Progressive Osseous Heteroplasia is not an Autosomal Dominant Trait but Reflects Superimposed Mosaicism in Different GNAS Inactivation Disorders.

Abstract

Progressive osseous heteroplasia (POH) is a rarely occurring genetic condition characterized by severe segmental ossification involving the skin and deep connective tissues including the muscles. So far, the disorder is generally described as an autosomal dominant trait. By contrast, the following arguments are in favor of the alternative concept that POH should rather be taken as a non-specific segmental manifestation of different GNAS inactivation disorders such as Albright hereditary osteodystrophy (AHO) with hormone resistance, AHO without hormone resistance, and osteomatosis cutis. Presently, POH has got its own OMIM number 166350 but this is obviously wrong because the disorder does not reflect heterozygosity for a GNAS mutation. Conversely, the disorder is most likely due to an early event of postzygotic loss of heterozygosity with loss of the corresponding wild-type allele. This alternative concept, as proposed in 2016, offers a plausible explanation for the following features of POH. Familial occurrence is usually absent. POH is usually observed in families with one of the three GNAS inactivation disorders as mentioned above. Mosaicism is suggested by the pronounced segmental manifestation of POH and by its lateralization. Some patients have, in addition to POH, bilaterally disseminated features of osteomatosis cutis or AHO, and other patients have family members with one of these nonsegmental disorders. Remarkably, POH tends to appear much earlier than the nonsegmental GNAS inactivation disorders. – Molecular support of the concept was documented in a superficial variant of POH called 'plate-like osteoma cutis'. In several other autosomal dominant skin disorders, molecular corroboration of the theory of superimposed mosaicism has been provided. – For all of these reasons, it is unlikely that POH can further be taken as a distinct autosomal dominant trait. Generation of more molecular data in multiple cases of POH occurring in GNAS inactivation disorders will be crucial to corroborate the proposed concept.