Fibrodysplasia Ossificans Progressiva

The gene mutation for patients with classic FOP is located on chromosome 2q23-24, a locus that includes the activin A type I receptor gene. Bone morphogenetic proteins (BMPs) are extracellular ligands that exert their effects by binding serine/threonine kinase BMP receptors that include activin A receptor, type I (ACVR1). Patients have heterozygous single nucleotide substitution (guanine to adenine at position 617), which results in a change of amino acid 206 from arginine to histidine. BMP signaling is responsible for induction of pathways that lead to endochondral bone formation. Fibrodysplasia ossificans progressiva may be inherited as an autosomal dominant disorder with full penetrance (no skipped generations) but variable expressivity (variable phenotypic expression of the gene in affected members of the same family) and no sexual or ethnic predilection. However, most cases arise as a spontaneous mutation.

Characteristic skeletal malformations of the feet include reduction defects (absent phalanges) in the toes, most commonly in the great toe. Congenital bunions are also common, and their presence suggests the possibility of the disorder long before heterotopic ossification begins. The limbs may be short, but this deformity is less prevalent than the toe anomalies. The congenital skeletal abnormalities cause few problems, and the affected child remains asymptomatic until heterotopic bone formation begins. This generally occurs by age 10 (the average age at onset is 4 years) with a series of firm, painful, asymmetric soft tissue lumps in the muscles of the neck and back. These lumps, which vary in size and shape, usually appear spontaneously but may be precipitated by trauma as minor as an intramuscular injection. The severity of FOP differs among patients, but most become immobilized and wheelchair bound by the third decade. Axial involvement precedes appendicular involvement; in the limbs, proximal ossification occurs before distal ossification. The muscles of mastication are often affected, but visceral smooth muscles, sphincters, diaphragm, larynx, tongue, extraocular muscles, and the heart are clinically uninvolved. There may be a conductive hearing loss, but ocular problems do not occur. Systemic signs of disease, such as fever and malaise, are usually absent. Flares may be spontaneous or precipitated by minor trauma such as intramuscular injections.

As heterotopic ossification develops in the soft tissues throughout the body, extra-articular ankylosis of the joints occurs, beginning proximally and axially, then progressing distally throughout the appendicular skeleton. Although longitudinal growth is normal, it may be masked by deformities caused by bony ankylosis of the spine and limbs. Paradoxically, osteoporosis resulting from immobilization may occur as the disease progresses, most notably about ankylosed joints. Fractures of the osteoporotic bone or the heterotopic new bone occur occasionally.

Although clinical and radiographic findings are dramatic, laboratory studies of serum calcium, phosphate, and alkaline phosphatase, a complete blood cell count, and the erythrocyte sedimentation rate are normal.

Before clinical involvement, the muscles are histologically normal. Spontaneous edema of the interfascicular muscles occurs first, followed by proliferation of perivascular fibroblastic connective tissue. Involved muscle fibers degenerate rapidly and are replaced by a process of either intramembranous or endochondral ossification. Finally, formation of mature heterotopic lamellar bone that is indistinguishable from normal bone takes place. The disease process is true ossification, not calcification.

The mechanism by which the abnormal gene causes such protean regulatory defects is not known. Protein modeling of the glycine-serine domain of ACVR1 suggests that constitutive activation of ACVR1 with increased BMP signaling is the cause of the ectopic chondrogenesis and osteogenesis.

The diagnosis of FOP is based on clinical and radiographic findings. Primary malformations include the great toe almost always. Osteochondromas are common. Fusion of vertebral bodies occur. Femoral necks may be short but broad. Bone scans shows modeling and remodeling of the heterotopic bone. There is no increase in risk for fractures. There is no effective treatment, although administration of diphosphonates and glucocorticoids has been advocated. However, this treatment merely delays the mineralization of bone rather than impairing the production of heterotopic osteoid. Surgery may help a joint to fuse in a more functional position. Even in the late stages of the disease, patients should be considered severely disabled rather than ill. Genetic counseling should be provided to families in which the disease occurs.

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Jul 3, 2016 | Posted by in MUSCULOSKELETAL MEDICINE | Comments Off on Fibrodysplasia Ossificans Progressiva
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