Endocrine Abstracts

Pseudohypoparathyroidism type 1B (PHP-1B) is a rare, familial or sporadic, imprinting disorder due to the epigenetic dysregulation of the GNAS locus, whose main product is the α subunit of the stimulatory G protein (Gsα). Sporadic PHP-1B cases (spor-PHP-1B) display broad methylation abnormalities at multiple GNAS DMRs, but the underlying molecular mechanism is still unknown.

Classically, PHP-1B patients show PTH and TSH resistance, but, in the past years, also physical features of Albright hereditary osteodystrophy (AHO) were described, suggesting the existence of an overlap among PHP subtypes. Moreover, mutations in PRKAR1A and PDE4D genes, and deletions of 2q37 were reported in small subsets of clinically diagnosed PHP patients with no detectable GNAS defects, highlighting the clinical overlap with diseases in differential diagnosis. Brachydactyly-mental retardation syndrome (BDMR), associated with 2q37 deletions, may present a spectrum of clinical features, including intellectual disabilities, developmental delays, behavioural abnormalities and skeletal abnormalities, among which brachydactyly type E.

In the present study, we screened our series of spor-PHP-1B pts with (n=21) or without AHO (n=33) for BDMR-associated deletions to find modifier genes possibly involved in the phenotypic heterogeneity observed in PHP-1B, and we detected 2 different deletions (ranging from ~2.83-Mb up to ~4.5-Mb) in 2 unrelated pts with AHO. Additional analysis confirmed rearrangements and allowed to roughly delineate the genetic defects extension.

Deletions overlapped with previously described rearrangements and included several genes already proposed as causative for BDMR. Interestingly, our mutated patients displayed molecular (GNAS loss of imprinting) and endocrine characteristics (overt PTH resistance) usually absent in BDMR, although so far only one BDMR patient with raised PTH levels was described (Power et al. 1997 J Med Genet). These preliminary results prompt us to confirm the causative role of found genetic variants, and to clarify their role in the pathogenesis of specific and unexpected clinical manifestations.