Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva: a rare genetic

musculoskeletal disorder

Samdaniel Sutanto

Correspondence:
Faculty of Medicine Krida Wacana Christian University
Jalan Arjuna Utara No. 6 Jakarta Barat 11510
email: drsamdanielsutanto@gmail.com

Abstract: Fibrodysplasia ossificans progressiva is a rare genetic disorder of soft tissue that
characterized by hallux valgus deformity and progressive heterotopic ossification. The case
has been reported with worldwide prevalence approximately 1 case in 2 million individuals
with no ethnic, race, gender, or geographic predisposition has been described. Patients will
experience sporadic episodes of swellings and they could be exacerbated by injury. Recently,
a mutation in bone morphogenetic protein type I receptor has been identified in all affected
individuals. Although most cases are sporadic, some familial cases are reported with
autosomal dominant pattern. There is no known effective treatment for this condition.
Prevention is based on prophylactic measures against soft tissue injury and infections. Most
patients are wheelchair-bound by the age of 30 and they commonly die due to complications
of thoracic insufficiency syndrome.

Keywords: Fibrodysplasia ossificans progressiva, heterotopic ossification.

Abstrak: Fibrodysplasia ossificans progressiva adalah gangguan genetik langka dari jaringan
lunak yang ditandai dengan kelainan hallux valgus dan ossifikasi heterotopik secara
progresif. Kasus ini telah dilaporkan dengan prevalensi di seluruh dunia sekitar 1 kasus dari 2
juta orang tanpa telah dijelaskan mengenai etnis, ras, jenis kelamin, atau kecenderungan
geografis. Pasien akan mengalami peristiwa pembengkakan sporadis dan pembengkakan
tersebut dapat diperburuk oleh cedera. Baru-baru ini, mutasi pada reseptor morfogenetik
tulang tipe I telah diidentifikasi pada seluruh individu yang terjangkit. Meskipun sebagian
besar kasus bersifat sporadis, beberapa kasus bersifat familial telah dilaporkan dengan pola
dominan autosom. Tidak ada pengobatan efektif yang diketahui untuk kondisi ini.
Pencegahan didasarkan pada tindakan profilaksis terhadap cedera jaringan lunak dan infeksi.
Sebagian besar pasien telah menggunakan kursi roda pada usia 30 tahun dan mereka
umumnya meninggal akibat komplikasi dari sindrom insufisiensi toraks.

Kata Kunci: Fibrodysplasia ossificans progressiva, ossifikasi heterotopik.

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Fibrodysplasia Ossificans Progressiva
Introduction
The metamorphosis or transformation of
one normal tissue or organ system into
another through a pathological process is
still remains a mystery. This phenomenon
has been hidden for centuries in an
extremely rare human disorder,
fibrodysplasia ossificans progressiva
(FOP).
People who are affected by this
condition will experience the progressive
ossification in their skeletal muscles and
soft connective tissues. Progressive
ossification is usually noticed in early
childhood in characteristic anatomic
patterns. Any injuries or inflammations
may cause swelling and trigger the
ossification rapidly in the affected area.
FOP is heritable and there is no treatment
for FOP.
Because FOP is so rare, this
condition is frequently misdiagnosed by as
malignancy and patients are often subjected
for biopsy which resulted in permanent loss
of joint mobility due to secondary post-
traumatic ossification. Physicians should be
aware of this condition. By recognizing the
signs of the FOP earlier and prevent the
patients from being injured or traumatized,
the ossification in FOP patients can be
minimized.
Clinical Features
Figure 1. The Radiograph of the Feet
Showing Congenital Malformation of the
Great Toes.20
FOP is a rare genetic disorder which
characterized by congenital malformation
of the great toes (hallux valgus deformity
with microdactyly) and progressive
heterotopic ossification in soft tissues such
as tendons, ligaments, aponeurosis, fascia,
and skeletal muscle.1-4 It first described by
Guy Patin who presented the case from a
young patient who “turned into wood” in
1692.4
Children who are affected with FOP
appear normal at birth except for the
congenital malformation of the great toes
which are present in all affected
individuals.2,3,5 Congenital malformation of
the great toes (Figure 1) is the earliest
recognizable clinical feature at birth and
this type of malformation is usually
presented as symmetrical congenital
malformation of the proximal phalanx and
the metatarsal bones.6,7 The proximal
phalanx is consistently shortened and
located lateral from the axis of the
metatarsal bones at its distal end, while the
metatarsal bones are also shortened and
sharpened to medial side, deviating the
proximal phalanx to the lateral from the
metatarsal axis.7
Children who are affected with FOP
will experience sporadic episodes of soft
tissue swellings which are usually painful
and they are often mistaken for tumors.1,4,5
Some of these swellings may regress
spontaneously, but some of these swellings
can transform tendons, ligaments,
aponeurosis, fascia, and skeletal muscles
through heterotopic ossification into
ribbons, plates, and sheets of heterotopic
bone (Figure 2).5 Several kinds of tissue are
known to be unaffected by this condition.
The diaphragm, tongue, extra-ocular
muscles, cardiac muscle, and smooth
muscle are spared from the heterotopic
ossification in FOP.5,8
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Fibrodysplasia Ossificans Progressiva

