Progressive extraskeletal ossification is the defining feature of a group
of very rare genetic syndromes, including fibrodysplasia ossificans
progressiva and progressive osseous heteroplasia. Recent advances in human
molecular genetics have enabled the molecular characterization of
disease-causing mutations for some of these
conditions1,2.
Despite our increasing understanding of the biochemical etiology of
heterotopic ossification syndromes and newly applicable molecular genetic
screening tools, individual patients with progressive heterotopic ossification
still pose a difficult diagnostic challenge.
We report the case of a female patient with a four-decade history of
recurrent, progressive heterotopic ossification limited to the right
hemicorporeum. This condition, which does not meet the clinical or molecular
diagnostic criteria of any known syndrome, represents a new syndrome of
heterotopic ossification, which we have named focal fibronodular heterotopic
ossification. Our patient was informed that data concerning the case would be
submitted for publication.
A sixty-three-year-old right-hand-dominant woman presented to our
institution for evaluation and treatment of a complex deformity of the right
upper extremity. Distinctive features of the deformity at the time of
presentation included multiple firm nodular soft-tissue masses located on the
dorsal and volar surfaces of the right hand and wrist, involving the thumb,
index finger, and long fingers. The patient had severe contractures of the
index finger and first web space in areas of particularly large and dense
nodule formation; small skin ulcerations that appeared to be chronic and
infected were seen in these areas and at the volar base of the first
metacarpal (Figs. 1-A, 1-B, and
2). The patient had a
concomitant dense sensory and motor neuropathy of the median nerve of the
right hand. Full physical examination revealed other areas of hard, nodular
swelling, specifically in the patient's right shoulder, right upper arm, right
lateral forefoot, and right iliac crest. Notably, the affected areas were
limited to the right hemicorporeum.
The medical history of the patient included an uneventful birth, no
congenital skeletal malformations, and a normal early childhood development.
The family history did not include hormone insensitivity, Albright hereditary
osteodystrophy, or any disorders of extraskeletal ossification. At the time of
presentation, the patient had three living children who did not display any
signs of heterotopic ossification or any findings consistent with
fibrodysplasia ossificans progressiva, progressive osseous heteroplasia,
Proteus syndrome, or Albright hereditary osteodystrophy.
At eight years of age, the patient had experienced a transient episode of
weakness in the right arm that lasted for two weeks. The cause of this
incident was not fully investigated at the time, and the symptoms resolved
spontaneously after a series of chiropractic manipulations of the right upper
extremity.
When the patient was thirty years of age, a firm, exophytic lesion had
developed on the right small toe. This lesion was excised, but multiple
nodular mineralized masses developed at the surgical site. Despite
re-excision, the masses recurred.
When the patient was thirty-four years of age, pain and weakness had
developed in the right upper extremity. Radiographs made at the time revealed
a simple cyst in the proximal portion of the right humerus, and the patient
subsequently underwent an incisional biopsy. Histologic evaluation of the
biopsy tissue was consistent with the diagnosis of a simple bone cyst. Over
the following two years, the cystic lesion in the proximal portion of the
humerus persisted and additional cystic lesions developed in the right lateral
epicondyle and the distal aspect of the radius. Both humeral lesions were
treated with curettage and packing with use of autogenous cancellous bone
graft obtained from the right anterior iliac crest. Firm, nodular, ossified
soft-tissue masses developed postoperatively at all three surgical sites.
When the patient was forty-three years of age, a new enlarging soft-tissue
mass, measuring >10 cm in diameter, had been excised from the right arm.
Shortly thereafter, another lesion developed on the right index finger; this
mass was excised and the resultant skin defect was treated with a skin graft.
Six years later, the right small toe was amputated because of an enlarging
soft-tissue lesion; the surgical site was treated postoperatively with 2500 Gy
of radiation. Medical records dating from the time of the right toe amputation
documented that the lesion on the proximal part of the right humerus that had
been excised six years before had recurred and was "the size of a
grapefruit." Unfortunately, radiographs of this lesion are no longer
available for review. "Atypical neurofibromatosis" had been the
proposed diagnosis. One year later, the patient underwent a right carpal
tunnel release. Sensory and motor dysfunction of the median nerve was
documented with preoperative electromyography. Coincident with the carpal
tunnel release, a 4 × 5-cm mass was excised from the palmar aspect of
the index finger. Despite two postoperative doses of radiation (2500 Gy and
2100 Gy), the lesion of the index finger recurred and caused a flexion
contracture of the proximal interphalangeal joint.
