Pseudohypoparathyroidism and GNAS epigenetic defects : clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients

Context: The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster, 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 appears to be limited to PTH and TSH. Recently, methylation defects have been detected in few patients with PHP and mild AHO, indicating a molecular overlap between the two forms. Objectives: The aim of the study was to screen patients with clinically diagnosed PHP-Ia for methylation defects and to investigate the presence of correlations between the molecular findings and AHO severity. Patients and Methods: We investigated differential methylation of GNAS regions and STX16 microdeletions in genomicDNAfrom 40 patients with sporadicAHOand multihormone resistance, with no mutations in Gs -coding GNAS exons. Results: Molecular analysis showed GNAS cluster imprinting defects in 24 of the 40 patients analyzed. NoSTX16 deletion was detected. The presence of imprinting defects was not associated with the severity of AHO or with specific AHO signs. Conclusions: We report the largest series of the literature of patients with clinical AHO and multihormone resistance and no mutation in the Gs gene. Our findings of frequent GNAS imprinting defects further confirm the existence of an overlap between molecular and clinical features of PHP-Ia and PHP-Ib and highlight the necessity of a new clinical classification of the disease that takes into account the recent knowledge on the molecular basis underlying these defects.