ECE2009 Oral Communications Paediatric Endocrinology/Bone (6 abstracts)
The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 113 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, while PHP-Ib patients do not have AHO and hormone resistance is limited to PTH and TSH. Recently, methylation defects have been detected in 5 patients with PHP-Ia, indicating a molecular overlap between the two forms.
The aim of this study was to screen for methylation defects patients with clinically diagnosed PHP-Ia and to investigate the presence of correlations between the molecular findings and AHO severity. We investigated differential methylation of GNAS regions and STX16 microdeletions in genomic DNA from 40 patients (28 females, 12 males) with clinical diagnosis of sporadic PHP-Ia, i.e. AHO with multi-hormone resistance, with no mutations in Gsα-coding GNAS exons. Molecular analysis showed GNAS cluster imprinting defects in 22 of the 40 PHP-Ia patients analyzed. No STX16 deletion was detected. No correlation was found between the severity of AHO and the presence or absence of Imprinting defects.
In conclusion, we report the largest series of the literature of patients with PHP-Ia and confirm the existence of an overlap between molecular and clinical features of PHP-Ia and PHP-Ib. These data provide new information on this rare disease and emphasize the clinical heterogeneity of genetic defects within the GNAS locus.