At sixty-three years of age, the patient was referred to our institution
for evaluation. Physical examination revealed numerous hard, nodular lesions
of the right shoulder, elbow, hand, foot, and iliac crest. There were small
draining skin ulcerations over prominent nodular lesions in the thenar area of
the hand and on the lateral surface of the right foot. A technetium-99
radionuclide bone scan revealed increased uptake in all of the nodular areas.
Laboratory evaluation of serum calcium, phosphorus, alkaline phosphatase,
lactic dehydrogenase, C-reactive protein, and parathyroid hormone levels were
normal. A twenty-four-hour urine collection revealed normal amounts of
hydroxyproline, calcium, potassium, and phosphate. An electromyographic study
and a nerve-conduction study revealed motor and sensory abnormalities of the
right axillary, radial, musculocutaneous, and median nerves; these findings
were consistent with multiple mononeuropathies rather than a brachial plexus
lesion.
A consultation with the Endocrinology Service resulted in the suggested
diagnosis of atypical myositis ossificans. The patient was started on oral
bisphosphonate therapy. The ossific lesions did not regress, however. Drainage
persisted from the right thenar area, and the contracture at the proximal
interphalangeal joint of the right index finger and the first web space
worsened, resulting in a loss of functional pinch.
Approximately one year after referral to our institution, the patient
underwent excision of the right second ray and wide resection of the calcific
masses over the dorsal and volar aspects of the right hand and wrist.
Microneurolysis of the median nerve was also performed. The nerve was encased
in mineralized tissue throughout its distal course. Because of the presence of
thenar-muscle atrophy, local infection, and nodular mineralization, it was
necessary to route the index profundus tendon around a pulley created with
part of the flexor carpi ulnaris in order to restore thumb opposition. A
capsulotomy of the carpometacarpal joint of the thumb was also performed in
order to place the thumb in a more functional position. The resulting
soft-tissue defect was covered with a latissimus dorsi muscle flap that was
harvested from the unaffected left side of the patient, and vascular
anastomoses were created in an end-to-side fashion to the ulnar artery in the
mid-part of the forearm and to a large branch of the forearm venous system. A
nonmeshed split-thickness skin graft, harvested from the contralateral buttock
region, was applied for muscle coverage.
Surgical pathology specimens consisting of excised tissue were submitted
for examination. Histopathologic analysis revealed multiple nodules of
hyalinized fibrous tissue involving the skin, subcutaneous tissue, and
tendons. The nodules were composed of hypocellular fascicles of fibroblasts
that were interspersed between broad bundles of hyalinized collagen. In many
of these nodules, a gradual or sharp transition to deposits of bone was
present (Figs. 3-A through
3-E). In some areas, sheet-like deposits of woven bone were
present, while in other areas within the same lesion, cortical and cancellous
lamellar bone with interspersed fatty marrow was present. No cellular atypia
or neural components were observed.
There were no postoperative complications, and the patient recovered well
on a maintenance dose of etidronate (400 mg orally, twice daily for six months
following surgery). At the time of the five-year follow-up, there was no
evidence of recurrence at the operative site, although a small (0.5 ×
1.0 cm) nodule had developed just adjacent to the flap on the dorsum of the
hand. Hand function had improved considerably, as the surgery had restored
side-to-side pinch. The patient was using the hand mostly in the performance
of assistive functions. She had recovered only protective sensation in the
thumb and long finger.
Similarities between the syndrome that affected our patient and progressive
osseous heteroplasia prompted us to pursue a genetic diagnosis. The recent
identification of mutations in GNAS1, the gene that encodes the alpha
subunit of the stimulatory G protein of adenylyl cyclase, as the cause of
progressive osseous heteroplasia has enabled molecular screening for
progressive osseous
heteroplasia1.
Samples of genomic DNA isolated from peripheral blood samples taken from our
patient were screened by one of the authors (E.M.S.) for mutations in the
GNAS1 gene. No mutations were identified in the coding sequence of
the GNAS1 gene in our patient.
In this case report, we present a new syndrome of heterotopic ossification
that involved the right side of our patient. This new condition, which we have
termed "focal fibronodular heterotopic ossification," shares some
clinical findings with previously described disorders of heterotopic
ossification, including intra-articular and extra-articular chondromas and
osteochondromas, extraskeletal chondromas, osteomas, myositis ossificans,
pseudomalignant heterotopic ossification, and extraosseous osteosarcoma. It is
also similar to rare genetic syndromes, including fibrodysplasia ossificans
progressiva, progressive osseous heteroplasia, juvenile hyaline fibromatosis,
and Proteus syndrome, although it is clearly a distinct entity.