Typically, progressive heterotopic

ossification follows characteristic anatomic
patterns where the process usually seen first
in the dorsal, proximal, axial, and cranial
regions of the body (neck, shoulders, back)
and later in the ventral, caudal, and distal
regions of the body (trunk and limbs). 8 The
formations of heterotopic bone are usually
span over joints, locking them in place, and
resulted in the ankylosis of the joints and
progressive immobility.8
Minor trauma such as intramuscular
immunizations, mandibular blocks for
dental work, fatigue, muscle stretching,
blunt muscle trauma for bumps, bruises,
falls, and influenza-like illnesses can trigger
a painful episodes of swellings which lead
to the progressive heterotopic
ossification.5,8,9 Surgical attempts to remove Figure 2. 3D CT Scan of the Back of A
heterotopic bones may cause the condition Twelve-year Old Child Showing Extensive
become worse by triggering the episodes of Heterotopic Bone Formation.5
explosive and painful new bone
formations.9 lymphocytes, macrophages, and mast
In addition to congenital cells.11 Following a brief inflammatory
malformation of the great toes, other stage, a robust angiogenesis and
malformations are frequently observed in neovascularity which is characterized by
thumbs and cervical spine.10 Neck stiffness fibroproliferative lesion is noted.9,11
is an early finding in most patients and can As the lesion matures,
precede the appearance of heterotopic fibroproliferative tissue undergoes an
ossification at that site. Characteristic avascular condensation into cartilage
malformations of the cervical spine include followed by a revascularization stage and
large posterior elements, tall narrow endochondral ossification which is
vertebral bodies, and fusion of the facet prominent and identifying histological
joints between C2 and C7.9,10 Other skeletal feature of the intermediate lesions.9,12
malformations often associated with FOP Cartilage and bone formation that replaced
including short malformed thumbs, the fibroproliferative tissue are present in
clinodactyly, short broad femoral neck, and muscle and adjacent connective tissue. The
osteochondromas which most notably at the endochondral ossification proceeded in a
proximal medial tibias.10 sequence that appears to be entirely normal,
with calcified cartilage being replaced by
Histopathology of FOP Lesions woven bone and eventually remodeling into
normal lamellar bone with marrow
Lesion formation in FOP is a pathological elements.12
process of skeletal metamorphosis that
begins with a catabolic stage associated Etiology
with muscle cell injury and death which is
characterized by inflammatory Most cases of FOP are usually sporadic due
mononuclear cell infiltrate involving to spontaneous mutation. However, familial

