Pseudohypoparathyroidism is defined by resistance to parathyroid hormone rather than its deficiency — most often from mutations in the GNAS gene (which encodes the α-subunit of the stimulatory G protein), accounting for around 70% of cases — so patients have hypocalcemia and hyperphosphatemia despite high PTH levels. Management remains conventional: calcium supplementation and active vitamin D analogues (calcitriol) to maintain serum calcium, which addresses the hypocalcemia but not the underlying signaling resistance. An important conceptual distinction is that, unlike true hypoparathyroidism (PTH deficiency) — for which physiologic PTH replacement is now available (palopegteriparatide, approved 2024) — PTH replacement is mechanistically less applicable here, because the defect lies downstream at the receptor and G-protein level. This is why research is directed at GNAS-targeted and molecular approaches aiming to correct the signaling defect itself.
Further reading: management of hypoparathyroidism and pseudohypoparathyroidism (Khan et al., JBMR 2022); GNAS and the biology of PTH resistance.