title: Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medical Sciences, Endocrine Unit, Fondazione Policlinico Instituto di Ricovero e Cura a Carattere Scientifico, University of Milan, 20122 Milan, Italy. giovanna.mantovani@unimi.it
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
authors.forename: Sara
authors.initials: S
authors.lastname: Bondioni
authors.forename: Agnès
authors.initials: A
authors.lastname: Linglart
authors.forename: Mohamad
authors.initials: M
authors.lastname: Maghnie
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cisternino
authors.forename: Sabrina
authors.initials: S
authors.lastname: Corbetta
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Lania
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Anna
authors.initials: A
authors.lastname: Spada
mesh_terms: D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000008:administration & dosage; D002864:Chromogranins; D004252:DNA Mutational Analysis; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D005820:Genetic Testing; D013007:Growth Hormone-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008875:Middle Aged; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D013972:Thyrotropin / Q000494:pharmacology*
chemical_list: D002864:Chromogranins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D013007:Growth Hormone-Releasing Hormone; D001120:Arginine; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs