Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib

Giovanna Mantovani, Sara Bondioni, Agnès Linglart, Mohamad Maghnie, Mariangela Cisternino, Sabrina Corbetta, Andrea G. Lania, Paolo Beck-Peccoz, Anna Spada

Research output: Contribution to journalArticlepeer-review


Context: Pseudohypoparathyroidism (PHP) types 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, whereas 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: The objective of the study was to screen patients with clinically diagnosed PHP-Ib for genetic defects and 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 nine of 10 patients, whereas a preserved GH response to a 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, whereas 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.

Original languageEnglish
Pages (from-to)3738-3742
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Issue number9
Publication statusPublished - Sep 2007

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism


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