Context: Pseudohypoparathyroidism type Ia and Ib (PHP-Ia and -Ib), are caused by mutations in GNAS exons 1-13 and GNAS methylation defects, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, while PHP-Ib patients do not have AHO and hormone resistance is limited to PTH and, as reported in one paper, TSH. No study addressed the question of GH deficiency in PHP-Ib patients.

Objectives: To screen patients with clinically diagnosed PHP-Ib for genetic defects and to investigate the presence of resistance to TSH and GHRH.

Patients/methods: We investigated GNAS differential methylation and STX16 microdeletions in genomic DNA from 10 patients with clinical diagnosis of sporadic PHP-Ib, i.e. PTH resistance without AHO. Resistance to GHRH was assessed by GH response to GHRH plus arginine. Thyroid function and ultrasonography were also evaluated.

Results: Molecular analysis showed GNAS cluster imprinting defects in all PHP-Ib patients and the first de novo STX16 deletion in one apparently sporadic patient. Subclinical or clinical hypothyroidism due to resistance to TSH was present in 9 of 10 patients while a preserved GH response to GHRH plus arginine test was present in all patients, with one exception.

Conclusions: We report the first molecular analysis of Italian patients with PHP-Ib. Clinical investigation shows that, like PHP-Ia patients, PHP-Ib patients are resistant to TSH while they maintain a normal responsiveness to GHRH, at variance with PHP-Ia patients. These data provide new information on this rare disease and emphasize the clinical heterogeneity of genetic defects within GNAS.