3
Fibrodysplasia Ossificans Progressiva
cases are also reported with an autosomal
dominant pattern with complete
penetration6 and can be inherited from
either mothers or fathers.13 To identify the
chromosomal locus of the FOP gene, a
conservative genome-wide linkage analysis
was conducted using a subset of five
families with the most stringent and
unambiguous features of FOP and the
approach identified linkage of FOP to
2q23-24. The activin receptor IA/activin-
like kinase 2 (ACVR1/ALK2) gene was
identified in an interval of the linkage.
ACVR1/ALK2 is a bone morphogenetic
protein (BMP) type I receptor that is
expressed in many tissues such as skeletal
muscles and chondrocytes. ACVR1
therefore is a strong candidate gene that
responsible for FOP, which is associated
with similar clinical findings and
dysregulation of the BMP signaling
pathway.13
DNA sequence analysis of the
ACVR1 gene demonstrated the presence of
an identical heterozygous single nucleotide
mutation at cDNA position 617
(c,617G→A) in all affected individuals,
results in the substitution of the arginine by
histidine at codon 206 (p.R206H) within the
GS domain of the receptor.14 Protein
structure modelling of the mutation predicts
destabilization of the GS domain, consistent
with overexpressed ACVR1 as the
underlying cause of the ectopic
chondrogenesis, osteogenesis, and joint
fusion in FOP patients.9,13
Several mutations are also been
reported. Two patients from Italia have a
novel ACVR1 mutation c.774G→C leading
to the substitution of the arginine by serine
at codon 258 (R258S) in the kinase domain
of the protein.15,16 Two FOP patients from
United Kingdom have another type of
mutations. The first patient is heterozygous
for the novel mutation c.605G→T in
ACVR1, and the second patient is
heterozygous for the novel mutation
c.983G→A found within the ACVR1.16
Epidemiology
The case of FOP worldwide has been
reported with prevalence of approximately
1 case in 2 million individuals. There is no
ethnic, race, background, gender, or
geographic predisposition has been
described.17
Radiographic Findings
Plain radiographs and computerized
tomography (CT) may play a role in
confirming the diagnosis of FOP and
evaluating its extent. Characteristic features
might be seen in the plain films consist of
deformity of the great toes with or without
absence of a phalanx, soft tissues
ossifications, shortened broad femoral neck
pseudo-exostoses, and prominent calcaneal
spur. Bony bridging between the axial and
appendicular skeleton might be seen in
advanced stages.18 CT and magnetic
resonance imaging (MRI) can detect
swellings and ectopic ossification prior to
plain radiography in early stage lesions.19
MRI appearance of FOP has been reported
with soft tissue swellings showing the
signal intensity similar to muscle on T1-
weighted images and high signal intensity
with T2-weighted images.19,20
Treatment and Prevention
There is currently no known treatment for
this condition. Corticosteroids are used as a
first-line treatment at the beginning of
swellings based primarily on its potent anti-
inflammatory effects, but they should not
be used as a treatment of swellings that
affect major joints, the jaw, or the
submandibular area. Corticosteroids are
also restricted to the prevention of swellings
following major or minor soft tissue
injury.21 Nonsteroidal anti-inflammatory
drugs (NSAIDs), cyclo-oxygenase-2
inhibitors, leukotriene inhibitors, and mast
4
Fibrodysplasia Ossificans Progressiva
cell stabilizers are used symptomatically in
managing chronic discomfort and ongoing
swellings.22
In children with FOP, restriction of
activity may be helpful to prevent them
from fall, but it may be prevent patients
from optimizing their level of function and
compromises independence and may be
unacceptable to patients.5 Aggressive
physical therapy is not recommended for
FOP patients, as stretching of soft tissues
around a joint can exacerbate the
lesions.19,23 Joints are should not be
passively stretched and active range-of-
motion exercises should be encouraged if
the movements are comfortable for FOP
patients.23
Prophylactic measures that
minimize respiratory infection and prevent
influenza or pneumonia are important to
reduce morbidity and mortality due to
thoracic insufficiency syndrome.
Vaccinations that administered by
intramuscular injection should be avoided.5
Great care is necessary in dental therapy to
prevent caries and it must avoid
intramuscular injections of local anesthetics
and stretching of the jaw.5,9,22 Surgical
procedures to remove heterotopic bone are
contraindicated because it may provoke
explosive heterotopic ossification at the
operative site.22
Prognosis and Complications
Most of FOP patients are wheelchair-bound
by the age of 30 and their life expectancy
approximately 50-60 years due to
cardiorespiratory failure from thoracic
insufficiency syndrome, the most common
causes of death among FOP patients. 6
Several factors contribute to thoracic
insufficiency syndrome development in
FOP patients including costovertebral
malformation with early orthotopic
ankylosis of the costovertebral joints, ribs
fusion, ossification in intercostal muscles,
paravertebral muscles, and aponeuroses.
Progressive spinal deformity including
kyphoscoliosis and thoracic lordosis are
also known to be contributed.24
Neurological symptoms including
severe headache, neuropathic pain, other
sensory abnormalities, and myoclonus has
been described among the FOP patients. 25
Hearing loss is also occurs in FOP patients
which onset is usually in childhood or
adolescence. Hearing loss is mostly
conductive and possibly caused by
ossification in middle ear, but in some
patients hearing loss is sensorineural.26
Conclusion
FOP is a rare genetic condition that still
doesn’t have any effective medical
treatment that can stop its progression. By
recognizing the early signs including
congenital malformation of the great toes
and sporadic episodes of painful swellings
could be helpful in making the diagnosis of
FOP. Prevention from soft tissue injury and
infections of the respiratory system may
reduce the morbidity and mortality due to
thoracic insufficiency syndrome in FOP
patients.
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