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. (J Clin Endocrinol Metab 92: 3738 -3742, 2007) P SEUDOHYPOPARATHYROIDISM (PHP) refers to a heterogeneous group of rare metabolic disorders characterized by hypocalcemia and hyperphosphatemia due to PTH resistance (1, 2). The two main subtypes of PHP, PHP types Ia and Ib, are caused by genetic alterations within or upstream of the GNAS locus. GNAS gives rise to several different transcripts, including Gs␣, XL␣s (extra-large variant of Gs␣), neuroendocrine secretory protein (NESP) 55, and several additional sense and antisense transcripts. The complexity of the GNAS locus is furthermore reflected by the parent-specific methylation pattern of most of its different promoters (Fig. 1A) (reviewed in Ref. 3).Heterozygous loss-of-function mutations in exons 1-13 of the Gs␣ gene inherited from the mother lead to PHP-Ia, in which Albright's hereditary osteodystrophy (AHO), a disorder characterized by a constellation of physical features (short stature, obesity, round face, brachydactyly, and sc calcifications), is associated with end-organ resistance to different hormones activating the Gs-coupled pathways, primarily PTH, TSH, gonadotropins (reviewed in Refs. 1, 4 and 5), and, more recently reported, GHRH (6, 7). In contrast, PHP-Ib patients do not show AHO, and hormone resistance appears to be limited to the renal actions of PTH and, as sugges...

Genetic and epigenetic states of the GNAS complex in pseudohypoparathyroidism type Ib using methylation-specific multiplex ligation-dependent probe amplification assay

“…In addition to those epigenetic alterations, genetic deletions are found within STX16, NESP55, or AS. A 3 kb deletion of STX16 was first identified and considered to be the most frequent mechanism of AD-PHP-Ib (11,12,13,14). Several other deletions have been reported since then, including a 4.4 kb deletion within STX16 (24), a 19 kb deletion in NESP55 (15), 4 and 4.7 kb deletions of NESP55/AS (16), and a 4.2 kb deletion within AS (17).…”

“…Therefore, the loss of methylation of A/B DMR is common in all patients with PHP-Ib. Genetic deletions within STX16 and NESP55/AS are not present in most sporadic PHP-Ib cases (12,13,14,18). In particular, the PTH concentration in the absence of treatment is positively correlated with the percent of methylation at the A/B DMR of GNAS (18).…”

“…AD-PHP-Ib, which is maternally transmitted in an autosomal dominant manner, is typically associated with loss of imprinting at exon A/B DMR due to microdeletions disrupting the upstream STX16 gene, which likely harbors a cis-acting control element crucial for establishing the methylation imprint at exon A/B (10). A heterozygous 3 or 4.4 kb deletion of STX16 has been identified in affected individuals and unaffected carriers of AD-PHP-Ib cases (11,12,13,14) and a few apparently sporadic PHP-Ib cases (14). In addition, deletions of NESP and/or AS have been identified in AD-PHP-Ib patients (15,16,17).…”

Case Report: An Unusual Cause for Hypocalcemia

“…Patients with PHP type 1a may have disturbances in taste, smell, vision, and hearing, and they may be hyporesponsive to the biologic effects of other peptide hormones that use the alpha subunit of the Gsa protein to enhance cAMP production. The hormones under this class include thyrotropin, antidiuretic hormone, the gonadotropins, glucagon, adrenocorticotropin, and growth hormonereleasing hormone h. Primary hypothyroidism occurs in most patients with PHP type 1a [7,8].…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…In patients with PHP1B, the degree of TSH resistance can vary with time 52,53,102,206 . The average level of TSH is 5.3 ± 4.7 mUI/l (4.8 ± 3.4 mUI/l and 5.4 ± 5.2 mUI/l in autosomal dominant PHP1B and sporadic PHP1B, respectively), ranging from 0.8 mUI/l to 50.0 mUI/l (reFs 36,44,[46][47][48][49]51,53,54,87,89,91,102,105,131,143,153,164,166,169,178,200,[206][207][208][209][210] ).…”