Context: Pseudohypoparathyroidism (PHP) type Ia is a rare maternally transmitted disease due to maternal loss-of-function mutations of GNAS, the gene encoding G_s, the alpha stimulatory subunit of the G protein. Affected individuals display hormonal resistance (mainly PTH and TSH resistance) and Albright hereditary osteodystrophy. PHP type Ib, usually defined by isolated renal resistance to PTH and sometimes mild TSH resistance, is due to a maternal loss of GNAS exon A/B methylation, leading to decreased G_s expression in specific tissues.

Objective and Results: We report a girl with obvious Albright osteodystrophy features, PTH resistance, normal G_s bioactivity in red blood cells, yet no loss-of-function mutation in the GNAS coding sequence (exon 1 through 13). The methylation analysis of the four GNAS Differentially Methylated Regions (DMRs), i.e. NESP, AS, XL and A/B revealed broad methylation changes at all DMRs, including GNAS exon A/B, leading to a paternal epigenotype on both alleles.

Conclusions: This observation suggests that: 1) the decreased expression of G_s due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone; and 2) PHP type Ib is a heterogeneous disorder that should lead to studying GNAS epigenotype in patients with PHP and no mutation in GNAS exon 1–13, regardless of their physical features.