Mantovani Giovanna, Bondioni Sara, Linglart Agnès, Maghnie Mohamad, Cisternino Mariangela, Corbetta Sabrina, Lania Andrea G, Beck-Peccoz Paolo, Spada Anna
Department of Medical Sciences, Endocrine Unit, Fondazione Policlinico Instituto di Ricovero e Cura a Carattere Scientifico, University of Milan, 20122 Milan, Italy.
J Clin Endocrinol Metab. 2007 Sep;92(9):3738-42. doi: 10.1210/jc.2007-0869. Epub 2007 Jun 26.
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.
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.
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.
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.
假性甲状旁腺功能减退症（PHP）Ia型和Ib型分别由GNAS外显子1 - 13的突变和GNAS甲基化缺陷引起。PHP - Ia患者表现出Albright遗传性骨营养不良（AHO）以及对甲状旁腺激素（PTH）和其他激素的抵抗，而PHP - Ib患者没有AHO，且激素抵抗仅限于PTH，并且正如一篇论文所报道的，还包括促甲状腺激素（TSH）。尚无研究探讨PHP - Ib患者生长激素（GH）缺乏的问题。
本研究的目的是对临床诊断为PHP - Ib的患者进行基因缺陷筛查，并调查其对TSH和生长激素释放激素（GHRH）的抵抗情况。
患者/方法：我们调查了10例临床诊断为散发性PHP - Ib（即无AHO的PTH抵抗）患者基因组DNA中的GNAS差异甲基化和 syntaxin 16（STX16）微缺失情况。通过GH对GHRH加精氨酸的反应评估对GHRH的抵抗。还评估了甲状腺功能和超声检查。
分子分析显示所有PHP - Ib患者均存在GNAS簇印记缺陷，且在1例明显散发的患者中首次发现了新生的STX16缺失。10例患者中有9例因对TSH抵抗而出现亚临床或临床甲状腺功能减退，而除1例患者外，所有患者对GHRH加精氨酸试验的GH反应均正常。
我们报告了对意大利PHP - Ib患者的首次分子分析。临床研究表明，与PHP - Ia患者一样，PHP - Ib患者对TSH有抵抗，而与PHP - Ia患者不同的是，他们对GHRH保持正常反应性。这些数据为这种罕见疾病提供了新信息，并强调了GNAS内基因缺陷的临床异质性。
