculomotor superior division palsy. (From Silva MN, Saeki N, Hirai S, et al.
Unusual cranial nerve palsy caused by cavernous sinus aneurysms: clinical and anatomic considerations reviewed. Surg Neurol
1999;52(2):144e5; with permission.)

anaerobic streptococcus species.23 In the case of


chronic sinusitis (ie, rhinocerebral aspergillosis and
mucormycosis), the most common fungal pathogens
include Aspergillus and Mucorales.23 Treatment includes appropriate antifungal or antimicrobial therapy,
endoscopic drainage, and anticoagulation (low molecular weight heparin or warfarin).23,24
 Of particular clinical importance to the surgeon are
odontogenic infections with extension into deep fascial
spaces. For instance, infections of the masticator,
canine, buccal, or lateral pharyngeal spaces can result
in life-threatening complications such as cavernous
sinus thrombosis and erosion into the internal carotid
artery.25 Pathogens most commonly involved include
Streptococcus species, Fusobacterium, and Bacteroides.23 Management includes surgical incision and
drainage of the affected spaces, in addition to appropriate antimicrobial therapy.25
 An example of a noninfectious cause is an inflammatory pseudotumor that is responsive to steroid
administration.21,26

 Carotid-cavernous fistulas may be divided into direct or


indirect fistulas. Direct fistulas demonstrate direct
continuity between the cavernous segment of the carotid artery and the cavernous sinus. They form after
closed head injuries or ruptured aneurysms and present
with a classic triad of chemosis, pulsatile exophthalmos,
and a bruit over the affected eye.20 Management includes endovascular treatment using detachable balloons, onyx (ethylene vinyl alcohol copolymer), or
coils.20,27,28 Indirect fistulas form a shunt with the
meningeal branches of the carotid artery and often
spontaneously resolve.20
 Giant internal carotid aneurysms (>2.5 cm) cause pain
and ophthalmoplegia. Endovascular embolization or
coiling may be indicated in select patients (see
Fig. 1).20
 Neoplasms that may cause cavernous sinus syndrome
include pituitary adenomas, malignancy with perineural
spread (ie, nasopharyngeal carcinoma [NPC]), meningioma, and hemangiomas. These lesions usually require
excision.20

Syndromes Affecting the Central Nervous System

Superior orbital fissure syndrome


 Genetics
 This syndrome has no genetic predilection.
 Although the syndrome is fairly uncommon, causes of
superior orbital fissure syndrome include tumors in the
retrobulbar space, retrobulbar hematomas, infection in
the cavernous sinus or retrobulbar space, as well as
facial trauma.29,30
 The incidence of traumatic superior orbital fissure in
cases involving facial fractures was reported to be
0.3%.30
 In the case of blow-in fractures of the orbit, the incidence of superior orbital fissure syndrome was reported
to be as high as 10%.31
 In a study by Chen and colleagues,30 four cases of carotid-cavernous sinus fistula were confirmed by angiography out of 33 cases of superior orbital fissure
syndrome.
 Clinical features
 It is important to note the anatomy of the superior
orbital fissure because its contents reflect the clinical
features of the syndrome. The superior orbital fissure
contains the trochlear, lacrimal, and frontal nerves, as
well as the superior ophthalmic vein, the superior and
inferior branches of the oculomotor nerve, the nasociliary nerve, and the abducens nerve (Fig. 5).32,33
 Superior orbital fissure syndrome is characterized by
ptosis of the upper eyelid, ophthalmoplegia, hypoesthesia of the ipsilateral V1 dermatome, proptosis,
and mydriasis (Fig. 6).34,35 Additional clinical signs
include lacrimal hyposecretion and loss of the corneal
reflex.
 Differential diagnosis
 If there is visual acuity involvement, orbital apex syndrome should be considered. Cavernous sinus syndrome
should also be considered if there is involvement of V2
dermatome instead of V1 division of the trigeminal
nerve.

Fig. 5 Diagram displaying the contents of the superior orbital


fissure. a, artery; n, nerve; v, vein. (From Anderson BC, McLoon LK.
Cranial nerves and autonomic innervation in the orbit. In: Dartt DA,
editor. Encyclopedia of the eye. Oxford (United Kingdom): Academic Press; 2010. p. 539; with permission.)

187
 Treatment considerations for the oral and maxillofacial
surgeon
 Appropriate imaging should include CT scan with angiography and/or magnetic resonance angiography if a
carotid-cavernous sinus fistula is suspected. If a carotid-cavernous sinus fistula is diagnosed, prompt
embolization is recommended.36,37
 Obtain ophthalmologic consultation for patients with
associated globe injuries.
 Treatment modalities in the literature have been
controversial. There are advocates for high-dose steroid therapy and surgical decompression, as well as for
no intervention.36,38
 In the event of facial fractures requiring repair, open
reduction and internal fixation may generally be performed without fear of causing a worsening of associated cranial nerve palsies.30
 Early repair of orbital blow-in fractures had a favorable
outcome in subjects with associated superior orbital
fissure syndrome.31

Trotter syndrome
 Genetics
 Although Trotter syndrome itself has no genetic basis, it
is based on a constellation of clinical symptoms secondary to the uncontrolled growth of nasopharyngeal
carcinoma (NPC). There is, however, an identifiable
genetic pattern for NPC.
 NPC is a rare epithelial malignancy with only 25 to 30
cases per 100,000 person-years reported.39 It is most
commonly seen in Southeast Asia and the Mediterranean Basin.39 NPC is a multifactorial condition.
 Infection with Epstein-Barr virus has been associated
with NPC, after numerous studies demonstrated the
presence of its DNA in nasopharyngeal tumors.39,40
 Human leukocyte antigen (HLA), which are responsible
for presentation of viral antigens to the immune system,
are located within the major histocompatibility complex on chromosome 6p21.3.39 Furthermore, genomewide association studies of NPC have consistently
identified single nucleotide polymorphisms within the
HLA coding region, suggesting strong evidence for association between these mutations and NPC.39,41
 An association between diets high in preservatives
(salted fish, eggs, and vegetables) and NPC has also
been found.42
 Clinical features
 The syndrome was first described by Trotter in 1911 as a
neoplastic lesion deep to the lateral nasopharyngeal
wall.43 A classic triad of presenting symptoms (ie,
deafness, neuralgia along the mandibular division of the
trigeminal nerve, and soft palatal paralysis or immobility) was originally described (see Fig. 1).43 Symptoms
corresponded to the lateral and anterior spread of the
neoplasm submucosally and, in late stages, included
other symptoms.43,44
 The first symptom of decreased hearing or frank deafness
is due to involvement of the eustachian tube.44,45 As the
lesion progresses, involvement of the third division of
the trigeminal nerve leads to neuralgias of the side of the
head, ear, and lower jaw, as well as paresthesia of the
tongue.44,45 As the levator veli palatini muscle becomes

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Lui et al.

Fig. 6 Superior orbital fissure syndrome demonstrates ptosis, pupillary dilation, and ophthalmoplegia. (A) Right lid ptosis. (B) Radiograph showing a fracture (red arrows) causing compression of superior orbital fissure. (C) Right pupillary dilation. (DeF) Right
ophthalmoplegia. (From Turvey TA, Golden BA. Orbital Anatomy for the Surgeon. Oral Maxillofac Surg Clin North Am 2012;24(4):528; with
permission.)

affected, mobility of the ipsilateral soft palate becomes


compromised.44 Further progression to the ipsilateral
medial pterygoid muscle results in trismus and, in late
stages, cervical lymphadenopathy was noted.43,44
 The aforementioned symptoms, which mimic temporomandibular disorders, are associated with NPC.45
Because of these nonspecific symptoms, diagnosis is
often delayed for 6 to 9 months.45
 Differential diagnosis
 The differential diagnosis includes temporomandibular
joint disorders, myofascial pain disorder, sinusitis, trigeminal neuralgia, otitis media, and scleroderma.46
 Generally, CT and MRI are important in identification of
NPC. However, CT may fail to show the tumor at an
early stage. MRI with gadolinium-diethylenetriamine
pentaacetic acid (Gd-DTPA) should be used as a first
choice if NPC is suspected in its early stages.45
 Clinical features of Trotter syndrome may often produce a spurious diagnosis of temporomandibular joint
disorders. Because of this, Reiter and colleagues45
highlighted several distinguishing features to aid in the
early diagnosis of malignancy. These include continuous
ear symptoms (ie, decreased hearing, fullness, and
tinnitus), abnormal electromyogram patterns of the
soft palate, absence of degenerative changes of the
temporomandibular joint seen on imaging, and, in later
stages, severe hard-end limitation in mouth opening.
 Treatment considerations for the oral and maxillofacial
surgeon
 The treatment of NPC requires a multidisciplinary
approach involving a head and neck surgeon, radiation
and medical oncologist, and a dentist, as well as an oral
and maxillofacial surgeon.42
 NPC is typically treated with radiation therapy with
or without concurrent chemotherapy. Radiation is

administered to the nasopharynx and bilateral necks


reaching doses of 60 to 70 Gy in 35 to 40 fractions.42
For this reason, dental clearance before initiation of
radiation therapy is paramount in the prevention of
osteoradionecrosis of the jaw if postradiation oral surgery is anticipated. Concurrent combination chemotherapy may include cisplatin and 5-fluorouracil (5-FU),
or Taxol and 5-FU, to avoid late toxicity effects.42 Local
recurrence may be treated with brachytherapy or surgical intervention.42
 Surgical therapy is reserved for local recurrence with
regional involvement. Contraindications to surgery
include internal carotid involvement, erosion into skull
base, and intracranial involvement (Fig. 7).42,47
 Local recurrence may be treated by resection using
a variety of surgical approaches: Lateral rhinotomy
with medial hemimaxillectomy, endoscopic nasopharyngectomy, Weber-Ferguson incision with maxillary
swing approach, lateral infratemporal approach, and Le
Fort I down fracture.42
 Regional recurrence will require either a radical neck
dissection or a modified radical neck dissection with
removal of levels I through V nodes.42

Horner syndrome
 Genetics
 Because Horner syndrome is a sequela of an underlying
disease process, it is not associated with a specific
genetic trait or inheritance pattern.
 The most common identifiable cause of Horner syndrome is postganglionic lesions followed by preganglionic lesions, whereas the central lesions were the least
common.48

Syndromes Affecting the Central Nervous System

189

Fig. 7 (A) NPC with extension into mandibular division of trigeminal nerve in the masticator space (white arrow); Meckel cave and
sphenoid sinus (black arrows). (B) NPC extension into sphenoid sinus, cavernous sinus, and maxillary division of trigeminal nerve (black
arrows). (C) Encasement of internal carotid artery by NPC (black arrows). (From Moonis G, Cunnane MB, Emerick K, et al. Patterns of
perineural tumor spread in head and neck cancer. Magn Reson Imaging Clin N Am 2012;20:445; with permission.)

