Anda di halaman 1dari 76

Mowat-Wilson syndrome

Rome 2009
3rd European Course in Dysmorphology

Meredith Wilson
Children’s Hospital at Westmead
University of Sydney
The start…. 1996
Clinical Genetics Department Weekly Review Meeting
Children’s Hospital at Westmead, Sydney

• David Mowat presented a child with severe intellectual handicap,

Hirschsprung disease (HSCR) facial dysmorphism, microcephaly,
& seizures, with “Angelman-like” smiling, upturned face
• Meredith Wilson recalled another patient with MR, HSCR and
markedly similar facies
• MW recalled a third patient, known to have a 2q22 deletion
• 4th patient found by discussion with HSCR Surgical Research
team at CHW
• Paediatrician of 4th (Jeff Chaitow) recognised 5th patient by facial
phenotype – did not have HSCR
• Bronwyn Kerr identified 6th patient after discussion with MW
Literature searching
Published “HSCR-microcephaly-MR” disorders

– A heterogeneous group, none well delineated

– Goldberg-Shprintzen syndrome (reported 1981 in sibs),

not well defined, but possibly autosomal recessive

Published 2q22 deletions

– Lurie et al review 2q deletions included one patient with

del 2q22, HSCR and severe MR (no photo)
Syndrome features
• Typical facies
• Mental retardation –
usually severe

• Microcephaly
• Epilepsy
• Hirschsprung
• Short stature

• Congenital heart disease
• Hypospadias
del 2q22-23 no HSCR • Agenesis corpus
Conclusions JMG 1998
• Either a contiguous gene syndrome or a new
dominant single gene disorder involving a locus
in 2q22-q23
• Not Goldberg-Shprintzen syndrome, based on
both dysmorphism and likely AD inheritance
• Distinctive facies the key to diagnosis
• HSCR not obligatory
• Other major malformations (heart, urogenital,
CNS) variable
2001: SIP1 gene identified
2 groups independently reported
heterozygous mutations in SIP1
(encodes Smad-interacting protein-1)

• Wakamatsu et al Nature Genetics (April)

• Cacheux et al, Hum Mol Genetics (July)
Wakamatsu, N. et al. Nat Genet. 27 (April 2001)
Further studies 2001-2002
• Amiel et al Am J Hum Genet (Oct 2001)

• Yamada et al Am J Hum Genet (Dec 2001)

• Zweier et al (March 2002)

Confirmed phenotype and added genotype data

American Journal of Medical Genetics 108:177-181 (2002)

“We demonstrate that there is a recognisable clinical entity with a

specific facial gestalt, mental retardation and variable MCAs which we
propose be called the ‘Mowat-Wilson' syndrome”

>200 patients published since

MWS phenotype
• Distinctive facial features
• Intellectual handicap moderate-profound
• Majority have ≥1 major anomaly involving
HSCR, heart, CNS or genitourinary system
• Most have epilepsy
MWS- Prenatal/Birth
• Prenatal
Occasional reports NT
Cardiac malformation
Agenesis corpus callosum

• Neonatal
Weight, length, head circumference often normal
Hypotonia, poor feeding
+/- Hirschsprung disease
+/- congenital malformation
Facial features
• *** Fleshy uplifted ear lobes,
central depression
• ** Puffy anterior neck
• ** Triangular chin
• Round head, tall forehead,
square face, full cheeks
• Excess nuchal skin
• Deep set but “large” eyes
• Splayed “M” contour upper
• Rounded prominent nasal tip
• Deep central philtrum
• Earlobes uplifted, rounded, fleshy, central depression

• Shaped like red blood corpuscle (or orecchiette pasta)

MWS - Infants
• upper lip more prominent
• everted lower lip
• “M” shaped upper lip: full
medially, narrow laterally;
• prominent philtral pillars
• high paramedian peaks
of crista philtrae
• deep philtrum
Square face, triangular chin
MWS- children
• Uplifted face with open mouth/smiling expression
• Broad separated eyebrows with sparse medial flare
• Some have disorganized hair growth patterns within
the brows but brows well confined (no synophrys)
• Ear lobes less uplifted, less central depression
• Aquiline nasal profile developing
• Overhanging nasal tip with prominent columella
• Disproportionate lengthening of lower face
• Prominent chin or prognathism
Facial phenotype evolves with age
• In older children, the eyebrows are broad and horizontal
with a wide medial separation
• The nasal tip lengthens and depresses and the columella
becomes more prominent
• The mid-portion of the nose starts to fill, eventually
becoming convex
• In adolescents and adults the face is long, the nasal tip
overhangs the philtrum, and there is often prognathism
with a long, pointed or “chisel-shaped” chin
Hand and foot anomalies
• Slender fingers
• Mild camptodactyly
• Thickening of the interphalangeal joints in older individuals

