Pseudohypoparathyroidism type 1B caused by methylation changes at the GNAS complex locus.

Pseudohypoparathyroidism type 1B (PHP1B) consists of a heterogeneous group of disorders characterised by resistance to parathyroid hormone (PTH). There are several different PHP1B subtypes that are all associated with methylation changes at GNAS. These epigenetic changes are caused by maternal deletions in GNAS or STX16, by paternal uniparental isodisomy of chromosome 20q (patUPD20q) or by undefined genetic mutations. The GNAS methylation changes are ultimately responsible for resistance to PTH signalling in the proximal renal tubules. However, there is no PTH resistance in the distal renal tubules nor in bone cells; consequently, patients with PHP1B have reduced urinary calcium excretion and can readily mobilise calcium (and phosphate) from the skeleton. We report a case of a sporadic PHP1B patient with broad GNAS methylation changes that were presumably caused by an unknown genetic mutation outside the GNAS locus. PTH resistance was preceded by several years by autoimmune negative hypothyroidism. Treatment consisted of calcium substitution and calcitriol.