pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is a group of rare inherited disorders characterized by end-organ resistance to parathyroid hormone (PTH). The resulting biochemical pattern is hypocalcemia with hyperphosphatemia and elevated circulating PTH. PHP most often occurs with Albright hereditary osteodystrophy (AHO), a constellation of skeletal and soft-tissue features that may accompany the condition. The underlying defect typically involves the GNAS gene, which encodes the alpha subunit of the stimulatory G protein (Gsα) and is subject to genomic imprinting.

The PHP family is subdivided by the presence of AHO and by the pattern of hormone resistance. PHP type 1A combines PTH resistance with AHO and is usually due to maternally inherited GNAS mutations, with resistance to several hormones beyond PTH. PHP type 1B largely presents with PTH resistance and little or no AHO, often caused by epigenetic changes at the GNAS locus. PHP type 1C is clinically similar to type 1A but may lack a detectable GNAS mutation. Pseudopseudohypoparathyroidism (PPHP) refers to the AHO phenotype without biochemical PTH resistance.

Clinically, patients may experience symptoms of hypocalcemia such as numbness, muscle cramps, tetany, seizures, or brain irritability, and laboratory tests show low calcium, high phosphate, and high PTH. Skeletal findings of AHO include short stature with brachydactyly and subcutaneous calcifications. Diagnosis combines biochemical testing with genetic or epigenetic analyses and, in some settings, PTH-stimulated cAMP tests.

Management focuses on correcting calcium and phosphate abnormalities, typically with calcium supplementation and active vitamin D (calcitriol), while monitoring for resistance to other hormones (thyroid, gonadal). Treatment is lifelong and requires regular endocrinology follow-up. The condition is rare and varies in severity and associated hormone resistance.