Genetics of pseudohypoparathyroidism: bases for proper genetic counselling.

Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH). Patients with PHP-Ia often show additional hormone resistance and characteristic physical features that are collectively termed Albright's hereditary osteodystrophy (AHO). These features are also present in pseudopseudohypoparathyroidism (PPHP), but patients with this disorder do not show hormone resistance. PHP-Ib patients, on the other hand, predominantly show renal PTH resistance and lack features of AHO. From the genetic point of view, PHP-I is caused by defects in the GNAS gene or in the 5' region of this gene locus. PHP-Ia is caused by heterozygous inactivating mutations in any of the 13 exons codifying the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gsα), while PHP-Ib is due to alterations in the methylation pattern of the 5' regions of the locus, usually associated with upstream microdeletions that are maternally transmitted. The imprinting pattern that affects the GNAS locus has important implications for the inheritance pattern and consequently for appropriate genetic counselling.