 Clinical features
 Horner syndrome or oculosympathoparesis is caused by
an interruption of sympathetic innervation along a
three-neuron pathway to the eye and its adnexa. It is
classically characterized as unilateral miosis, ptosis,
apparent enophthalmos, and anhidrosis of the affected
side (Fig. 8).49,50
 Ptosis is a result of interruption of the sympathetic
ller muscle, which accounts for
innervation of the Mu
approximately 2 mm of upper eyelid elevation. Miosis is
caused by unopposed parasympathetic innervation to
the iris constrictor muscle. The facial anhidrosis occurs
because of lack of sympathetic innervation to the sweat
glands of the face.51 The apparent enophthalmos is due

Fig. 8 A patient with Horner syndrome displaying right miosis,


ptosis, and apparent enophthalmos. (From Rempell JS, Harris NS,
Brown DF, et al. Left eye ptosis. J Emerg Med 2009;36(4):396; with
permission.)

to ptosis of the upper lid and slight elevation of the


lower eyelid, resulting in narrowing of the palpebral
fissure, which gives the impression of enophthalmos.52
 Knowledge of the anatomy of the sympathetic innervation involving Horner syndrome is necessary. First-order
neurons originate in the posterior lateral hypothalamus
and travel down the spinal cord to synapse with secondorder neurons between C8 and T2 at ciliospinal center of
Budge-Waller. These second-order neurons travel superiorly along the sympathetic chain passing through the
inferior and middle cervical ganglions and, eventually,
synapse with third-order neurons at the superior cervical ganglion. Postganglionic or third-order neurons from
the superior cervical ganglion continue to ascend along
the carotid artery nerve to innervate the sweat glands
of the face. In addition, these third-order neurons travel
along the ophthalmic division of the trigeminal to
innervate the lacrimal gland, the dilator muscle of the
ller muscle, and its analog in the lower eyelid
pupil, Mu
(Fig. 9).51,53
 Differential diagnosis
 Lesions can occur along course of the sympathetic innervations to the end organs that are involved in Horner
syndrome.
- Diseases associated with first-order neurons include
Arnold-Chiari malformation, syphilis, basal skull

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Lui et al.
underlying causes of Horner syndrome may be beyond
the scope of an oral and maxillofacial surgeon and may
warrant referral.

Frey syndrome

Fig. 9 Diagram displaying the anatomy of the oculosympathetic


pathway. AS, ansa subclavia; CCA, common carotid artery; ECA,
external carotid artery; FON, first-order neuron; ICA, internal carotid
artery; ICG, inferior cervical ganglion; MCG, middle cervical ganglion; SCG, superior cervical ganglion; SON, second-order neuron;
TON, third-order neuron. (From Reede DL, Garcon E, Smoker WR,
et al. Horners syndrome: clinical and radiographic evaluation.
Neuroimaging Clin N Am 2008;18(2):370; with permission.)

tumors, cerebrovascular accident, multiple sclerosis, intrapontine hemorrhage, neck trauma, pituitary tumor, and syringomyelia.54
- Diseases associated with second-order neurons
include Pancoast tumor; birth trauma with injury to
lower brachial plexus; aneurysm or dissection of
aorta; subclavian or common carotid artery; iatrogenic complications from surgical intervention such
as radical neck dissection, thyroidectomy, carotid
angiography, coronary artery bypass graft, chest tube
insertion, or central venous catheterization; Hodgkin
disease; leukemia; tuberculosis; mediastinal tumor;
odontogenic abscess; acute otitis media; neuroblastoma; and lumbar epidural anesthesia.54,55
- Diseases associated with third-order neurons include
internal carotid artery dissection, migraines, cluster
headaches, carotid artery thrombosis, carotidcavernous fistula, herpes zoster, orbital apex tumor,
or idiopathic conditions.54
 Treatment considerations for the oral and maxillofacial
surgeon
 The presence of Horner syndrome is a sign for a potential underlying disease. Treatment of the underlying
condition often resolves the symptoms. However, many

 Genetics
 There are no known inheritance patterns because Frey
syndrome is an acquired disease.
 Gustatory sweating is most commonly seen secondary
to parotid surgery; however, it also can occur after
radical neck dissection or blunt and penetrating trauma
to the region overlying the parotid gland.56,57 There is
no age or sex predilection.58
 The incidence of Frey syndrome after parotid surgery
varies with reports ranging from 2% to 80%.59 Interestingly, if tested using a Minors starch-iodine test, more
than 90% of patients after parotid surgery will exhibit
some evidence of Frey syndrome.60 Symptoms are
perceived in only about 25% to 50% of patients, and they
are severe enough to warrant treatment in only 6% to
15% of cases.60,61
 Frey syndrome usually has a latency of 6 to 18 months.
It can, however, occur in less than 6 months or more
than 36 months.58
 In the pediatric population, case reports of auriculotemporal syndrome following trauma after forceps
delivery have been published in the literature.62
 Clinical features
 The classic appearance of Frey syndrome is sweating,
flushing, and sensation of warmth in the preauricular
and temporal areas during mastication.59
 The Minor iodine-starch test can be used to delineate
the extent of the lesion. The test is administered by
applying an alcohol-iodine-oil solution to the affected
side of the face. The solution is allowed to dry and
lightly covered with starch powder. The patients are
then given a lemon candy for a gustatory stimulus for
10 minutes. Blue discoloration of the starch iodine
mixture is interpreted as a positive finding (Fig. 10).63e65
 The condition occurs from the severing of postganglionic parasympathetic cholinergic secretomotor
fibers from the otic ganglion. These fibers, which are
carried by the auriculotemporal nerve, become misdirected during axonal regeneration and feed the
sympathetic fibers to the sweat glands of the skin,
causing gustatory sweating. This phenomenon explains
the delay in appearance of clinical symptoms.56,66
 Differential diagnosis
 Food allergy can be misdiagnosed in cases with facial
flushing without hyperhidrosis, especially among the
pediatric population.67
 CNS tumors, although extremely rare, should be suspected in cases without evidence of localized trauma.68
 Treatment considerations for the oral and maxillofacial
surgeon
 Patients with Frey syndrome who have mild signs with
no symptoms can be observed. Those patients who
show symptoms and whose quality of life is affected
should be counseled. All risks and benefits should be
discussed before starting therapy.
 Medical therapy includes topical anticholinergics such
as atropine, glycopyrrolate, scopolamine hydrobromide,

Syndromes Affecting the Central Nervous System

191
shown to be an effective, safe, and minimally invasive
treatment with long-lasting effect.70
 Surgical treatment has been proposed, such as transection of the glossopharyngeal nerve, resection of
the auriculotemporal nerve, or tympanic neurectomy.
These modalities have variable success rates and are
not recommended.58

Ramsay-Hunt syndrome

Fig. 10 Positive result of the Minor iodine-starch test in a patient


with Frey syndrome, showing the area in dark blue due to gustatory
sweating in the affected parotid area. (From Malatskey S,
Rabinovich I, Fradis M, et al. Frey syndrome-delayed clinical onset:
a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2002;94(3):339; with permission.)

or antiperspirants containing aluminum chloride in


alcohol solution. These agents usually provide temporary relief, have poor compliance, and may possess
adverse side effects.56,69
 More recently, intracutaneous injections of botulinum
toxin A (BTX-A) into the affected area has been widely
accepted. BTX-A injections work by preventing the
release of the neurotransmitter acetylcholine at
cholinergic synapses. This treatment modality has been

 Genetics
 Ramsay Hunt syndrome (RHS) has an incidence of 5 per
100,000 per year. It is the second-most frequent cause
in nontraumatic peripheral facial palsy.71 The prevalence of RHS is more frequent in adults than in children
who have facial palsy.72
 In the pediatric population, the incidence is also higher
in older children than in children younger than 6-yearsold. Children are also found to have milder symptoms
and a better prognosis for complete recovery of facial
animation and hearing when compared with adults.
 Clinical features
 RHS occurs because of the reactivation of the varicellazoster virus in the geniculate ganglion, involving the
seventh cranial nerve.
 Clinically, it is characterized by acute peripheral
facial palsy with a painful herpetic eruption on the
ipsilateral auricle, external ear canal, anterior two-thirds of the tongue, or palate (Fig. 11).73,74 In addition to these classic symptoms, patients also
frequently have vestibulocochlear dysfunction due to
the close proximity of the eighth cranial nerve to
the geniculate ganglion.75 These patients frequently
reported tinnitus, hearing loss, nausea, vomiting,
vertigo, and nystagmus.76
 In addition to the classic presentation, other cranial
nerves, such the glossopharyngeal, trigeminal, vagus,
abducens, and hypoglossal, have also been known to be
involved.77,78

Fig. 11 (A) A patient with vesicular lesions of the auricle and external auditory meatus. (B) Facial nerve palsy resulting in both weakness
of the lips (white arrows) and loss of nasolabial folds (black arrows) on the right face with facial animation. (From Taguchi T, Ueda S,
Kudo T, et al. Ramsay-Hunt syndrome. J Infect 2011;62(2):181; with permission.)

192
 Differential diagnosis
 Many conditions can produce isolated facial nerve palsy
similar to RHS; however, they can frequently be ruled
out by a thorough history and physical. Those conditions
syninclude Bells Palsy, sarcoidosis, Guillain-Barre
drome, Lyme disease, otitis media, multiple sclerosis,
cerebrovascular accident, as well as peripheral lesions
causing compression of the facial nerve.79
 Treatment considerations for the oral and maxillofacial
surgeon
 Treatment with prednisone and acyclovir has proven to
be effective, especially if started early after onset of
facial paralysis.80 Early administration of therapy 3 days
after onset of facial paralysis showed a significantly
higher recovery when compared with patients whose
therapy was started 7 days or more after onset of facial
paralysis.81

Lui et al.
 Partial nerve degeneration was shown to be reduced
when early therapy was started with acyclovir-prednisone.82 Recovery from hearing loss was also shown to be
more successful when therapy was started earlier.

Melkersson-Rosenthal syndrome
 Genetics
 Melkersson-Rosenthal syndrome (MRS) is idiopathic.
However, evidence for an autosomal dominant inheritance pattern with a gene defect at chromosome 9p11,
which applied to patients with fissured tongue, has
been investigated.83
 Clinical and histologic features:
 MRS is an idiopathic granulomatous neuromucocutaneous disorder.84

Fig. 12 Patient with MRS displaying (A) left midfacial edema, (B) left facial nerve palsy, and (C) lingua plicata (fissured tongue). (From
Gerressen M, Ghassemi A, Stockbrink G, et al. Melkersson-Rosenthal syndrome: case report of a 30-year misdiagnosis. J Oral Maxillofac Surg
2005;63:1037; with permission.) (D) Photomicrograph ( 40) of an incisional biopsy taken from the labial mucosa of a patient with MRS,
exhibiting multiple focal, non-caseating granulomas. (Slide Courtesy of Dr Dean DeLuke.)