Fibrodysplasia ossificans progressiva is a rare genetic disorder that was
first described by Guy Patin in 1648 and that is characterized by progressive
extraskeletal ossification heralded by congenital malformation of the great
toes, thumbs, hips, and cervical
spine3,4.
Fibrodysplasia ossificans progressiva may arise spontaneously or may be
inherited in an autosomal dominant manner with variable expression and
complete
penetrance5. The
classic diagnostic triad for this disease consists of radiographic
abnormalities of the hands or feet; progressive heterotopic endochondral
ossification of skeletal muscle, tendon, and fascia; and a predictable pattern
of involvement that progresses from axial to appendicular, proximal to distal,
and cranial to
caudal6,7.
Increased heterotopic bone formation is observed in response to local trauma,
and extraskeletal ossification can lead to severe contractures. Patients with
fibrodysplasia ossificans progressiva have bilateral involvement of muscle,
tendons, and ligaments and a classically endochondral pattern of
ossification.
Despite some similarity between fibrodysplasia ossificans progressiva and
focal fibronodular heterotopic ossification, the diagnosis of fibrodysplasia
ossificans progressiva could be excluded in our patient on the basis of a lack
of congenital malformations of the toes, a lack of involvement of the axial
skeleton and chest wall, a lack of bilateral involvement, and a predominantly
intramembranous pattern of ossification.
Two disease loci have been genetically mapped in kindred with
fibrodysplasia ossificans
progressiva8,9,
and a disease-causing mutation for fibrodysplasia ossificans progressiva has
recently been identified in the glycine-serine activation domain of
ACVR1, the gene that encodes the activin A type-I receptor
8. ACVR1 is
a receptor for bone morphogenetic protein (BMP), which supports the hypothesis
that fibrodysplasia ossificans progressiva results from misregulated BMP
signaling10-12.
Recently, Ahn et al. demonstrated that the negative feedback antagonist
response to bone morphogenic protein-4 (BMP-4) stimulation is dramatically
reduced in fibrodysplasia ossificans progressiva cells compared with control
cells11. Kan et al.
further reported that progressive extraskeletal ossification develops in
transgenic mice that overexpress BMP-4 under control of the neuron-specific
enolase promoter, albeit in a pattern distinctly different from that observed
in animals with fibrodysplasia ossificans
progressiva12. De
la Pena et al. reported profound abnormalities in BMP-receptor trafficking and
downstream signaling in fibrodysplasia ossificans progressiva
cells13. The
pattern of expression of the neuron-specific enolase promoter, principally in
neurons and neuroendocrine cells, suggests that peripheral nerves may play a
role in the pathogenesis of heterotopic ossification. This hypothesis is
further bolstered by the long-standing observation that specific disorders of
the nervous system, such as closed head trauma and spinal cord injuries, can
lead to heterotopic ossification.
Progressive osseous heteroplasia, first described as a syndrome in 1994 by
Kaplan et al.14, is
a rare genetic disorder characterized by progressive heterotopic ossification
involving skin, subcutaneous fat, and deep connective
tissue15. The onset
of progressive osseous heteroplasia is usually during infancy. Maculopapular
rashes presage islands of heterotopic bone that later coalesce to form large
ossified plaques that slowly but inexorably progress to involve deep
connective tissues, leading to ankylosis of adjacent joints and retardation of
limb growth. Progressive osseous heteroplasia is distinguishable from
fibrodysplasia ossificans progressiva by bone deposition in the skin, the
absence of congenital skeletal malformations, the lack of preosseous tumorlike
swelling, and the presence of primarily intramembranous rather than
endochondral
ossification15. In
light of these findings, progressive osseous heteroplasia is clinically more
similar to focal fibronodular heterotopic ossification than is fibrodysplasia
ossificans progressiva, although progressive osseous heteroplasia can clearly
be distinguished from the condition seen in our patient on the basis of
clinical criteria. For example, the onset of symptoms in our patient was at
thirty years of age rather than in infancy, and triggering factors, such as
trauma or surgery, which do not characteristically lead to additional
progressive osseous heteroplasia lesions, led to additional ossified nodules
in adjacent tissues in our patient. In addition, large nodular lesions of
heterotopic bone are not observed in progressive osseous heteroplasia.
