Molecular and Clinical Aspects of Pseudohypoparathyroidism

The term pseudohypoparathyroidism (PHP) refers to a condition in which biochemical hypoparathyroidism (i.e., hypocalcemia and hyperphosphatemia) is due not to deficiency of parathyroid hormone (PTH) but rather to unresponsiveness of target tissues to the biological actions of PTH. Plasma concentrations of PTH are increased in patients with PHP, a feature that distinguishes this disorder from hypoparathyroidism, in which parathyroid insufficiency is associated with low plasma levels of PTH. Therefore, PHP differs fundamentally from true hypoparathyroidism. Patients with PHP type 1 fail to show a phosphaturic response to injected parathyroid hormone due to a defect in PTH signaling that impairs generation of cyclic AMP (cAMP) in the proximal renal tubular cells. These observations ultimately led to the discovery that PHP type 1 is caused by genetic or epigenetic defects that impair expression GNAS, an imprinted gene that encodes the alpha subunit of Gs, the heterotrimeric G-protein that couples receptors to stimulation of adenylyl cyclase. Clinical, endocrinological, and molecular studies over the past two decades have led to distinction of PHP type 1 into two major forms, PHP type 1a and type 1b. Individuals who have type 1a typically have end organ resistance to multiple hormones and manifest a combination of developmental defects that include variable neurocognitive disability, short stature, brachydactyly, obesity, and heterotopic bone formation. These features have been termed Albright hereditary osteodystrophy (AHO). By contrast, subjects with type 1b have hormone resistance that is usually limited to PTH, and few if any features of AHO. Accurate distinction between these two forms of PHP type 1 rests on the combination of clinical criteria and molecular testing. Subjects with type 1a have point mutations or small deletions within the maternally derived GNAS allele that reduce expression or function of the encoded Gαs protein. By contrast, subjects with PHP type 1b have paternal-specific DNA methylation imprints in critical regions of the maternal GNAS allele that reduce transcription of Gαs-specific mRNA. While small deletions and/or paternal uniparental disomy in the critical 20q13.2 locus have been found in most cases of familial PHP type 1b, genetic defects have not been identified in typical cases of sporadic PHP type 1b. PHP type 1 is an extraordinary developmental syndrome due to its unique clinical and endocrinological features, the variable phenotypes, and the remarkable complexity of the GNAS gene.