Syndromes Affecting the Central Nervous System


 The classic triad of symptoms include asymptomatic
orofacial edema (ie, lips, cheeks, chin, as well as the
buccal, lingual, gingival, or labial mucosal surfaces),
facial nerve palsy, and fissured tongue (Fig. 12).84,85
 It typically develops during the second decade of life;
however, early manifestations are possible at any
age.84 More than 30 cases of MRS have been reported
during childhood.84 It affects female patients three
times as often as male patients.84
 Patients may present with a monosymptomatic form or
an oligosymptomatic form. Cheilitis granulomatosa is a
monosymptomatic variant of MRS that affects young
adults and is characterized clinically by diffuse, nontender, soft-to-firm swelling of one or both lips. The
complete triad is present in only about 25% of patients.86
 Other associated symptoms include migraine-like
headaches, swelling of the oral mucosa and eyelids,
and dysgeusia or ageusia.84,85
 Histologically, this disorder displays noncaseating
epithelioid granulomatous inflammation, dermal edema
and mixed perivascular inflammation.85e87
 Differential diagnosis
 Diagnosis is largely based on presenting clinical findings
and corresponding histology.
 MRS is grouped into a spectrum of conditions with
similar clinical and pathologic features referred to as
orofacial granulomatosis.85
 Acutely, it may clinically appear to be angioedema.
Persistent orofacial swelling between attacks supports
the diagnosis.85
 The differential diagnoses include Crohns disease,
sarcoidosis, tuberculosis, Bells palsy, focal dental infection, foreign body reaction, and Ascher syndrome.85,88
 Treatment considerations for the oral and maxillofacial
surgeon
 There is no gold standard; treatment is primarily
symptomatic therapy.
 Nonsurgical management includes systemic and intralesional corticosteroid injection, which may provide
short-term relief.85 Anti-inflammatory agents such as
clofazimine, dapsone, sulfapyridine, danazol, and
hydroxychloroquine have also been investigated.85 A
novel treatment using infliximab, a recombinant humanized monoclonal TNF-alpha antibody, to treat patients with MRS has shown some promise.89
 Surgical management has been indicated for persistent
orofacial edema and facial nerve palsy refractory to
nonsurgical management. Wedge resection has been
used for diffuse upper and lower lip edema with zplasty for focal lip defects.90 Full-thickness resection of
skin and subcutaneous tissues of upper or lower eyelids
has been reported.90 Cheiloplasty and facial liposuction
have also been effective in improving facial esthetics.91
For persistent facial palsy, procedures such as static
and dynamic reanimation, cross-face nerve grafts, and
free muscle transfer have been advocated.90

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Chromosomal Syndromes
Rita Shiang, PhD
KEYWORDS
 Down syndrome  Trisomy 21  Klinefelter syndrome  Turner syndrome  Aneuploidy  Sex chromosomes
KEY POINTS
 Chromosomal aneuploidies are caused by nondisjunction of chromosomes in meiosis or mitosis.
 Down syndrome is caused by trisomy of chromosome 21.
 Klinefelter and Turner syndromes are sex chromosome aneuploidies, with an extra X chromosome in the former and a
missing X in the latter.
 Mosaicism is found in Down syndrome, Klinefelter syndrome, and Turner syndrome.
 The risk of Down syndrome and Klinefelter syndrome increases with maternal age, but this phenomenon is not observed for
Turner syndrome.
 The main features of Down syndrome are cognitive impairment, hypotonia, and characteristic facial features.
 The 2 main features of Klinefelter syndrome are hypergonadotropic hypogonadism and small testicular volume, although
most individuals with Klinefelter syndrome remain undiagnosed.
 The 2 main features of Turner syndrome are growth retardation, resulting in short stature throughout life, and infertility in
later years.

Down syndrome
Genetics
Down syndrome is the most frequently observed chromosomal
aneuploidy caused by trisomy 21 or partial trisomy 21.1,2 Most
(90%e95%) cases are caused by de novo chromosomal nondisjunction. About 2% to 6% of cases are caused by translocations
of 2 chromosome 21s or a Robertsonian translocation of chromosome 21 fused to another acrocentric chromosome. Another
2% to 3% of cases are mosaic for trisomy 21. The prevalence of
this disorder is 1/700 live births, but the risk of having a child
with Down syndrome greatly increases with the age of the
mother. The risk is 1/1000 at age 30 years and increases to 9/
1000 at age 40 years.3,4

Clinical features
The main features of Down syndrome include cognitive
impairment, hypotonia, and characteristic facial features. The
IQ of individuals with trisomy 21 is highly variable, and most
individuals fall between the moderate to severe range.5,6 IQ is
not stable and decreases with age.7 Specific cognitive weaknesses have been identified in expressive language, syntactic/
morphosyntactic processing, and verbal working memory.8
Craniofacial features include brachycephaly, midface hypoplasia, flat or depressed nasal bridge, micrognathia, and epicanthic folds (Fig. 1). In addition, there are outer (dysmorphic
Disclosures: No disclosures or conflicts of interests to report.
Department of Human and Molecular Genetics, Virginia Commonwealth University, PO Box 980033, Richmond, VA 23298-0033, USA
E-mail address: rshiang@vcu.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 197203
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.003

outer ear and stenosis of the external ear canal), middle


(malformation of the eustachian tube), and inner ear anomalies, which can result in hearing loss and cholesteatoma.9
Dental issues include variable tooth morphogenesis and eruption and a greater prevalence and severity of periodontal disease, but lower incidence of caries.10,11 Changes in the oral
cavity include macroglossia and a protruding furrowed tongue
as well as narrow palate, pharynx, and oropharynx. Many of
these craniofacial issues can lead to sleep apnea, and because
of a decrease of immune function in individuals with Down
syndrome, these can also lead to chronic infections.9 Congenital heart defects are not present in all individuals but
contribute greatly to mortality. These anomalies include
atrioventricular canal defect, tetralogy of Fallot, and patent
ductus arteriosus but particularly atrioventricular septal defects. There are many confounding issues with individuals with
trisomy 21. There is a greater risk for leukemia, both acute
lymphoblastic leukemia and acute myelogenous leukemia.12
Approximately 45% of individuals with Down syndrome age 45
years or older develop Alzheimer-related dementia.13,14 Individuals with trisomy 21 also have an increased risk of atlantoaxial instability (Fig. 2).15,16 The phenotype can be variable
in individuals with mosaic Down syndrome.17 The average life
expectancy is 49 years in the white population, although there
is racial disparity.18,19

Differential diagnosis
Trisomy 18 is an aneuploidy that manifests in severe cognitive
delay and heart problems but may also have problems in the
digestive, reproductive, and urologic systems. The disorder is
often fatal in infancy or early childhood. Males with more than
1 X chromosome also have cognitive delay, distinct facies, and
skeletal problems. Individuals with isolated hypotonia have no

oralmaxsurgeryatlas.theclinics.com

198

Shiang
associated with cervical instability, with the need for surgical
intervention. To prevent any additional problems, radiologic
evaluation of the cervical spine should be performed before
any procedures requiring anesthesia. The neck should be
maintained in a neutral position to prevent any extreme
flexion, extension, or rotation.9,15,16 Tracheal stenosis can be
more common in children with Down syndrome, which can lead
to complications in anesthesia during surgery, such as complicated intubation or greater airway narrowing after intubation
or bronchoscopy.9 Comprehensive assessment, including cardiac assessment, should be performed before surgery. Residual
cardiac defects such as conduction disturbances and atrial
rhythm anomalies can persist throughout the life of the individual, even after successful cardiac repair.20 Complications
such as recurrent infections and a higher incidence of pulmonary hypertension, which contribute to increased mortality and
morbidity, can also arise.20

Fig. 1 A young child with Down syndrome showing midface hypoplasia, flat or depressed nasal bridge, and epicanthic folds.

other distinctive features and have a normal chromosomal


complement. Zellweger syndrome, a disease of peroxisome,
also presents with hypotonia, cardiac defects, flat occiput and
face, epicanthal folds, and palmer crease, similar to Down
syndrome. Differential diagnosis can be made because individuals also present with congenital cataracts, hepatomegaly, contractures, and increased levels of iron and long-chain
fatty acids. They also have a normal chromosomal complement. Autism manifests in general development delay in
early childhood. A diagnosis of Down syndrome can be made
using karyotype analysis or array comparative genomic
hybridization.

Klinefelter syndrome
Genetics
Klinefelter syndrome is the most common sex chromosome
aneuploidy in males and is caused by having 1 extra X chromosome (47,XXY) (89.9%). Additional X chromosomes can also
be present (48,XXXY [1.1%]; 49,XXXXY [1.8%]), and mosaicism
can also exist (46,XY/47,XXY [6.6%]; 47,XXY/48,XXXY [0.2%]).
The prevalence was 1 in 660 men in a Danish population.21 The
risk increases with maternal age. The disorder is sporadic and
usually caused by meiotic or mitotic nondisjunction in germ
cells or in the fetus, respectively.

Clinical features
Treatment considerations for the oral and
maxillofacial surgeon
Atlantoaxial instability affects between 10% and 30% of individuals with Down syndrome, only 1.5% of whom need surgical intervention. Os odontoideum has been specifically

The 2 main features found in individuals with Klinefelter syndrome are hypergonadotropic hypogonadism with adults presenting with a high ratio of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) levels when compared with
their testosterone levels and small testicular volume.22 Tall

Fig. 2 A 10-year-old girl noted to have C1-C2 instability on routine screening. (A) Flexion and (B) extension radiographs showing 7 mm of
motion. (From Dimar JR, Carreon LY. Spine deformity in Down syndrome. Spine Deform 2012;(Preview Issue):78; with permission.)

Chromosomal Syndromes
stature was believed to be a hallmark of the disorder, and
growth in childhood and adolescence is accelerated, but mean
adult height of affected men is 184.7 cm, which is not greatly
different from the mean adult height of unaffected men
(182.6 cm) in Denmark.22 Cryptorchidism (14%), gynecomastia
(44%), and behavioral and learning problems (36%) are also
observed, but not in all individuals.22 Verbal processing seems
to be specifically affected.23,24 Other variable features include
eunuchoid body habitus, long arms and legs, sparse body hair,
and mandibular prognathism (Fig. 3).25 This variable phenotype
is seen in Fig. 4, which shows an atypical phenotypic presentation.26 Individuals with Klinefelter syndrome are also at
increased risk for metabolic syndrome, osteopenia/osteoporosis, breast cancer, autoimmune disorders, and mortality.26e29 Individuals with more X chromosomes seem to have a
more severe phenotype, including additional congenital malformations and greater cognitive involvement.30
Klinefelter syndrome is the most common chromosomal
abnormality in azoospermic infertile men.31 Testicular histology through childhood remains normal but with fewer germ
cells (Fig. 5).22 By adulthood, there are few seminiferous tubules, with spermatogenesis and hyperplasia of Leydig cells.
Undifferentiated and differentiated Sertoli cells can be
observed.22
Most individuals with Klinefelter syndrome are undiagnosed.
Only 10% of the expected numbers are diagnosed before puberty and 25% in adults, mainly because of infertility or
hypogonadism.21 The major reasons for diagnosis of Kleinfelter
syndrome are maternal age prenatally, developmental delay
before puberty (<11 years old), and small testes in individuals
between 11 and 19 years old.30,32
Selective early initiation of testosterone supplementation
has been shown to restore the sex dimorphic changes in fat
deposition through puberty33 and may also prevent the

199

Fig. 4 An atypical phenotype in an individual with Klinefelter


syndrome. This individual presented with relatively large muscle
mass, normal masculine body hair distribution, beard, and baldness, but also the typical abdominal obesity. He was diagnosed at
the age of 35 years, because of infertility. Height 181 cm, weight
94 kg, karyotype 47,XXY. (From Bojesen A, Hst C, Gravholt CH.
Klinefelters syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod
2010;16:397; with permission.)

development and persistence of gynecomastia. Thus, early


diagnosis would be helpful for early intervention with testosterone, although sperm retrieval is most successful at the
onset of puberty and before testosterone therapy.34

Differential diagnosis
Individuals with fragile X syndrome also present with intellectual disability and social anxiety, but their physical characteristics include an elongated face, large protruding ears, and
macroorchidism. Kallmann syndrome also presents with hypogonadism but is accompanied by a reduced sense of smell.
Kallmann syndrome and isolated hypogonadotropic hypogonadism are characterized by low levels of circulating sex
hormones. Marfan syndrome also presents with increased
height and long limbs but no hypogonadism. Klinefelter syndrome can be distinguished from these other disorders through
chromosomal analysis.
Fig. 3 Profile of a man with Klinefelter syndrome, showing
mandibular prognathism. The arrow points to the parotid region,
and in this rare case, parotid gland agenesis was observed. (From
Yilmaz YF, Titiz A, Yurur-Kutlay N, et al. Congenital bilateral parotid gland agenesis in Klinefelter syndrome. J Craniomaxillofac
Surg 2010;38:249; with permission.)

