Osteofibrous Dysplasia, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to osteofibrous dysplasia (OSFD) is conferred by heterozygous mutation in the MET gene (164860) on chromosome 7q31.

Description

Osteofibrous dysplasia is a tumor-like bone lesion that usually presents as a painless swelling or anterior bowing of the tibia (Park et al., 1993), although pain may occur in up to 25% of cases and presentation may follow pathologic fracture. Most reports of osteofibrous dysplasia describe isolated tibial lesions, although a significant subgroup describe isolated and ipsilateral fibular involvement. Cases with ulnar and radial involvement have been reported (summary by Hunter and Jarvis, 2002).

OSFD is characterized by radiolucent lesions located at the periosteal surface of the diaphyseal cortex, almost exclusively of the tibia and fibula. These lesions are congenital and spontaneously resolve during skeletal maturation; the residuum is most commonly mild bowing at the affected site. Prior to their resolution, secondary complications such as nonunion fractures and pseudoarthrosis formation can occur. Histologically, OSFD lesions exhibit 'zonal architecture' characterized by spindle-shaped fibroblast-like cells in the center of the lesions that are progressively replaced with peripherally located, more differentiated cells from the osteoblastic lineage. The cells lying at the center of the lesions stain for markers of undifferentiated mesenchymal cell states, whereas bridging zones of osteoid with surface osteoblasts and embedded osteocytic cells are interspersed between the lesions. In OSFD, the unossified zones eventually mineralize after replacement with normal osteoid and, finally, bone. This histologic progression corresponds with the clinical and radiographic resolution of the lesions (summary by Gray et al., 2015).

Hunter and Jarvis (2002) noted that there may be a relationship between osteofibrous dysplasia and adamantinoma of long bones (102660), although the latter condition usually presents at a later age.

Clinical Features

Beals and Fraser (1976) observed congenital bowing leading to pseudarthrosis of the tibia or fibula, or both, in 3 sibs and thereafter examined all available members of the kindred. These examinations demonstrated the syndrome of congenital bowing of the tibia, fibular hypoplasia, and pectus excavatum transmitted as an autosomal dominant trait. One individual also had apparently healed congenital pseudarthrosis of the ulna. Affected members were observed in 3 generations and 5 sibships with 2 instances of male-to-male transmission.

Sunkara et al. (1997) described 2 unrelated children with bilateral osteofibrous dysplasia. The first was a girl noted to have nontender bowing of her left tibia at birth. Radiographs revealed metaphyseal-diaphyseal lucent defects in the proximal tibia bilaterally, with anterior bowing and periosteal reaction of the left tibia. At 8 months of age, she presented with a pathologic fracture of the left tibia; tissue removed from the lesion was consistent with osteofibrous dysplasia. The second patient was a boy who was noted to have right anterior tibial swelling at age 2 years, at which time x-rays showed cortex-based lucencies in both tibias. By age 4 years, the lesions in both tibias had grown; biopsy of the larger lesion on the left, through which he subsequently developed a fracture, showed osteofibrous dysplasia.

Hunter and Jarvis (2002) could find only 2 reported cases of osteofibrous dysplasia in which tibial involvement was reported as bilateral. They described 2 brothers, 1 with bilateral and 1 with probable bilateral tibial involvement, and a girl from an unrelated family with bilateral tibial involvement. In 1 of the brothers, onset was at the age of 6 years, when swelling over the right leg was noted; in the other brother, a 'small bump' over the right anterior tibia was noted at the age of 4 years. The girl had presentation at the age of 8 years with bilateral shin pain and a bumpy prominence over the anterior aspect of the midshaft of both tibias.

Karol et al. (2005) reported a family in which 6 individuals over 3 generations had lytic lesion of the tibia that resembled osteofibrous dysplasia radiographically and histologically; 3 of the patients had been described previously by Roach et al. (1993). All 6 had pathologic fractures of the tibia or fibula in childhood, but none had femoral lesions or pathologic fractures in the upper extremities. X-rays showed well-demarcated lytic lesions, not limited to the cortex of the bone, with surrounding sclerosis. Histologic analysis of lesional tissue from one of the patients revealed a fibrous stroma with spicules of osseous trabeculae, rimmed with osteoblasts. In the 3 patients for whom x-rays obtained in adulthood were available, irregularities in the medullary canal of the fibula and thickening of the fibular diaphyseal cortex were observed, but there was no evidence of persistent disease. Radiographs of 10 clinically unaffected relatives did not reveal pathologic lesions in the tibia or femur, and there was no evidence of a previous fracture.

Pathogenesis

Gray et al. (2015) analyzed lesional tissue from an affected member of a 4-generation family with OSFD, originally reported by Beals and Fraser (1976), and observed the typical zonal architecture of OSFD. Histologic staining of the cells rimming the lesions revealed markers of osteoblastic differentiation such as osterix (SP7; 606633) and alkaline phosphatase (see 171760). Osteoclasts staining for tartrate-resistant acid phosphatase (ACP5; 171640) were also prominent at the periphery of the lesions. Noting that centrally located cells in OSFD lesions stain positively for markers associated with undifferentiated mesenchymal cells (Taylor et al., 2012), Gray et al. (2015) suggested that the pathogenesis of OSFD might be related to a delay in osteogenesis, with lesions resolving at the margins through the action of rimming osteoblasts and osteoclasts.

Molecular Genetics

In 8 affected individuals from a 4-generation family with OSFD, originally reported by Beals and Fraser (1976), Gray et al. (2015) identified heterozygosity for a 26-bp deletion in the MET gene (164860.0013). The deletion showed incomplete penetrance, being present in 1 unaffected family member, but it was not found in the Exome Variant Server or dbSNP (build 131) databases. Exome sequencing in a second family with OSFD, previously studied by Karol et al. (2005), revealed a heterozygous splice site mutation in the MET gene (164860.0014) that was also incompletely penetrant, being present in 5 affected and 4 unaffected family members. The same splice site mutation was detected in an affected mother and son from a third family, as well as in tissue from an unrelated female patient with OSFD, who was originally reported by Sunkara et al. (1997). Both mutations involve exon 14 and result in its exclusion from the MET transcript. Analysis of 20 tissue samples from patients with sporadic unilateral OSFD revealed a somatic missense mutation in 1 sample (Y1003S), also involving exon 14 of the MET gene. In transfected HEK293 cells, Gray et al. (2015) demonstrated that MET mutants involving deletion of exon 14 or the Y1003S mutation stabilize the MET receptor, resulting in a gain of function.

History

Frangenheim (1921) is credited with the first description of this disorder, which has gone by a variety of names, with osteofibrous dysplasia, suggested by Campanacci (1976), the most frequently used term. The abbreviation OFD has the disadvantage of confusion with the several orofaciodigital syndromes, e.g., OFD1 (311200).