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

Abstract

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.

• Authors: Giovanna Mantovani, Sara Bondioni, Agnès Linglart, Mohamad Maghnie, Mariangela Cisternino, Sabrina Corbetta, Andrea G Lania, Paolo Beck-Peccoz, Anna Spada
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 92 Issue 9 Pg. 3738-42 (Sep 2007) ISSN: 0021-972X [Print] United States
• PMID: 17595244 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromogranins
• Human Growth Hormone
• Insulin-Like Growth Factor I
• Thyrotropin
• Growth Hormone-Releasing Hormone
• Arginine
• GNAS protein, human
• GTP-Binding Protein alpha Subunits, Gs

Topics

• Adolescent
• Adult
• Arginine (administration & dosage)
• Chromogranins
• DNA Mutational Analysis
• Drug Resistance (genetics)
• Female
• GTP-Binding Protein alpha Subunits, Gs (genetics)
• Genetic Testing
• Growth Hormone-Releasing Hormone (administration & dosage, pharmacology)
• Human Growth Hormone (metabolism)
• Humans
• Insulin-Like Growth Factor I (analysis)
• Male
• Middle Aged
• Pseudohypoparathyroidism (genetics)
• Thyrotropin (pharmacology)