Treatment considerations for the oral and


maxillofacial surgeon
Because of the greater prevalence of certain systemic diseases, as noted earlier, appropriate medical evaluation is
important before anesthesia and surgery. Individuals with

200

Shiang

Fig. 5 Comparisons of micrographs of testicular specimens from individuals with Klinefelter syndrome at various ages. (Left) Individuals
with normal testicular function and (right) affected individuals. Testicular architecture of specimens from unaffected and affected individuals is similar from fetal life until puberty, except that the number of germ cells is severely reduced in the prepubertal Klinefelter
syndrome sample. During puberty, gross morphologic changes appear. Normally, spermatogenesis is initiated, but the seminiferous tubules
in the affected individual show widespread degeneration and hyalinization. In an adult individual with Klinefelter syndrome, few
degenerated tubules may contain germ cells, but most of the testicular tissue is composed of clumps of Leydig cells. Arrows indicate
gonocytes. Bars represent 100 mm. GW, gestational week. (From Aksglaede L, Skakkebaek NE, Almstrup K, et al. Clinical and biological
parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr
2011;100:799; with permission.)

Klinefelter syndrome also manifest with an increase of taurodontism and caries when compared with a control population.35,36 Shovel-shaped incisors have also been reported in
patients with Klinefelter syndrome.

2000 females in a Danish population.37 Turner syndrome occurs


sporadically, and nondisjunction in this case is mainly paternal.
There is no association with increased maternal age.

Turner syndrome

The 2 main features of Turner syndrome are growth retardation, resulting in short stature throughout life, and infertility in
later years.38 Growth failure begins prenatally and is observed
by 3 years of age. On average, adult height is 20 cm less than
typical height (Fig. 6).39e41 Although individuals with Turner
syndrome are not deficient in growth hormone, treatment with
growth hormone allows greater height attainment. It remains
to be determined if earlier growth hormone therapy increases
final height attainment.38 Infertility is caused by ovarian failure, the onset of which is variable but which can begin prenatally. A third of girls have onset of pubertal development,
but a smaller percentage have spontaneous menarche (16%).42
Most go on to show ovarian failure, although spontaneous

Genetics
Turner syndrome is mainly characterized by missing 1 or portions of an X chromosome in females. Many are missing an
entire X chromosome (45,X) (45%), and 15% are mosaic of 45,X/
46,XX. Individuals with Xq isochromosomes or mosaics of Xq
isochromosomes make up 11% of the population. The rest have
many different variants, including deletions and translocations
of the X chromosome, Xp isochromosomes, various combinations of mosaicism, and even karyotypes with Y chromosome
material. The prevalence of Turner syndrome was about 1 in

Clinical features

Chromosomal Syndromes

Fig. 6 Mean height including 2 standard deviations plotted


against age of females with Turner syndrome (dark lines) from 5
European cohorts. Mean heights can be compared with unaffected
females (light lines). The data were compiled using 5 cohorts, 4 of
which included individuals not treated with hormone therapy and
one included individuals treated with estrogen but not androgen.
(From Lyons AJ, Preece MA, Grant DB. Growth curve for girls with
Turner syndrome. Arch Dis Child 1985;60:933; with permission.)

pregnancy does occur in 2% to 5% of individuals who develop


spontaneous menarche.42,43 Individuals with Turner syndrome
do have estrogen deficiency and higher levels of LH and FSH
starting at puberty and continuing in adulthood. Most girls need
to be treated with hormone replacement therapy (HRT) to
induce puberty. HRT does not seem to affect final outcomes
with growth hormone therapy. Other features of Turner syndrome include congenital lymphedema, broad chest with
widely spaced nipples, anomalous auricles, low posterior hair

201
line, appearance of webbed neck, cubitus valgus, excessive
pigmented nevi, and horseshoe kidney, which occur with
varying frequency (Fig. 7).44
Heart anomalies are found in 50% of individuals with Turner
syndrome and are the main contributor to an increase in
mortality.45 Congenital structural abnormalities of the heart
include coarctation of the aorta (COA), bicuspid aortic valve
(BAV), and partial anomalous pulmonary venous return. The
presence of webbing of the neck, which indicates lymphedema, is significantly associated with BAV and COA.46,47 Aortic
dissection can develop in adults with Turner syndrome and is
found in 0.6% to 1.4% of individuals, which is a higher incidence
than found in the general population.48 Hypertension affects
up to 25% of adolescents and 50% of adults. It is mostly systolic
and is often nocturnal.49
Other morbidities associated with Turner syndrome include
increased rates of diabetes, metabolic syndrome, inflammatory
bowel disease, hypothyroidism, and celiac disease. These metabolic and autoimmune issues may be caused by a different body
composition in adult women. They weigh more and have greater
fat body mass and less lean body mass than women in the general
population.41 Scoliosis and kyphosis are identified in 10% to 20% of
girls with Turner syndrome. Also, decreased bone mineral density
is observed, which results in an increase in fractures, although
more fractures are also observed before puberty.50,51 HRT can
increase bone mineral density in adults.52,53
The standardized mortality is increased for all individuals
with Turner syndrome and is 4.08 for individuals with 45,X;
overall mortality is 2.86.37 Mortality is mainly caused by disorders associated with endocrine, nutritional, and metabolic
disorders, most likely associated with increased diabetes,
congenital anomalies, coronary disease, and cancer.37

Differential diagnosis
Noonan syndrome shares many features of Turner syndrome,
including short stature, webbed neck, and congenital heart
disease. Individuals with Noonan syndrome also present with
unusual facies, including hypertelorism and downward slanting
eyes, but have normal karyotypes.

Fig. 7 A young woman with Turner syndrome, showing excessive pigmented nevi, micrognathia, and prominent ears (left, profile) as well
as a wide short neck (right, frontal view). (From Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod
Dentofacial Orthop 2001;120:316; with permission.)

202

Treatment considerations for the oral and


maxillofacial surgeon
Individuals with Turner syndrome can have micrognathia (60%)
and a high arched palate (35%) (see Fig. 7).38,54 These issues,
along with a wide and short neck, and athrogryposis of the
temporomandibular joint in some individuals, can complicate
tracheal intubation (see Fig. 7). The short trachea along with
high bifurcation can also lead to endobronchial intubation and
inadvertent endotracheal extubation when the endotracheal
tube is under traction. The high incidence of cardiovascular
problems indicates preoperative echocardiogram and stress
tests. Coarctatation of the aorta mandates strict control of
blood pressure. Any metabolic presentations, such as diabetes,
also need to be managed during surgery.55,56

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nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta
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50. Gravholt CH, Juul S, Naeraa RW, et al. Morbidity in Turner syndrome. J Clin Epidemiol 1998;51:147e58.
51. Gravholt CH, Vestergaard P, Hermann AP, et al. Increased fracture
rates in Turners syndrome: a nationwide questionnaire survey.
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Anestesiol 2008;58:84e9 [in Portuguese].

Syndromes with Unusual Facies


Alia Koch, DDS, MD a,b,*, Sidney Eisig, DDS a,b
KEYWORDS
 Syndrome  Facies  Malformations  Development  Prader-Willi syndrome  Cornelia de Lange syndrome
 Fetal alcohol syndrome  Whistling face syndrome  Noonan syndrome

Cornelia de Lange syndrome

Key points
 Syndrome is a clinical diagnosis.
 Many craniofacial abnormalities include synophrys, long
philtrum, and cleft palate.
 Limb malformations are seen in these patients, along
with toe fusion.
 Developmental delay is common.

Genetics
Multiple genes have been associated with this syndrome,
including nipped-B-like protein (NIPBL) on chromosome 5,
SMC1A, SMC3, and HDAC8 on the X chromosome. Most of these
cases are secondary to spontaneous genetic mutations.

Clinical features
Cornelia de Lange syndrome is a clinical diagnosis, based on
signs and symptoms. Certain features are noted, including low
birth weight, developmental delay, small stature, microcephaly, low hairline with synophrys, flat nasal bridge, long
philtrum, low-set ears, widely spaced teeth, cleft palate, limb
differences, excessive body hair, and partial fusion of the second and third toes. Children often have long eyelashes (Fig. 1).
Cardiac abnormalities may also be present at birth.
Gastrointestinal difficulties, including vomiting, diarrhea, and
constipation, are common.
Behavior issues may play a role in children as well, including
self-injury and aggression. Patients may display behaviors
similar to autism.

The authors have nothing to disclose.


Hospital Dentistry, Oral and Maxillofacial Surgery, Columbia
University College of Dental Medicine, New York, NY, USA
b
Hospital Dental Service, New York-Presbyterian/Columbia University Medical Center, 180 Fort Washington Avenue, New York, NY 10032,
USA
* Corresponding author.
E-mail address: ak2045@columbia.edu
a

Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 205210


1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.004

Differential diagnosis
Whistling face syndrome
Fetal alcohol syndrome

Treatment considerations for Oral and Maxillofacial


Surgeons
A thorough physical examination is important at birth to look
for craniofacial abnormalities associated with this syndrome. A
cleft palate, if present, should be noted, in order to plan for
correction before speech development.
Because of the multisystem involvement of this syndrome,
including congenital cardiac defects, it is important to consult
the patients primary care physician before any procedure with
or without conscious sedation.

Prader-Willi syndrome
Key points
 Most patients inherit disease from paternal chromosome 15.
 Patients have severe hypotonia and feeding difficulties
in infancy.
 Patients develop morbid obesity and diabetes.
 Patients have hypogonadism with incomplete pubertal
development.
 These patients show learning disabilities and behavioral
problems.

Genetics
Prader-Willi syndrome is sporadically inherited from deletion or impaired expression of chromosome 15, specifically
15q11-13. Diagnosis is confirmed using DNA methylation or
fluorescent in situ hybridization analysis. The incidence
ranges from 1 in 10,000 to 1 in 20,000. There is equal distribution in male and female patients, as well as along
differing ethnicities. In 70% of the cases, the abnormal gene
is from a paternal inheritance; however, uniparental
maternal disomy can lead to Prader-Willi syndrome in 25% of
cases, with purely abnormal gene expression comprising 1% to
5% of the cases.

oralmaxsurgeryatlas.theclinics.com

206

Koch & Eisig


obsessive-compulsive disorder (OCD) and oppositional behavior
possibly secondary to hypothalamic dysregulation. Skin picking
is a common manifestation of OCD. Patients with Prader-Willi
have several dysmorphic features, including almond-shaped
eyes; dolichocephaly; and small mouth, hands, and feet. The
characteristic facial features may not be apparent at birth, but
develop over time. Prosodic speech is common, secondary to a
speech articulation defect. In addition, these patients show a
global motor delay, as well as learning disabilities caused by a
low intelligence quotient (Fig. 2).
Differential diagnosis
Craniopharyngioma
Central nervous system depression
Neonatal sepsis
Myopathy
Fragile X syndrome

Treatment considerations for Oral and Maxillofacial


Surgeons
These patients have numerous abnormalities, and are best
served with a multidisciplinary approach. In oral and maxillofacial surgery, the patients are high risk when considering
in-office surgical procedures and intravenous sedation. In
addition to the behavior management skills required, attention
needs to be directed toward airway management in these patients. Many are obese and produce a thick viscous saliva.

Fig. 1 (A, B) Facial appearance in Cornelia de Lange syndrome in


this young boy. Note synophrys with a low hairline along with
craniofacial anomalies including a flat nasal bridge and a long
philtrum. (From Minor A, Marwan S, Hogue JS, et al. Two novel
RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case. Gene
2014;537:2; with permission.)

Clinical features
These patients typically show central infantile hypotonia with
a poor suck at birth. The hypotonia is universal and can also
lead to lethargy, a weak cry, and decreased movement. This
condition leads to infant feeding difficulty, which causes an
extreme drive to eat. Patients typically display morbid obesity,
with short stature. The inability to feel satiated is secondary to
hypothalamic abnormalities and causes patients to display
food-seeking behavior, hoarding food, and eating of inedible
objects. These patients develop sleep apnea and diabetes. It
is common to see psychological disturbances, including

Fig. 2 This boy with Prader-Willi syndrome is obese, as is common


in the disease process. Also note his small stature, small hands, and
small feet. His eyes also have the characteristic almond shape. (From
Jorde LB, Carey JC, Bamshad MJ, et al. Medical genetics. 3rd edition.
Philadelphia: Mosby, An Imprint of Elsevier; 2003. p. 78.4.20.)

Syndromes with Unusual Facies

207

Patients with Prader-Willi can also show apneic episodes and


are hypotonic. A sleep study may be indicated in patients with
Prader-Willi. These concerns need to be addressed before
conscious sedation, and consideration of an operating room
setting is advisable. Early use of growth hormone replacement
in these patients can prevent the development of the facial
dysmorphic features.

Fetal alcohol syndrome


Key points
 Syndrome associated with alcohol intake during
pregnancy.
 Variability associated with timing of alcohol ingestion,
amount consumed, and duration of use.
 Craniofacial abnormalities include smooth philtrum and
thin vermilion.

Genetics
Alcohol passes the placental barrier, causing damage to the
developing central nervous system primarily but also causes
changes in the facial form, learning disabilities, functional
disabilities, and behavioral problems. At present, the pattern
develops in the offspring of expectant women who consume
large quantities of alcohol. The prevalence of fetal alcohol
syndrome is 2 per 1000 live births. The variability of expression
is thought to be related to the timing of alcohol ingestion
relative to fetal development, the amount consumed, and the
duration of alcohol use during pregnancy. Alcohol interferes
with neural migration in the first trimester and damage to the
hippocampus in the third trimester.

Clinical features
Fetal alcohol syndrome affects numerous systems. These patients frequently have growth deficiency, in which height and
weight are measured to be less than the tenth percentile.
There are 3 distinctive facial characteristics that must be
present to diagnose this syndrome: smooth philtrum, thin
vermilion, small palpebral fissures. Having all three changes
indicates abnormal brain development, although brain damage
may be present without these signs.
Alcohol can severely affect the central nervous system.
Changes include microcephaly and structural changes in the
brain. Neurologic symptoms include epilepsy, seizures, poor
gait, neurosensory hearing loss, and impaired fine motor skills.
Functional changes such as learning disabilities, poor academic
achievement, poor memory, inattention, and low performance
in an academic setting are all seen in this disease. Other
craniofacial changes include epicanthal folds, poor nasal
bridge support, and a short, upturned nose.
Cardiac and renal systems can be affected as well. Atrial
septal defects are rare, but have been seen. Hypoplastic,
dysplastic, and aplastic kidneys have also been described.
A multiteam approach is necessary to diagnose this syndrome. The following criteria are necessary to have a diagnosis
of fetal alcohol syndrome: growth deficiency, all three facial
features noted earlier, clinically significant central nervous
system damage, and a history of prenatal alcohol use (Fig. 3).

Fig. 3 This young girl was born with fetal alcohol syndrome. She
has a thin upper lip, with a smooth philtrum. She also has small
palpebral fissures. (From Turnpenny PD, Ellard S. Emerys elements of medical genetics. 14th edition. Philadelphia: Churchill
Livingstone; 2011. Fig. 16.6; with permission.)

Differential diagnosis
Noonan syndrome
Williams syndrome
Aarskog syndrome

Treatment considerations for Oral and Maxillofacial


Surgeons
When an infant is born and concern for fetal alcohol syndrome
exists, a full physical examination is necessary to evaluate the
changes in the facial stigmata. Furthermore, a close examination is necessary to rule out diagnosis of a cleft lip and/or
palate. These patients need a multidisciplinary approach, and
referral to a craniofacial team to evaluate and treat the syndrome is appropriate. Throughout life, the patients facial
stigmata should be evaluated for possible orthognathic surgery.
In an office setting, concerns for surgical procedures and
conscious sedation need to be discussed with patients primary
care physicians and specialists. Primary concerns include
metabolism of medications through the liver and the renal
system. Appropriate dosing in these patients should be done in
accordance with blood tests evaluating renal and liver
function.

Whistling face syndrome

Key points
 Genetic disorder with recessive and dominant inheritance patterns.
 Patients show craniofacial and orthopedic changes.
 Syndrome defined as congenital myopathy.

208

Genetics
This syndrome is either autosomal dominant or autosomal
recessive, based on the type of expression of disease. The
phenotypic changes seen in this syndrome are caused by mutations in the embryonic myosin heavy chain (MYH3). There is
no sex or ethnic predilection. This disease has very few data,
because only 65 patients have been reported in literature.

Clinical features
This syndrome is considered a myopathy. There are several
clinical features associated with whistling face syndrome.
Patients have drooping upper eyelids, low-set ears, a long
philtrum, strabismus, and difficulty walking. Patients show

Koch & Eisig


microstomia, puckered lips, small tongue, a soft palate with
limited movement, and dimpling over the chin in a Y or H
shape.
Other associated craniofacial changes include small nose;
micrognathia; choanal atresia; hearing loss; flat midface; and a
masklike, rigid face. A webbed neck is common as well.
Patients have difficulty swallowing secondary to the mouth
deformities.
Multiple congenital joint contractures are defined as part of
the syndrome, showing a type 2A distal arthrogryposis with
ulnar deviation of the fingers. Patients show camptodactyly, as
well. Bilateral talipes equinovarus and kyphoscoliosis are
commonly seen.
Gastroesophageal reflux is common in infancy (Fig. 4).
Diagnosis is made when at least 2 of the major clinical
manifestations of distal arthrogryposis are found with

Fig. 4 (A) Whistling face syndrome: note the low-set ears and the neck contractures. (B) A patient with arthrogryposis of the hand with
contractures as seen in whistling face syndrome. (C) Patients with whistling face syndrome show an abnormally crowded dentition. (D)
Numerous signs of whistling face syndrome. Note the webbed neck, low-set ears, microstomia, downslanting eyes, and mask facies.
(Courtesy of D. DeLuke, DDS, MBA, Richmond, VA.)

Syndromes with Unusual Facies


craniofacial changes. Prenatal diagnosis can be made by ultrasonography at 20 weeks and by genetic testing.
Differential diagnosis
Arthrogryposis
Cornelia de Lange syndrome
Trisomy 18

Treatment considerations for Oral and Maxillofacial


Surgeons
Early intervention is necessary in this disease in order to
minimize the effect of the myopathy on growth and development. Because muscle physiology is abnormal, endotracheal
intubations and intravenous line placement can be difficult. It
is prudent to conduct awake fiberoptic intubations in patients
with the syndrome. These patients are at risk for developing
malignant hyperthermia.
After surgery, patients are at risk for respiratory failure
secondary to myopathy and skeletal changes.
Tracheostomy should be considered for those patients with
severe narrowing of the upper airway.

Noonan syndrome

Key points
 Autosomal dominant inheritance with mutation in the
RAS mitogen-activated protein kinase pathway.
 Clinical examination for characteristic changes is
necessary for diagnosis.
 Patients with disease are high risk for congenital cardiac disease.
 This syndrome affects multiple physiologic systems,
including renal, cardiac, hematologic, and endocrine.

209

Genetics
Noonan syndrome has an autosomal dominant inheritance
pattern with an incidence of 1 in 1000 to 1 in 2500. Male and
female incidence is equal. Genetics of the disease are not well
understood, although the genes of the RAS mitogen-activated
protein kinase (MAPK) pathway have been found to cause
Noonan syndrome. More specifically, mutations in the protein
tyrosine phosphatase nonreceptor type 11 gene are now
identified. There have also been numerous other genes identified; however, the diagnosis still relies on a clinical
examination.

Clinical features
A clinical examination is essential for the diagnosis of Noonan
syndrome.
After birth, these patients show early feeding difficulties,
webbed neck, low posterior hairline, ptosis, hypertelorism,
low-set posteriorly rotated ears, and downslanting palpebral
fissures (Fig. 5). Learning disabilities are a concern for these
patients as well.
There are several different systems affected by the disease.
A solitary kidney, duplicate collecting system, and renal
pelvis dilatation are common findings in the renal system in
approximately 10% of the Noonan syndrome population. Eighty
percent of male patients have cryptorchidism. Male patients
also have delayed puberty and infertility, secondary to Leydig
and Sertoli cell dysfunction.
On hematology, these patients typically have thrombocytopenia, coagulation factor deficiencies, and platelet
dysfunction. Factor 11 deficiency is the most common.
Short stature is common, affecting from 50% to 70% of individuals. The cause is not clear. Growth hormone therapy has
been shown to be effective.
These patients have associated cardiac defects, including
pulmonary valve stenosis, and are at increased risk of developing hypertrophic cardiomyopathy. Echocardiography is

Fig. 5 Young boy with Noonan syndrome. The patient has hypertelorism with downslanting palpebral fissures. His ears are posteriorly
rotated and low set. (From Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin
Endocrinol Metab 2011;25(1):161e79; with permission.)

210
essential to monitor heart function and cardiac wall thickness
before any treatment or surgeries.
The RAS-MAPK pathway is associated with oncogenesis and,
as such, patients with Noonan syndrome are at higher risk
for leukemia and solid tumors compared with the general
population.
Differential diagnosis
Turner syndrome
Williams syndrome
Aarskog syndrome

Treatment considerations for Oral and Maxillofacial


Surgeons
Noonan syndrome is a multisystem disease, thus requiring
appropriate management in all its aspects.
The diagnosis and management of hematologic disorders is
important in any surgical procedures, and appropriate laboratory tests should be ordered to prevent any complications
after surgery. Appropriate laboratory tests include a complete
blood count with platelet count, prothrombin time and International Normalized Ratio, and activated partial thromboplastin time.
Patients with Noonan syndrome have numerous congenital
cardiac malformations and, secondary to the use of growth
hormone, may also have developed ventricular wall thickening.
In the management of these patients in the oral and maxillofacial surgery office, it is of great importance to discuss with
the patients cardiologist any future surgical procedures that
may or may not include conscious sedation.
Renal function should be assessed and medications appropriately dosed. Besides medications, any intravenous fluid
therapy for patients undergoing conscious sedation needs to be
appropriately dosed based on kidney function.

