Fibrodysplasia ossificans progressiva and progressive osseous heteroplasia

Abstract

Heterotopic ossification (HO) as a primary clinical finding is uncommon, but it occurs in two human genetic disorders: fibrodysplasia ossific, ans progressiva (FOP) and progressive osseous heteroplasia (POH). In these disorders, the progression and stages of the ectopic bone formation appear normal, but disregulation of cell differentiation leads to improper induction of bone formation—in other words, normal bone forms in the wrong place at the wrong time. Cases of POH were initially recognized following misdiagnosis as FOP. However, POH can be distinguished from FOP by several criteria: the presence of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumor-like swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional patterns of HO, and the predominance of intramembranous rather than endochondral ossification. Both FOP and POH are rare conditions, with most cases apparently the result of a de novo (spontaneous) mutation: however, when inherited, both are transmitted through an autosomal-dominant inheritance pattern. Although FOP can be inherited from either a mother or a father, POH is only inheried paternally. Consistent with this parental inheritance pattern, POH patients carry inactivating mutations of the GNAS gene, a gene that is regulated through genomic imprinting and allele-specific gene expression. The genetic cause of FOP remains undetermined. A combination of clinical and genetic evaluations can identify FOP and POH, two distinct disorders of extensive HO.