• Talipes EV or positional talipes, everted foot position

• Broad halluces, unilateral duplication hallux, hypertrophy of the
first ray of the foot reported

• Hypoplastic phalanges but long halluces (Garavelli 2003)

• Brachytelephalangy with broad thumbs and halluces in patient
with missense mutation (Heinritz 2006).
• Hypoplasia of the halluces in patient with 11 Mb deletion (Zweier
8 years 15 years
Large/long halluces

Talipes equinovarus
MWS - feet

Pes planus, everted feet

MWS: congenital anomalies
• Hirschsprung disease (HSCR)
• Congenital heart defect
• Hypospadias
• Agenesis corpus callosum
• Structural eye anomalies
Clinical features in 57 patients with MWS
Our series Published
(n=57) (n=102)
Male: Female 30: 27 (1:1) 62:40 (1.5:1)
Mental retardation All All
Microcephaly 47/57 (82%) 78/94 (83%)
Seizures 24/31 (77%) 71/97 (73%)
HSCR 26/57 (46%) 65/102 (64%)
Congenital heart disease 32/57 (56%) 50/99 (50%)
Urogenital/renal anomalies 28/57 (49%) 45/88 (51%)
Hypo/agenesis of corpus callosum 24/57 (42%) 36/87 (41%)
Structural eye anomalies 1 6

Dastot–Le Moal, Wilson and Mowat et al., Hum Genet 2007

Summary of literature 2009
Clinical feature Percentage
Male: Female 1.4
Typical facies 98
Mod-severe MR 99
Epilepsy 75
Microcephaly 80
Short stature 50
Hirschsprung 45-55
Agenesis/hypoplasia corpus callosum 45-50
Congenital heart disease 50
Pulmonary artery sling +/- tracheal 3
stenosis 50-55 (males)
Hypospadias 12
Renal anomalies 4
Structural eye anomalies
Hirschsprung disease (HSCR)
• Failure of vagal B
neural crest (NC)
cells to migrate, A
proliferate, C
differentiate or
survive in the
bowel wall to
form both
plexuses of the Classification of HSCR based
on length of intestine with
enteric nervous aganglionosis.
system A=Short segment HSCR
B=Long segment HSCR
Ba enema C=Total colonic aganglionosis
Genetics of isolated HSCR
Familial clustering
• Low penetrance : risk to sibs ~ 4% overall
• Variable expression: USS-SS-LS-TCA
• Sex dependent; M:F ratio 4:1 for S-HSCR

Coding sequence mutations in RET

• 50% of familial cases
• 15% sporadic cases
Polymorphisms in RET
• Intron 1 polymorphism leading to a hypomorphic RET allele
in ~90% of sporadic HSCR

Complex inheritance
• RET mutations/polymorphisms occur in conjunction with
other autosomal susceptibility loci
• Typical newborn presentation in most
• Long segment (LS) or short segment
(SS) - most have SS disease
• Total colonic aganglionosis reported
• Chronic constipation – late diagnosis
• Sex affected penetrance; M>F but not
as marked as in isolated HSCR
• No definite genotype:phenotype
• Early series affected by ascertainment
bias: HSCR in >80%
• Later series lower incidence
2003 Wilson et al 61%
2005 Zweier et al 41%
2007 Dastot-Le Moal et al 46%
2009 Garavelli et al 31%
Published overall 54%
Role of RET in syndromic HSCR
Penetrance of HSCR in isolated and syndromic cases
c.f. frequency of the hypomorphic RET “T” allele

•HSCR RET-dependent in syndromes for which

epidemiologic data are closer to those observed
in isolated HSCR

• HSCR RET-independent in syndromes for

which the HSCR penetrance is high, e.g. MWS
and WS4
Clinical outcome HSCR in MWS
Bonnard et al J Ped Surg (2009): only published series