Koch & Eisig


In addition, because these patients have numerous cardiac
and renal anomalies, it is important to review the antibiotic
premedication guidelines to ensure that premedication is
dosed appropriately when deemed necessary.

Further readings
Astley SJ, Clarren SK. A case definition and photographic screening tool
for the facial phenotype of fetal alcohol syndrome. J Pediatr 1996;
129:33e41.
Benarroch F, Hirsch HJ, Genstil L, et al. Prader-Willi syndrome: medical
prevention and behavioral challenges. Child Adolesc Psychiatr Clin
N Am 2007;16:695e708.
CdLS Foundation Website. Cornelia de Lange syndrome Foundation.
Chacko E, Graber E, Regelmann MO, et al. Update on Turner and Noonan
syndromes. Endocrinol Metab Clin North Am 2012;41:713e34.
Chen H. Freeman-Sheldon Syndrome. In: Chen H, editor. Atlas of genetic diagnosis and counseling. US: Springer; 2012. p. 883e9.
Church MW, Abel EL. Fetal alcohol syndrome hearing, speech, language, and vestibular disorders. Obstet Gynecol Clin North Am
1998;25:85e97.
Clarren S, Alvord EC Jr, Sumi SM, et al. Brain malformations related to
prenatal exposure to ethanol. J Pediatr 1978;92:64e7.
Coles C, Brown RT, Smith IE, et al. Effects of prenatal alcohol exposure
at school age. Neurotoxicol Teratol 1991;13:357e67.
Driscoll D, Miller J, Schwartz S, et al. Prader-Willi syndrome. NCBI
Bookshelf; 2012.
Institute of Medicine, Stratton K, Howe C, Battaglia F, et al. Fetal
alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. National Academy Press.
Landgraf M, Nothacker M, Kopp IB, et al. The diagnosis of fetal alcohol
syndrome. Dtsch Arztebl Int 2013;42:703e10.
Nargozian C. The difficult airway in the pediatric patient with craniofacial anomaly. Anesthesiol Clin North America 1998;16:839e52.
Streissguth A, Aase JM, Clarren SK, et al. Fetal alcohol syndrome in
adolescents and adults. JAMA 1991;265:1961e7.
Toriello H. Role of the dysmorphologic evaluation in the child with
developmental delay. Pediatr Clin North Am 2008;55:1085e98.

Syndromes with Unusual Dental Findings


or Gingival Components
John E. Fantasia, DDS
KEYWORDS
 Papillon-Lefevre syndrome  Hereditary gingival fibromatosis type 1  Klippel-Feil syndrome
 Oral-facial-digital syndrome type I  Oligodontia  Taurodontism

Papillon-Lefevre syndrome

Key points
 Periodontal disease associated with Papillon-Lefevre
syndrome (PLS) affects the primary and permanent
dentition.
 Keratosis of the palms and soles and the dorsal surfaces
and other skin sites are characteristic components of
the syndrome.
 Cathepsin C gene mutations result in a gene product
that does not have functional cathepsin C (CTSC)
activity.
 PLS and Haim-Munk syndrome (HMS) are allelic variants
of cathepsin C gene mutations.

Genetics
Papillon-Lefevre syndrome (PLS) is an autosomal-recessive
disorder caused by mutations on the cathepsin C gene. The
cathepsin C (CTSC) gene mutations have been mapped to
11q14.1-14.3. Heterozygous carriers of the mutation do not
have clinical manifestations of the disease. CTSC is a lysosomal protease and functions as an activator of neutrophil
serine proteases. Defective CTSC function likely impairs microbial degradation, cytokine pathways, neutrophil recruitment, and macrophage dysfunction. Also, impaired natural
killer cell cytotoxicity is noted in PLS. Haim-Munk syndrome
and perhaps aggressive prepubertal periodontitis are similar
to PLS in that they too demonstrate inactivation of CTSC. A
late onset variant of PLS without alteration of the CTSC gene
has been described, but this clinical situation is likely due to
another genetic cause.

The author has nothing to disclose.


Hofstra North Shore-Long Island Jewish School of Medicine, 270-05
76th Avenue, New Hyde Park, NY 11040, USA
E-mail address: fantasia@lij.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 211219
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.006

Clinical features
The syndrome was first described by Papillon and Lefevre in
1924. The clinical findings associated with PLS include palmoplantar erythema and hyperkeratosis, and severe periodontitis
that affects both the primary and the permanent dentitions
(Figs. 1 and 2). Haim-Munk syndrome, described in 1965, has in
addition to the findings that characterize PLS, atrophic
changes to the nails, and finger findings of acro-osteolysis and
clawlike volar curves noted radiographically. Susceptibility to
infection has been described in these hereditary forms of
palmoplantar keratoses. Tooth loss is preceded by gingival
inflammation and subsequent periodontal bone loss and tooth
mobility; Aggregatibacter actinomycetemcomitans (AA) is an
identified pathogen in PLS. Tooth loss follows the pattern of
eruption, incisors lost first, and then the more posterior
dentition. Both primary and permanent dentition are affected.
The permanent dentition is often lost in the teenage or early
adult years. Upon tooth loss, the alveolar mucosa is normal in
appearance. Gorlin reported calcified falx and choroid plexus
in PLS.

Differential diagnosis
All forms of aggressive periodontitis should be included in the
differential. These forms of aggressive periodontitis include
syndromes associated with decreased number of neutrophils,
including the various types of severe congenital neutropenia
syndromes, cyclic neutropenia, bone marrow failure syndromes, as well as syndromes with abnormal neutrophil function, such as Chediak-Higashi syndrome, and leukocyte
adhesion deficiency types 1 and 2. In addition, syndromes of
metabolic or structural defects, such as Kindler syndrome,
Ehlers-Danlos syndrome type IV and VIII, hypophasphatasia,
and hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome should also be included in the differential.

Treatment considerations
Careful attention to oral hygiene and periodontal care are
essential; however, disease is progressive even with conventional approaches to periodontal disease. It has been recommended that compromised primary teeth should be
extracted 6 months before eruption of the permanent

oralmaxsurgeryatlas.theclinics.com

212

Fig. 1 Gingival manifestation of PLS. (Adapted from Dhanrajani P. Papillon-Lefevre syndrome: clinical presentation and a brief
review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2009;108:e1e7; with permission.)

dentition. Ishikawa reported suspect bacterial pathogens,


including AA and a benefit of extraction of the primary dentition, but the permanent dentition status was followed only for
several years. Antimicrobial therapy has been tried, including
amoxicillin and metronidazole regimens for periodontal disease as well as treatment with retinoids for dermatologic
manifestations. Retinoids have not consistently proved effective for periodontal disease. Various studies of implant placement in the PLS patient have been described, yet too few to
form solid recommendations.

Hereditary gingival fibromatosis type 1

Key points
 Hereditary gingival fibromatosis type 1 (HGF1) is a
benign progressive fibrous gingival enlargement.
 HGF1 is the result of a mutation in the SOS1 gene on
chromosome 2p21.
 HGF1 severity is variable among affected individuals;
severe forms can impede tooth eruption.
 Gingival fibromatosis is a feature of many syndromes.
 Gingival hyperplasia related to medications (anticonvulsants, calcium channel blockers, and cyclosporine)
can clinically simulate HGF1.
 HGF1 treatment consists of gingivectomy; timing of the
procedure is controversial.

Genetics
Hereditary gingival fibromatosis 1 (GINGF1) is an autosomaldominant form of gingival overgrowth caused by a heterozygous frameshift mutation in the SOS1 gene on chromosome
2p21. Additional forms of HGF (GINGF2, GINGF3, and GINGF4)
have been mapped to other chromosome loci. A less common
autosomal-recessive form and sporadic cases of HGF are
recognized. Mutation on the SOS1 gene has also been reported
in Noonan syndrome. The exact mechanism by which the SOS1

Fantasia

Fig. 2 Hyperkeratosis of the palms. (Adapted from Dhanrajani P. Papillon-Lefevre syndrome: clinical presentation and a brief
review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2009;108:e1e7; with permission.)

gene mutation results in the gingival overgrowth is not


currently known.

Clinical features
HGF1 is characterized by slowly progressive fibrous overgrowth
of the gingival tissues of the maxilla and mandible (Fig. 3).
Typically, the overgrowth is nonhemorrhagic and the affected
tissues are firm and of normal color, but secondary inflammatory changes can occur. The condition manifests at the time of
eruption of the primary or permanent dentition, and the degree of gingival overgrowth can be variable. Delayed tooth
eruption may occur. This phenomenon is referred to as variable
expressivity. Thus, members of an affected family may
demonstrate varying degrees of severity of the gingival overgrowth. Severe cases may completely cover the dentition. A
kindred with HGF and associated hypertrichosis has been
described. The clinical presentation of HGF1 may be indistinguishable from syndromes that may have gingival overgrowth
as a component of the disease and gingival overgrowth secondary to particular medications known to cause gingival hyperplasia. The histopathology of HGF1 is characterized by
abundant collagen with interspersed spindle-shaped fibroblasts, typically without an inflammatory component, but a
chronic inflammatory component consisting of plasma cells and
lymphocytes may be a secondary finding. The surface stratified
squamous epithelium often exhibits elongation of the rete
pegs into the underlying collagenous stroma. The histopathology is nonspecific and similar to the pathologic abnormality
noted in syndrome-related and medication-related gingival
overgrowths.

Differential diagnosis
A comprehensive review of syndromes that may have gingival
fibromatosis has been published by Hart and colleagues. These
syndromes include but are not limited to Jones syndrome
(gingival fibromatosis with progressive deafness), gingival
fibromatosis with hypertrichosis, gingival fibromatosis with
distinctive facies, Ramon syndrome, Zimmerman-Laband

Unusual Dental Findings or Gingival Components

213

Fig. 3 (A, B) Hereditary gingival fibromatosis. (Adapted from Kather J, Salgado MA, Salgado UF, et al. Clinical and histomorphometric
characteristics of three different families with hereditary gingival fibromatosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2008;105:348e52; with permission.)

syndrome, juvenile hyaline fibromatosis, Cross syndrome, and


Rutherfurd syndrome. Katz and colleagues reported a case of
gingival fibromatosis and associated supernumerary tooth,
chest deformity, auricular cartilage deformation, joint laxity,
and undescended testes. Wynne and colleagues reported HGF
with associated hearing loss and supernumerary teeth. Medication-related gingival hyperplasia also enters into the differential diagnosis. Anticonvulsant medications, calcium channel
blockers, and the immunosuppressive medication cyclosporine,
as well as oral contraceptives, can result in gingival overgrowth. The diagnosis of HGF requires an adequate history and
clinical examination with the exclusion of the aforementioned
related conditions.

Treatment considerations
Gingivectomy is the recommended treatment. It has been
suggested that this is best accomplished after the permanent
teeth have erupted. However, severe cases of HGF may require
gingivectomy to allow the dentition to erupt when the gingival
overgrowth is thought to be responsible for lack of anticipated
tooth eruption. Repeated debulking of the affected gingival
tissues may be necessary.

