Endocrine Abstracts

The term pseudohypoparathyroidism (PHP) defines a heterogeneous group of rare, related and deeply impairing metabolic diseases due to end-organ resistance to the actions of PTH, associated to molecular defects at the GNAS locus. Different subtypes of PHP have been described based on the existence of additional clinical features, such as resistance to other hormones acting via GPCRs and Albright’s hereditary osteodystrophy (AHO). Recently, the detection in a small subset of PHP patients with no GNAS defects of genetic defects associated with diseases showing a phenotypic overlap with PHP, such as acrodysostosis (ACRDYS) and brachydactyly-mental retardation syndrome (BDMR), challenged the distinction of these complex disorders. Despite the high detection rate of genetic and epigenetic defects by currently available molecular approaches, about 30% of PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS genetic or epigenetic defects also for chromosomal regions and genes associated to diseases that undergo differential diagnosis with PHP. To this purpose, we screened our AHO/PHP patients negative for GNAS point mutations, structural rearrangements and imprinting defects (sporadic or genetic-based), for the presence of genetic mutations at PRKAR1A (n=58), PDE4D (n=18), as well as for deletions affecting the subtelomeric region of the long arm of chromosome 2 (n=38). We detected 2 missense mutations at the PRKAR1A gene, 2 intronic mutations at the PDE4D gene and two deletions involving the chromosome 2q37 and overlapping with previously described rearrangements affecting this subtelomeric region. In silico analysis predicted a pathological effect for all genetic defects found in our patients.

These findings highlight the complexity in performing an accurate diagnosis of PHP, further confirming the molecular and clinical overlap among these disorders, as well as the pivotal role of the cAMP pathway in the development of the AHO phenotype.