Progressive osseous heteroplasia (POH) describes a severe, debilitating disease characterized by ectopic intramembranous bone formation that affects not only the subcutis, but also the skeletal muscle and the deep connective tissue [145]. Heterozygous inactivation mutations within the Gsα coding GNAS exons have also been identified in patients with POH. In fact, some of those mutations are identical to those found in patients with PHP-Ia or PPHP [145-147]. It is therefore possible that POH is an extreme manifestation of the ectopic bone formation of AHO that normally involves the subcutaneous tissue. However, POH is rarely accompanied with any AHO features or hormone resistance [146, 148]. Furthermore, in many kindreds, it has been shown that the disease develops only after paternal inheritance [147], suggesting that genomic imprinting also plays a role in the pathogenesis of POH. Because this disorder is paternally inherited, deficiency of GNAS products that show paternal specific expression and share exons with Gsα, such as XLαs, could contribute to ectopic bone formation. Consistent with this hypothesis, no mutations in exon 1 has thus far been reported in cases with isolated POH [147, 149, 150]. However, the roles of XLαs and other imprinted GNAS products in POH remain currently undefined.
