Pseudohypoparathyroidism (PHP) is caused by inactivation of GNAS. There are multiple PHP phenotypes resulting from GNAS inactivation, including PHP -Ia, -Ib, and –Ic. Additional phenotypes include pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). These disorders are associated with varying degrees of hormone resistance and skeletal abnormalities including short stature, subcutaneous ossifications, and brachydactyly. GNAS is an imprinted locus on chromosome 20q13.32 with a primary mechanism for GNAS inactivation resulting from methylation defects. Epigenetic inactivation of GNAS can occur through paternal uniparental disomy, isolated epimutations, and alterations in regulatory elements of GNAS or STX16.
Disorders of GNAS inactivation are examples of disorders involving imprinted genes. Imprinted genes are only expressed from either the maternally or paternally derived member of a homologous chromosome pair. Disorders of GNAS inactivation are caused by the lack of expression of GNAS. PHP -Ia, -Ib, and –Ic are caused by inactivation of the maternal GNAS complex locus while PPHP, POH, and OC are caused by inactivation of the paternal GNAS complex locus.