HSCR Recurrent Enteral Continent ZEB2

enterocolitis feeding
1 TCA Ex 8 mut

2 RS Ex 8 mut
3 TCA deletion
4 TCA deletion
+ +
5 RS deletion
+ +

Suggested outcome may be worse in MWS: ? due to

more extensive myenteric dysplasia causing persistent
problems ….not proven
Upper GIT in MWS
• Pyloric stenosis reported in 5%
– also reported in non-syndromic HSCR
• Swallowing incoordination
• Dysphagia
• Gastroesophageal reflux
• Enteral feeding
Congenital heart disease
50-55% of reported individuals
• patent ductus arteriosus
• atrial septal defect
• ventricular septal defect
• tetralogy of Fallot
• pulmonary atresia
• pulmonary valve stenosis
• pulmonary artery sling or stenosis*
• aortic coarctation
• aortic valve stenosis
Pulmonary artery sling (PAS)
• Rare
• LPA arises from RPA and forms a vascular
ring around the trachea
• Frequently associated with tracheal stenosis
or complete tracheal rings: “ring-sling”

• PAS +/- tracheal stenosis reported in 3% MWS

Consider MWS in dysmorphic neonate with PAS

PAS/tracheal stenosis
Reference Mutation Pulmonary Tracheal Other/
artery sling stenosis cardiac
Ishihara et al., c.857_858delAG, p.Glu286ValfsX7 PDA
2004 Patient 28 (exon 7) + +
Zweier et al., c.696C>G, p.Tyr232X Asplenia
2005 Patient 5 (exon 6) + +
Zweier et al., c.852_853delCA, p.Tyr285ArgfsX9
2005 (sibs) (exon 7)

Patient 22 + - Atypical LPA

Patient 23 + + PFO
Adam et al, 2006 c.1910 C>T , S637X
Patient 9 (exon 8) +
Dastot-Le Moal et c.2231_2232dupTA, p.Ala745X Aortic valve
al, 2007 (exon 8) ? + stenosis
Strenge et al, c.821_823insC, p.Q275fsX279 PDA, VSD,
2007 (exon 7) + + coarctation
Wilson, 2009 (not VSD, coarct,
published) Pending + - splenic cysts
CNS structural
• Absent/ hypoplastic corpus callosum

• Frontotemporal hypoplasia
• Hippocampal hypoplasia
• Pachygyria
• Nodular subependymal heterotopia

• Not reported with polymicrogyria (typical in

Goldberg-Shprintzen syndrome)
MRI abnormalities in MWS
Corpus callosum Temporal lobe

Agenesis Hypoplasia Temporal hypoplasia

Hippocampal dysplasia
Genitourinary abnormalities
Reported in ~ 50%
• Hypospadias in 45-50%
of males
• Bifid scrotum
• Webbed penis
• Undescended testes
• Vesico-ureteral reflux
• Megacystis
• Neurogenic bladder
Ocular abnormalities

• Strabismus common • Chorioretinal/ iris

(>50%) coloboma
• Nystagmus (resolving) • Microphthalmia
• Hypermetropia/myopia • Cataract
• Astigmatism • 4% in literature
Dental anomalies

• wide diastema upper +/- lower central incisors

• chisel-shaped central incisors

• small and palatally placed lateral incisors

Hearing & Pigmentation
• Occasional reports of
sensorineural or conductive
deafness – probably coincidental

• Several reports of patchy

depigmentation hair/skin
(personal communications)

• Note patient with cutis tricolore

syndrome (Ruggiero et al 2003)
and overlapping phenotype
• Present in ~ 75% reported individuals
• Age of onset months-10 years
• Mixed seizure types
• No consistent EEG findings
• Some have resistant seizure disorder
• Several individuals have dramatically
seizure control improved after puberty
Autonomic dysfunction?
• Neurogenic bladder in several patients

• One patient with episodic bradycardia,

urinary retention, hypersomnolence,
hypercarbia, hypoxia, coma, pinpoint

• Possible diffuse ANS dysregulation

• Disability moderate- severe- profound
• Most described as placid and happy
• Frequent smiling and uptilted head posture,
• Do not exhibit unusual laughter

• Very limited speech, usually few recognizable words

• Many have better receptive abilities
• Signing may aid communication

• Frequent chewing/mouthing/drooling
• Bruxism
• Retching to gain attention
Milestone N Mean SD Min Max

Age of sitting 53 21.46 mo 13.87 mo 6 mo 60 mo

Age of cruising 41 39 mo 16.68 mo 12 mo 102 mo

Age of walking 40 49.05 mo 19.7 mo 18 mo 96 mo

Data collected by Liz Evans, Sydney, Australia

PhD candidate University of NSW 2009
Intellectual disability
Data collected by Liz Evans, Sydney, Australia
PhD candidate University of NSW 2009

