Etiology and Signs/Symptoms

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• Caused by a monogenic disorder, i.e. alterations in one gene

  • ACVR1/ALK2 gene located in chromosome 2

  • Recurrent heterozygous gain of function and autosomal dominant mutation

• Can be sporadic (not often) or inherited

• The ACVR1/ALK2 gene encodes for a transmembrane serine/threonine kinase receptor, ALK2, which binds with bone morphogenetic proteins (BMPs) present in the bone matrix

  • involves the BMP signalling pathway: help with the formation of bone and other organ systems

  • BMPs induce the development of heterotopic bone in the skeletal muscle

• Majority of FOP cases show a similar genetic mutation which consists of a change of nucleotide in the codon at position 617 from G to A in the ACVR1/ALK2 gene

  • This results in a substitution mutation in the codon at position 206 from arginine to histidine (R206H) within the ALK2 protein

• Additional mutations are also in exons 4-7 within the ACVR1/ALK2 gene: Q207E, G328W, R258S​, and R206H

• This results in the change of expression of two domains, including the serine/threonine kinase domain and the glycine/serine-rich domain

  • Both of these domains have important roles in intracellular signalling

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• Congenital crooked big toe (hallux valgus) deformity that is most often bilateral (>97%)

  • Prenatal ultrasound may identify a hallux valgus deformity as early as 23 weeks gestation

  • Radiographs of the halluces (big toe) demonstrate short, malformed first metatarsal and dysplasia

• Progressive heterotopic ossification (extraosseous bone formation) (~100%) that may manifest as a palpable mass. Ossification is either spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from vaccinations or surgical procedures.

  • Visible in radiographs​

• Painful, recurrent soft-tissue swellings (flare-ups) that may precede localized heterotopic ossification. This may occur in the form of scalp nodules in infancy, which may be an early or presenting feature (~100%)

  • May present with a fever during flare-ups​

• Limb reduction defects that may affect the fingers in atypical or nonclassic FOP and may be mistaken for a brachydactyly syndrome in individuals who have not yet developed heterotopic ossifications.

• Hearing loss: Conductive hearing loss is present in 50% of individuals with FOP and may be slowly progressive. Onset is usually in childhood and may result from middle ear ossification. In some individuals, a sensorineural component may be present. Acute hearing loss is not usually associated with FOP and should prompt evaluation for other causes.

• Renal stones: Individuals with FOP have a threefold increased risk of renal stones, which may be due to a combination of immobilization coupled with increased bone turnover. There has been no comprehensive study of stone composition in individuals with FOP.

• Lymphedema: may occur with flare-ups affecting the limbs. This may be acute, subacute, or chronic. In some individuals, underlying deep vein thrombosis may be present.

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Additional skeletal malformations and manifestations variably seen:

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• Variable thumb malformations may be present in some individuals, including hypoplasia and dysplastic phalanges.

• Limb reduction defects affecting the fingers may be seen in atypical FOP.

• Cervical spine fusions between C2 and C7 may be noted on cervical spine radiographs and may contribute to limitations in mobility as heterotopic ossification progresses. This occurs from intra-articular ankylosis of facet joints and early degenerative changes of the cervical spine.

• Scoliosis affects up to 65% of individuals, may be rapidly progressive as a result of paravertebral lesions, and may contribute to thoracic insufficiency syndrome.

• Congenital short broad femoral necks may be identified in pelvic radiographs. This rarely affects function.

• Developmental hip dysplasia is present in 60% of individuals with acute hip pain.

• Osteochondromas are reported in up to 90% of individuals, with the proximal medial tibia the most common location.

• Enchondromas, a benign tumour originating in cartilaginous tissue, have been described in several individuals; the prevalence is unknown.

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