Juvenile hyaline fibromatosis is a rare inherited connective-tissue
disorder with onset during infancy or early
childhood16. It was
first described by Murray in 1873 under the name "molluscum
fibrosum," but it was later called "Puretic
syndrome"17,18.
Characteristic clinical findings in patients with juvenile hyaline
fibromatosis include pearly skin papules or subcutaneous nodules; plaques on
the back, ears, scalp, and hands; joint contractures; and gingival
hypertrophy. Histologically, the lesions show an abundant eosinophilic matrix
with embedded spindle and epithelioid cells without nuclear atypia.
Multinucleated giant cells with intracytoplasmic granules are also
present19,20.
Extraskeletal ossification has not been associated with juvenile hyaline
fibromatosis lesions. In five families with juvenile hyaline fibromatosis,
mutations in the capillary morphogenesis factor-2 gene (CMG2) have
been identified, and dysregulation of basement membrane architecture resulting
from these mutations has been proposed as an important etiologic
factor21,22.
Our patient did not exhibit clinical findings consistent with juvenile hyaline
fibromatosis (i.e., early onset, skin papules, and gingival hypertrophy); and
her condition was further distinguishable by the prominent presence of
ossification.
Proteus syndrome, first described by Cohen and Hayden in
197923, is a
hamartomatous disorder characterized by connective tissue nevi, epidermal
nevi, hemihypertrophy, hyperostoses, lipomas, and vascular malformations that
are present at birth and progress
thereafter24. Named
by Wiedemann in 1983 after a Greek god who could change his appearance at
will, Proteus syndrome has historically posed a difficult diagnostic challenge
due to the broad spectrum of clinical presentations that it
encompasses25-27.
More recently, Proteus syndrome has been defined more rigorously with use of a
combination of general and specific
criteria24. General
or mandatory criteria for the diagnosis of Proteus syndrome are a mosaic
distribution of lesions, sporadic occurrence, and progressive
worsening—all of which were met in the case of our patient. Specific
criteria include cerebriform connective-tissue nevi, epidermal nevi,
hemihypertrophy, skull hyperostosis, megaspondylodysplasia, splenomegaly,
vascular malformation, dysmorphic facies, and characteristic tumors including
ovarian cystadenoma and parotid monomorphic adenoma. Our patient did not
display any of these specific criteria. Mutations in the tumor suppressor gene
PTEN have been reported in some patients with Proteus
syndrome28. Because
mutations in this gene have not been found in all patients with clinically
diagnosed Proteus syndrome, it is possible that the disorder may be caused by
mutations in more than one gene or that the current clinical diagnostic
criteria may be overly inclusive.
Although the genes responsible for rare syndromes of heterotopic
ossification have not been fully identified, recent progress in this area
makes a genetic etiology for dysregulated extraskeletal ossification seem
likely. In our patient, the sporadic occurrence and strict confinement of
symptoms to the right hemicorporeum is suggestive of an etiology involving
somatic mosaicism, as in the McCune-Albright syndrome in which activating
mutations of GNAS1 found only in affected tissues cause polyostotic
fibrous dysplasia, café au lait skin patches, and endocrine
abnormalities, while germline mutations are not observed and are believed to
be lethal early in embryogenesis. Asymmetric expression itself, however, does
not prove genetic mosaicism, as patients with progressive osseous heteroplasia
with germline inactivating mutations in GNAS1 show dramatic
differences in phenotype from side to side. Notably, a patient with strictly
hemimelic progressive osseous heteroplasia has been described; however, tests
for genetic mosaicism were not
reported29. Other
musculoskeletal disorders, including Klippel-Trénaunay-Weber syndrome,
neurofibromatosis, localized giantism, and hemihypertrophy, may also
exclusively affect one side of the body, although the molecular causes of
these conditions are not fully characterized. Asymmetry may suggest that the
disease-causing mutation is necessary but not sufficient for expression of the
disease phenotype.
Existing literature regarding progressive heterotopic ossification
documents few effective medical or surgical treatments. Treatment of
fibrodysplasia ossificans progressiva with oral bisphosphonates has generally
been associated with poor
results30,31.
We undertook operative intervention in the case of our patient to eliminate a
chronic infection and simultaneously to improve the function and appearance of
what had become a disfigured and disabled hand. A contralateral latissimus
dorsi muscle flap was chosen, among other reasons, to avoid use of tissues
that might be affected by a disease-causing somatic mutation. Eventually, more
effective treatments will be based on a fundamental understanding of the
molecular etiology of this and other related conditions of progressive
heterotopic ossification. ?