Estimated ID of 29 participants who received developmental assessments

Estimated Level of ID N Percent of sample

Moderate 4 14%
Severe 23 79%
Profound 2 7%
Total 29 100%
Intellectual disability
Data collected by Liz Evans, Sydney, Australia
PhD candidate University of NSW 2009

Estimated level of ID assigned to all 71 MWS participants

(from assessment or by interview)

Level of ID N Percent
Mild 1 1.41
Moderate 9 12.68
Severe 45 63.38
Profound 16 22.54
TOTAL 71 100.00

MWS patients mainly from Australia/USA/Italy/Japan/UK)

Other concerns
• Many adults (>35%) underweight

• Sleep disturbance frequently reported

• Frequent chewing, mouthing, bruxism

• Intellectual disability at least moderate range
but more often in the severe range
• Better receptive than expressive skills
• Many display a happy, sociable demeanour.
• Interventions recommended for
– improving expressive communication skills
– increasing independence in activities of daily living
– managing sleep disturbance
– managing feeding difficulties
MWS survival
• No long term data
• Early death (infancy or childhood)
reported, but not usual
• 50 year old patient known
Differential diagnoses
• Goldberg-Shprintzen

• Pitt-Hopkins

• Ruggieri-Happle (cutis tricolore)

Goldberg-Shprintzen syndrome
• First described 1981 in sibs with HSCR,
microcephaly, hypertelorism, short stature,
submucous cleft palate
• Since, individuals with HSCR-MR-microcephaly
often published as “Goldberg-Shprintzen”
despite clinical and genetic differences
• Brooks et al (2005) reported AR mutations in
KIAA1279 confirming “GOSHS” as a separate
Goldberg-Shprintzen syndrome
• MR severe
• Microcephaly
• Synophrys Facies differ from MWS
• Arched brows
• Hypertelorism
• HSCR (most)
• Polymicrogyria
• Coloboma
Pitt-Hopkins syndrome
• AD, de novo mutations involving TCF4
• Severe MR, microcephaly, +/- seizures
• Deep-set eyes, thin eyebrows
• Prominent lips, exaggerated Cupid’s bow
• Prognathism
• Clubbed fingertips
• Hyperventilation
• HSCR described but uncommon
Clinical features differentiating
Hypospadias ++ - -
Congenital heart disease ++ - -
Agenesis corpus callosum ++ - (hypo)
Polymicrogyria - ++ -
Hyperventilation - - +
Severe myopia - - +
Clubbed fingertips - - +
ZEB2 gene

SIP1 Smad-interacting protein 1

ZFHX1B Zinc finger homeobox 1B

ZEB2 Zinc finger E-box binding homeobox 2

Location 2q22.3
Genomic organisation of ZEB2

• Coding sequence exons 2-10

• Functional domains
N-ZF: N-terminal zinc finger cluster
SBD: Smad-binding domain
HD: Homeodomain
CtBP: C-terminal binding protein interacting
C-ZF: C-terminal zinc finger cluster
Figure: Wilson et al, Mowat-Wilson syndrome, in
Epstein (Ed), Inborn Errors of Development, 2008
ZEB2 mutations reported to Nov 2009
221 reported, over 115 different mutations
Approximately 50% of mutations in exon 8 (largest exon)
Type of mutation Number % Total
All 221
Cytogenetic deletion 2 <1
Translocation disrupting gene 2 <1
Large gene deletions 43 19
Small insertions/deletions 91 41
Nonsense 72 32
Complex 2 <1
Splicing* 5 2
Missense* 3 1.3
Inframe del* 1 <0.5

* some reported with mild/atypical phenotypes

MWS-recurrence risk
• McGaughran et al 2005 2 sibs
• Zweier et al 2005 2 sibs*
• Ohtsuka et al 2008 3 sibs
• Cecconi et al 2008 2 sibs
* Paternal somatic mosaicism shown

Clinical features vary between siblings

Empiric recurrence risk ~ 2% (0.6-5.75%)
• Ballarati et al (2009) report patient with MR and
some MWS features & complex chromosome
rearrangement involving 2q22
• 46,XY,t(1;15) (q42;q11.2)ins(1;2)(q42;q?21q?31)
• 2q22 segment including ZEB2 translocated &
inserted into chromosome 1