Klippel-Feil syndrome

Key points
 Klippel-Feil syndrome (KFS) represents failure of the
process of vertebral segmentation and exhibits phenotypic variation and a spectrum of clinical severity.
 Fused vertebrae results in limited range of motion, and
a short neck. A low posterior hairline completes the
triad. Often the complete triad is not observed.
 Dangerous instability and neurologic symptoms can
occur in the more severe cases; osteoarthritis and
stenosis may develop over time.
 Cleft palate has been noted in KFS.

caused by a mutation in the MEOX1 gene on chromosome


17q21, and KFS3 is autosomal-dominant, caused by a mutation
in the GDF3 gene on chromosome 12p13. The GDF6 and GDF3
genes code for proteins in the bone morphogenic protein
family. The GDF6 gene codes for a protein that is involved in
bone growth, boundaries between bones, and vertebral formation. Thus, a reduction in functional protein likely leads to
the incomplete separation of vertebrae that characterizes the
syndrome. The GDF3 protein is involved in bone development
also, but the exact function is unclear.

Clinical features
KFS has variable clinical presentations but is characterized by
defective formation or segmentation of the cervical spine, short
webbed neck, limited range of motion of the neck with a
decrease in lateral bend and rotation, and low posterior hairline. Klippel and Feil, in 1912, first described this syndrome
reporting massive fusion of the cervical and thoracic vertebrae
in a 46-year-old man. Clarke in 1998 reported follow-up data of
a family with KFS, the new proband had separation of the C2-3
vertebrae at 10 weeks of age, but showed progressive ossification with complete fusion of C2-3 at 4 years of age. They
concluded that fusion is postnatal. Congenital scoliosis has been
reported in more than 50% of patients and rib abnormalities in
30% of patients. Cervical ribs have also been reported. Laryngeal cartilage malformations resulting in vocal impairment has
been described, as well as conductive, sensorineural, or mixedtype hearing loss. Sprengel deformity is identified in about 30%
of affected individuals. Sprengel deformity is related to limb
bud formation and characterized by upward displacement of
the scapula. The deformity may be minimal with no restriction
in motion to severe mobility restrictions. Thompson and colleagues reported on 6 family members with autosomal-dominant KFS; 4 of the 6 had cleft palate. Multiple jaw cysts in a
patient with KFS were reported by Eisenbud and colleagues.
Additional findings reported in KFS include facial asymmetry,
hemifacial microsomia, synkinesia, torticollis, renal anomalies,
cardiovascular abnormalities, upper extremity anomalies, cranial nerve abnormalities, and ear defects (Figs. 4 and 5).

Differential diagnosis
Genetics
Most cases of Klippel-Feil syndrome (KFS) occur sporadically.
KFS1 is autosomal-dominant, caused by a mutation in the GDF6
gene on chromosome 8q22; KFS2 is autosomal-recessive,

KFS should be considered when one or more of the following is


encountered: cleft palate, torticollis, neural tube defects,
scoliosis, Sprengel deformity, neck pain, instability of the
upper cervical spine, cranial or cervical nerve palsies, and
laryngeal cartilage anomalies.

214

Fantasia
that characterizes KFS is of importance to the surgeon, anesthesiologist, and operating room, radiology, and emergency
medicine personnel caring for these patients. This special
attention to the cervical spine deformity is emphasized in the
context of radiology assessment protocols, craniofacial
trauma, or surgeries such as cleft, orthognathic, dentoalveolar,
neurosurgical, orthopedic, or other surgical or endoscopic
procedures that may affect the stabilization and positioning of
the cervical spine. Modified activities, bracing, or traction may
be used to treat symptoms related to KFS.

Oral-facial-digital syndrome type I

Key points
 Oral-facial-digital syndrome type I (OFD1) is characterized at birth based on the identification of characteristic oral, facial, and digital findings.
 Some cases of OFD1 are diagnosed only after the identification of polycystic kidney disease in late childhood
or adulthood.
 Oral findings associated with the syndrome include
various clefts, bifid or lobed tongue with nodular
hamartomatous growths, hypodontia or supernumerary
teeth, and accessory hyperplastic frenula.
 Facial findings include hypertelorism, broad nasal
bridge, and ala hypoplasia, with facial asymmetry and
micrognathia.
 The most common finger findings are brachydactyly,
syndactyly, and clinodactyly; toe anomalies are less
common.
 There are multiple OFD syndrome types often with
overlapping clinical features with different inheritance
patterns than OFD1.

Genetics

Fig. 4 (A) Computed tomogram of cervical spine demonstrating


fusion of C2 through C4. (B) Magnetic resonance imaging of cervical
spine demonstrating cord contusion from C3 through C6 consistent
with central cord syndrome. (From ODonnell DP, Seupaul RA. Case
report Klippel-Feil syndrome. Am J Emerg Med 2008;26:252.e1e2;
with permission.)

Oral-facial-digital syndrome I (OFD1) is characterized by an Xlinked dominant mode of inheritance with lethality in male
patients. Approximately 25% of female patients diagnosed with
the condition have an affected mother. The condition is highly
penetrant and exhibits variable clinical expressivity. The OFD1
gene, Cxof5 (Xp22.2022.3), is expressed in adult tissues.
Several different mutations in the gene have been defined. The
gene encodes OFD1 protein, is centrosomal, and localizes to
the basal body of primary cilia. OFD1 belongs to a group of
diseases characterized by cilia dysfunction and is classified as a
ciliopathy. The protein is widely expressed in the early stages
of development in all the tissues affected by the syndrome.
There are several other OFD syndromes that have overlapping
clinical features with OFD1.

Clinical features
Treatment considerations
Fusion of cervical vertebrae places these patients at risk for
cervical cord syndrome. Cord impairment can occur after even
mild trauma. Special attention to the cervical spine deformity

Oral findings associated with OFD1 include pseudocleft of the


midline of the upper lip, bifid or lobulated tongue, nodular
hamartomatous lipoma-like masses of the tongue, hyperplastic accessory frenula, submucosal clefting, cleft palate

Unusual Dental Findings or Gingival Components

215

Fig. 5 Multiple views of a patient with Klippel-Feil Syndrome. Note the characteristic short, webbed neck and low posterior hairline.
(From Andro C, Pecquery R, De Vries P, et al. Split cervical spinal cord malformation and vertebral dysgenesis. Orthop Traumatol Surg Res
2009;95:549; with permission.)

or cleft uvula, hypodontia (especially the lower lateral incisors), or supernumerary teeth. Facial findings include
micrognathia, facial asymmetry, broad nasal bridge, hypertelorism, and nasal ala hypoplasia. Abnormalities of the
digits include brachydactyly, syndactyly, clinodactyly, and
less commonly, polydactyly. The fingers are more frequently
affected than the toes. Brain abnormalities include
agenesis of the corpus callosum, cerebellar abnormalities,
arachnoid cysts, and other central nervous system malformations. Fifty percent of individuals have some degree of
intellectual disability. Polycystic kidney disease is present in
50% of affected individuals, usually diagnosed no earlier
than late childhood. Some have cysts of the liver, pancreas,
and ovary. Milia of the skin are usually present at birth but
can undergo resolution with resultant pitting scars (Figs. 6
and 7).

Differential diagnosis

clinical features listed above can overlap with other OFD syndromes but the X-linked dominant inheritance pattern, male
lethality, and the presence of cystic kidney disease aid in
separating OFD1 from these other forms.

Treatment considerations
Surgical corrections of cleft lip or palate are indicated.
Removal of tongue nodules may be necessary because of the
size of these hamartomatous growths. Orthodontia and
correction of malocclusion is needed. Surgical intervention for
ankyloglossia, if severe, may be warranted, and referral to
speech pathology if indicated. Affected individuals should have
a hearing evaluation. Monitoring of the patient for polycystic
kidney disease is required.

Oligodontia

The differential diagnosis includes other OFD syndrome types,


and conditions characterized by cystic renal disease. The

Key points
 Oligodontia is defined as agenesis of 6 or more permanent teeth; the number does not include the absence of
third molars.
 Hypodontia is defined as agenesis of less than 6 teeth;
the number does not include the absence of third molars.
 Faulty use of the terms oligodontia and hypodontia is
problematic.
 Oligodontia and hypodontia may be part of a genetic
syndrome or occur as a familial or sporadic nonsyndromic disorder.
 There are numerous syndromes that have hypodontia or
oligodontia as an associated finding.

Fig. 6 Multiple upper lip frenula. (From Garcia Gonzalez M,


Castro MP, Nieto DV, et al. Oral-facial-digital syndrome type 1:
surgical approach and a case report. J Plast Reconstr Aesthet Surg
2014;67:396e8; with permission.)

Genetics
Autosomal-dominant, autosomal-recessive, and X-linked inheritance occurs. Transcription factor gene mutations have

216

Fantasia

Fig. 7 Brachydactyly and clinodactyly of the fifth finger (A) and radiograph of both hands showing short metacarpals and phalanges (B).
(From Ozturk F, Doruk C. Orthodontic treatment of a patient with oral-facial-digital syndrome. Am J Orthod Dentofacial Orthop
2012;141:S110e8; with permission.)

been identified in the following syndromes: oligodontia cleft


palate MSX1, Witkop MSX1, Wolf-Hirschhorn MSX1, oligodontia
PAX9, Axenfeld-Rieger types PITX1, FOXC1, cleft palate, and
ankyloglossia TBX22. WNT signaling pathway gene mutations
have been identified in oligodontia colorectal neoplasia
AXIN2. Also, gene mutations that affect the TNF/NF-kB
signaling pathway have been described in several of the
hypohidrotic ectodermal dysplasia syndromes with EDA,
EDAR, EDARADD gene mutations identified. Disruption of this
signaling pathway also includes but is not limited to incotinentia pigmenti, Ellis van Creveld, Van der Woude, Williams,
and oculodentodigital syndromes. Tooth agenesis may
also occur with disruption of the transforming growth factor-b, fibroblastic growth factor, and Sonic Hedge Hog
pathways.

Clinical features
Tooth agenesis (excluding third molars, typically bilateral and
symmetric such as the maxillary lateral incisors or premolar
dentition, or single tooth agenesis) has been estimated to occur
in up to 20% of the population. The absence of more than 6 teeth
(oligodontia) is less common. Tooth agenesis is associated with
numerous syndromes, and nonsyndromic forms that are either
familial or sporadic have been described. The gene involved in
cases of tooth agenesis often defines which teeth are missing.
For example, MSX1 associated tooth agenesis typically affects
the maxillary first premolars and PAX9-associated tooth agenesis is most frequently associated with the absence of the
maxillary and mandibular second molars. Alveolar bone hypotrophy is noted in the absence of teeth (Fig. 8).

Fig. 8 (AeD) Oligodontia. (From Qin H, Xu HZ, Xuan K. Clinical and genetic evaluation of a Chinese family with isolated oligodontia. Arch
Oral Biol 2013;58:1180e6; with permission.)

Unusual Dental Findings or Gingival Components

Differential diagnosis
The absence of teeth especially when multiple and symmetric
should prompt consideration for a familial occurrence and
possible association of syndromic features for which hypodontia and oligodontia may be a component. Other potential
causes of tooth agenesis include systemic or external influences that could adversely affect tooth formation, such as
infection, radiation, chemotherapeutics, and other environmental factors.

Treatment considerations
Radiographic imaging is needed to confirm the absence of
teeth. Prosthetic rehabilitation with partial dentures, full
dentures, overdentures, or implant placement is recommended. The adequacy of alveolar bone height may be problematic, and augmentation of the affected segments may be
required. Syndromic oligodontia may have additional considerations based on the specific syndrome.

