Hypocalcemia and hyperphosphatemia despite elevated levels of parathyroid hormone (PTH) are the typical laboratory abnormalities encountered in the different forms of pseudohypoparathyroidism (PHP). Most PHP variants caused by genetic mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several sites, but in rare cases other molecular defects have been discovered.
GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Inactivating mutations involving the maternal GNAS exons 1-13 cause PHP type Ia (PHP1A). These heterozygous defects cause disease because Gsα expression from the paternal allele is dramatically reduced and absent in certain tissues, such as the proximal renal tubules, thyroid, and pituitary. Consequently, there is little or no Gsα protein in the presence of maternal GNAS mutations thus leading to PTH-resistant hypocalcemia and hyperphosphatemia. When located on the paternal allele, the same or similar Gsα-specific mutations are the cause of pseudopseudohypoparathyroidism (PPHP). Besides the biochemical abnormalities, patients affected by PHP1A show developmental abnormalities, referred to as Albrights Hereditary Osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who typically show no laboratory abnormalities. If GNAS mutations cannot be found in such patients, defects in other genes, including PTHLH, PDE4D, PDE3A, and possibly others need to be considered.
PHP type Ib is another PHP variant. The autosomal dominant form of that disorder (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss-of-methylation (LOM) at exon A/B alone or at all maternally methylated GNAS exons and their promoters. LOM of exon A/B and the resulting biallelic expression of A/B transcript reduces through as-yet unknown mechanisms Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, the most frequent disease variant, which remains unresolved at the molecular level, with the exception of those cases with duplication of the paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q). Some patients with clinical and laboratory abnormalities indistinguishable from those in PHP1B, but with normal GNAS methylation, can also be encountered because of PTH mutations thus expanding the PHP spectrum of related disorders.