• ZEB2 not deleted (mutation analysis not done)

• Breakpoint 794 kb from ZEB2 ? position effect
ZEB2 genotype:phenotype
• No genotype: phenotype correlation established*

• Most mutations lead to drastic C-terminal truncation

of protein (unstable product)

• Haploinsufficiency likely mechanism of pathology

• Large deletions (involving contiguous genes) may

give additional features

*few reports atypical phenotype with rare mutations

Atypical patients with ZEB2 mutations
Reference Mutation Phenotype

Yoneda et al (2002) 3bp inframe del mild-mod MR

exon 3 constipation

Heinritz et al (2006) missense cleft lip/palate

Q1119R brachydactyly
exon 10 severe MR

Zweier et al (2006) splice acceptor mild MR

IVS1-1G>A subtle facies
5’ UTR

Gregory-Evans (2004) missense Trisomy 21

R953G + MWS facies
exon 8 HSCR
Missense mutations ZEB2
• Missense mutations are very uncommon
(only 3 reported)

• 2 with atypical phenotypes (Heinritz 2006,

Zweier 2006)
• 1 with typical but severe phenotype (Dastot-
Le Moal 2007)

• Missense mutation → other phenotypes?

Approach to mutation testing
1. ZEB2 FISH for deletions larger
than 200–300 kb (15%)

2. Direct sequencing of ZEB2 (80%)

3. MLPA or qPCR for single or multiple

exon deletions (5%)
zinc finger E-box binding homeobox 2
• Encodes Smad-interacting protein-1(SIP1)

• SIP1: one of two members of the vertebrate ZFHX1 family

zinc finger (ZF) and homeodomain/ homeodomain-like
(HX)- containing proteins

• SIP1: transcriptional co-repressor (mainly): involved in the

transforming growth factor-β (TGF-β) signalling pathway

• ZEB2 highly evolutionarily conserved, widely expressed

in embryological development
transforming growth factor-β (TGF-β) signalling pathway

Smad proteins -
mediators with
pivotal role in
relaying TGF-β
signals from cell
surface receptors
to the nucleus.

SIP1 interacts
with Smads 1-5

SIP1 functions
as co-repressor
of many genes
SIP1 binding to target genes

SIP1 “two-handed” ZF
binding to motifs in promoter
region of target genes
Figure courtesy M Goossens
SIP1 expression
• strongly transcribed early developing peripheral and
central nervous systems of mice and humans

– neural crest–derived cells, including enteric nervous

system and facial neurectoderm

– neural retina, predominantly retina ganglion cell layer, and

whole lens

• transcribed in early developing human and mouse

heart, yolk sac, thymus, liver, skeletal muscles,
genital tubercle, kidneys and bladder

• likely to have pleiotropic effects in early

Neural crest (NC) derivatives
Cranial connective tissue and musculoskeletal
structures head & face

Vagal populate gastrointestinal tract and

cardiovascular region

Truncal peripheral sensory neurons, glial cells,

some neuroendocrine cells, melanocytes
Mouse Models
Heterozygote SIP1 null mice
Van de Putte et al 2003
• most have agenesis corpus callosum, do not have HSCR

Homozygous SIP1 knockout mouse

• lethal E9.5 (4-5 wks human): severe growth retardation, neural
tube failure to close, cardiovascular function defects
• Migration arrest neural crest cells: no vagal or truncal NC cells

Conditional SIP1 KO in neural crest-derived cells

Van de Putte et al 2007
• survives to juvenile
• hippocampus and corpus callosum consistently missing
• defective craniofacial, heart, melanocytes, enteric nervous system
and sympatho-adrenal function
MWS – prenatal diagnosis
Fetal ultrasound unreliable/inconclusive
• Nuchal translucency – several reports 
• Agenesis/hypoplasia corpus callosum
• Congenital heart disease

DNA testing for known family mutation

David Mowat Patient photographs
Department of Medical Genetics Mowat-Wilson
Sydney Children’s Hospital Raoul Hennekam
Lesley Adès
Julie McGaughran
Florence Dastot-Le Moal
Kate Gibson
Michel Goossens Sharron Worthington
Service de Biochimie et Génétique
..and many others
Hôpital Henri Mondor, Paris
Parents of individuals with MWS
Liz Evans Goldberg-Shprintzen
University of NSW
Alice Brooks
Kristi Jones