Taurodontism

217
Say syndrome, Ackerman syndrome, X-chromosome aneuploidy
including Klinefelter syndrome, trisomy 21, and cleft lip and
palate subphenotypes. Autosomal-dominant, autosomalrecessive, and x-linked recessive inheritance patterns are
noted depending on the specific syndrome association.

Clinical features
Taurodontism is a condition affecting the teeth, usually the
molars, with pulp chambers enlarged in the vertical dimension
with resultant apical displacement of the bifurcation or
trifurcation of the tooth root. The condition is recognized on
dental radiographs or extracted teeth with root morphology,
suggesting the diagnosis and confirmed with radiographic
findings. There are varying degrees of severity of this defect
and the subclassification scheme of hypotaurodontism (mild),
mesotaurodontism (moderate), and hypertaurodontism (severe) has been suggested (Figs. 9 and 10). Diagnosis of taurodontism in the nonmolar dentition is difficult and
controversial; computed tomography may help with this diagnostic difficulty, but should be reserved for an affected tooth
needing endodontic management. It has been described as an
isolated finding, as a familial trait, as well as in geographic and
ethic groups including Eskimos and Aleuts, and fossil remains of
early man, and has been associated with syndromes.

Key points

Differential diagnosis

 Taurodont teeth have pulp chambers with a greater


apical occlusal height than normal teeth, with the
bifurcation or trifurcation of a molar displaced apically.
 The distance from the bifurcation or trifurcation to the
cementoenamel junction is greater than the occlusal
cervical distance.
 Taurodont teeth lack constriction at the cementoenamel junction.
 Hypotaurodontism, mesotaurodontism, and hypertaurodontism are subclasses of the condition.
 The molar teeth are the most commonly affected.
 Failure of the Hertwig epithelial root sheath diaphragm
to invaginate at the proper horizontal level has been
suggested as the developmental putative cause.
 Taurodontism can occur as an isolated phenomenon or
in association with various syndromes.

Other conditions with enlarged pulp chambers, such as Vitamin


Deresistant rickets, hypophosphatemia, shell teeth, regional
odontodysplasia, and internal resorption, should be included in
the differential. Attention to the radiographic or clinical shape
of the tooth root and cementoenamel junction morphology
should be helpful in defining taurodontism, although the definition can in some cases be arbitrary.

Treatment considerations
Taurodontism cannot be prevented and no treatment is
required. The identification of the condition mandates a need
for selected dental radiographs of family members to survey

Genetics
Taurodontism is rare, with prevalence in the primary dentition
of Japanese children reported to be 0.54%, and 5.6% in the
permanent dentition of Israeli adults. Other studies have
described a prevalence of 2.0% in Caucasian adults. The second
and third mandibular molars are the most commonly involved
teeth. Taurodontism has been described in several syndromes
including amelogenesis imperfecta type IV and type IC, distalless homeobox 3, simultaneously occurring taurdontism,
microdontia, and dens invaginatus, trichdentoosseous syndrome, oculodentodigital dysplasia, dentin dysplasia type I,
scanty hair-oligodontia-taurodontia syndrome, cranioectodermal dysplasia 4, hypohidrotic X-linked ectodermal dysplasia
1, otodental dysplasia, failure of primary tooth eruption, familial tumoral calcinosis hypophosphatemic syndrome, Barber-

Fig. 9 Representation of the subclasses of taurodontic teeth.


(From Jaspers MT, Witkop CJ. Taurodontism, an isolated trait
associated with syndromes and X-chromosomal aneuploidy. Am J
Hum Genet 1980;32:396e413; with permission.)

218

Fantasia

Fig. 10 (AeC) Taurodontism of the mandibular molars. (From Metgud S, Metgud R, Rani K. Management of a patient with a taurodont,
single-rooted molars associated with multiple dental anomalies: a spiral computerized tomography evaluation. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2009;108:e81e6; with permission.)

for taurodontism, and the need to exclude specific syndromes


associated with taurodontism as listed above.

Hereditary gingival fibromatosis type 1 (HGF1,


GINGF1)

Recommended readings

Hakkinen L, Csiszar A. Hereditary gingival fibromatosis: characteristic


and novel putative pathogenic mechanisms. J Dent Res 2007;86:
25e34.
Hart TC, Zhang Y, Gorry MC, et al. A mutation on the SOS1 gene causes
hereditary gingival fibromatosis type 1. Am J Hum Genet 2002;70:
943e54.
James PL, Prasad SV. Gingival fibromatosis: report of a case. J Oral Surg
1971;29:55e9.
Katz J, Guelmann M, Barak S. Hereditary gingival fibromatosis with
distinct dental, skeletal and developmental abnormalities. Pediatr
Dent 2002;24:253e6.
Kelekis-Cholakis A, Wiltshire W, Birek C. Treatment and long-term
follow-up of a patient with hereditary gingival fibromatosis: a case
report. J Can Dent Assoc 2002;68:290e4.
Wynne SE, Aldred MJ, Bartold MP. Hereditary gingival fibromatosis
associated with hearing loss and supernumerary teeth e a new
syndrome. J Periodontol 1995;66:75e9.

Papillon-Lefevre syndrome (PLS)


Bloch-Zupan A, Sedano HO, Scully C. Dento/Oro/Craniofacial anomalies and genetics. London: Elsevier; 2012. p. 170e4.
Dalgic B, Bukulmez A, Sair S. Papillon-Lefevre syndrome. Eur J Pediatr
2011;170:689e91.
Dhanrajani PJ. Papillon-Lefevre syndrome: clinical presentation and a
brief review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;
109:e1e7.
Gorlin RJ, Sedano H, Anderson VE. The syndrome of palmar-plantar
hyperkeratosis and premature periodontal destruction of the teeth.
A clinical and genetic analysis of the Papillon-Lefevre syndrome.
J Pediatr 1964;65:895e908.
Hart TC, Atkinson JC. Mendelian forms of periodontitis. Periodontol
2000 2007;45:95e112.
Hart TC, Hart PS, Bowden DW, et al. Mutations of the cathepsin C gene
are responsible for Pailon-Lefevre syndrome. J Med Genet 1999;36:
881e7.
Hart TC, Hart PS, Michalec MD, et al. Haim-Munk syndrome and
Papillon-Lefevre syndrome are allelic mutations in cathepsin C.
J Med Genet 2000;37:88e94.
Ishikawa I, Umeda M, Laosrisin N. Clinical, bacteriological, and
immunological examinations and the treatment process of two
Papillon-Lefevre syndrome patients. J Periodontol 1994;65:364e71.
Janjua SA, Iftikhar N, Hussain I, et al. Dermatolgic, periodontal, and
skeletal manifestations of Haim-Munk syndrome in two siblings.
J Am Acad Dermatol 2008;58:339e44.
Pilger U, Hennies HC, Truschnegg A, et al. Late onset Papillon-Lefevre
syndrome without alteration of the cathepsin C gene. J Am Acad
Dermatol 2003;49:S240e3.

Klippel-Feil syndrome (KFS)


Atlas of genetic diagnosis and counseling. Chapter 10. Springer; 2006.
p. 575e9.
Available at: http://ghr.nlm.nih.gov/condition/klippel-feil-syndrome.
Available at: http://www.omim.org/118100klippel-feil.
Available at: http://www.omim.org/135300. Gingival fibromatosis.
DeAngelo S, Murphy J, Claman L, et al. Hereditary gingival fibromatosis e
a review. Compend Contin Educ Dent 2007;28:138e43.
Eisenbud L, Broks H, Busch S. Klippel-Feil syndrome with multiple jaw
cysts. Oral Surg Oral Med Oral Pathol 1952;5:659e66.
Hart TC, Pallos D, Bozzo L, et al. Evidence of genetic
heterogeneity for hereditary gingival fibromatosis. J Dent Res 2000;
79:1758e64.

Unusual Dental Findings or Gingival Components


ODonnel DP, Seupaul RA. Klippel-Feil syndrome. Am J Emerg Med 2008;
26:252.e1e2.
Pierre S, Bats AS, Coumol X. Understanding SOS (Son of Sevenless).
Biochem Pharmacol 2011;82:1049e56.
Tracy MR, Dormans JP, Kasumi K. Klippel-Feil Syndrome: clinical features and current understating of etiology. Clin Orthop Relat Res
2001;(424):183e90.

Oral-facial-digital syndrome type I (OFD1)


Available at: http://www.omim.org/OFD1.
Gorlin RJ, Psume J. Orofaciodigital dysostosis: a new syndrome. A study
of 22 cases. J Pediatr 1962;61:520e30.
Gurrieri F, Franco B, Toriello H, et al. Oral-facial-digital syndromes:
review and diagnostic guidelines. Am J Med Genet Part A 2007;143A:
3314e23.
Paragon PA, Adam MP, Ardinger HH, et al. GeneReview [Internet]. In:
Toricello HV, Franco B, editors. Oral-facial-digital syndrome I.
Seattle (WA): University of Washington, Seattle; 1993e2014.
Thauvin-Robinet C, Cossee M, Cormier-Daire V, et al. Clinical, molecular, and genotype-phenotype correlation studies from 25 cases or
oral-facial-digital syndrome type 1: a French and Belgian collaborative study. J Med Genet 2006;43:54061.

Oligodontia
Available at: http://omim.org/oligodontia.
Bloch-Zupan A, Sedano H, Scully C. Dento/Oro/Craniofacial anomalies
and genetics. Chapter 2. Oxford (United Kingdom): Elsevier; 2012.
p. 9e74.

219
Frazier-Bowers SA, Guo DC, Cavender A, et al. A novel mutation in
human PAX9 molar oligodontia. J Dent Res 2002;81:129e33.
Kim JW, Simmer JP, Lin BPJ, et al. Novel MSX1 frameshift causes
autosomal dominant oligodontia. J Dent Res 2006;85:267e71.

Taurodontism
Casamassino PS, Nowak AJ, Ettinger RL, et al. An unusal triad: microdontia, taurodontism, and dens invaginatus. Oral Surg Oral Med Oral
Pathol 1978;45:107e12.
Daito M, Hieda T. Taurodont teeth in primary dentition. Jpn J Periodont
1971;9:94e106.
Dong J, Amor D, Aldred MJ, et al. DLX3 mutation with autosomal
domiant amelogensis imperfecta with taurodontism. Am J Med
Genet A 2005;133A:138e41.
Jaspers MT, Witkop CJ. Taurodontism, an isolated trait associated with
syndromes and X-chromosomal aneuploidy. Am J Hum Genet 1980;
32:396e413.
Jorgenson RJ. The conditions manifesting taurodontism. Am J Med
Genet 1982;11:435e42.
Kuchler EC, da Motta LG, Viera AR, et al. Side of dental anomalies and
taurodontism as potential markers for cleft subphenotypes. Cleft
Palate Craniofac 2011;48:103e8.
Ruprecht A, Batniji S, el Newihi E. The incidence of taurodontism
in dental patients. Oral Surg Oral Med Oral Pathol 1987;63:
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Shifman A, Chanannel I. Prevalence of Taurodontism in radiographic
dental examination of 1,200 young adult Israeli patients. Community Dent Oral Epidemiol 1978;6:200e3.
Varrela J, Alvesalo L, Maghall J. Taurodontism in 45, X females. J Dent
Res 1990;69:494e5.