Genetic Analysis and Evaluation of Resistance to Thyrotropin and Growth Hormone-Releasing Hormone in Pseudohypoparathyroidism Type Ib

• Published in: The journal of clinical endocrinology and metabolism 2007-09, Vol.92 (9), p.3738-3742
• Main Authors: Mantovani, Giovanna, Bondioni, Sara, Linglart, Agnès, Maghnie, Mohamad, Cisternino, Mariangela, Corbetta, Sabrina, Lania, Andrea G., Beck-Peccoz, Paolo, Spada, Anna
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Arginine - administration & dosage; Biological and medical sciences; Chromogranins; DNA Mutational Analysis; Drug Resistance - genetics; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Genetic Testing; Growth Hormone-Releasing Hormone - administration & dosage; Growth Hormone-Releasing Hormone - pharmacology; GTP-Binding Protein alpha Subunits, Gs - genetics; Human Growth Hormone - secretion; Humans; Insulin-Like Growth Factor I - analysis; Male; Medical sciences; Middle Aged; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases); Pseudohypoparathyroidism - genetics; Thyrotropin - pharmacology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2007-0869

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.