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

Department of Medical Sciences (G.M., S.B., A.G.L., P.B.-P., A.S.), Endocrine Unit, Fondazione Policlinico Instituto di Ricovero e Cura a Carattere Scientifico, University of Milan, 20122 Milan, Italy; Pediatric Endocrinology and Institut National de la Santé et de la Recherche Médicale U561 (A.L.), St. Vincent de Paul Hospital, 75014 Paris, France; Department of Pediatrics (M.M.), Istituto Giannina Gaslini Instituto di Ricovero e Cura a Carattere Scientifico, University of Genova, 16145 Genova, Italy; Department of Pediatrics (M.C.), Fondazione Instituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, University of Pavia, 27100 Pavia, Italy; and Endocrinology and Diabetology Unit (S.C.), Department of Medical-Surgical Sciences, Policlinico San Donato Instituto di Ricovero e Cura a Carattere Scientifico, San Donato Milanese, University of Milan, Milan, 20095 Italy

Address all correspondence and requests for reprints to: Giovanna Mantovani, M.D., Ph.D., Unità di Endocrinologia, Pad. Granelli, Fondazione Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico, Via Francesco Sforza, 35, 20122 Milano, Italy. E-mail: giovanna.mantovani{at}unimi.it.

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.

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