TY - CHAP M1 - Book, Section TI - Pseudohypoparathyroidism A1 - Spiegel, Allen M. A1 - Weinstein, Lee S. A2 - Valle, David L. A2 - Antonarakis, Stylianos A2 - Ballabio, Andrea A2 - Beaudet, Arthur L. A2 - Mitchell, Grant A. PY - 2019 T2 - The Online Metabolic and Molecular Bases of Inherited Disease AB - Pseudohypoparathyroidism is a term applied to a heterogeneous group of disorders whose common feature is resistance to parathyroid hormone.Most patients with pseudohypoparathyroidism are hypocalcemic and hyperphosphatemic despite elevated concentrations of parathyroid hormone in plasma. Hypocalcemia and hyperphosphatemia are due to loss of the phosphaturic action of parathyroid hormone and reduced formation of 1,25-dihydroxyvitamin D with resultant defective mobilization of calcium from bone and reduced gastrointestinal absorption of calcium.Clinical features and nature of the putative defect causing hormone resistance permit separation of pseudohypoparathyroidism into distinct subtypes.Pseudohypoparathyroidism type Ia is associated with resistance to multiple hormones in addition to parathyroid hormone, and with a constellation of physical abnormalities collectively termed “Albright hereditary osteodystrophy.” Patients with pseudohypoparathyroidism Ia may show clinical signs of, or even present with, endocrinopathies other than hypoparathyroidism, presumably due to generalized hormone resistance. Relatives of patients with pseudohypoparathyroidism may show features of Albright hereditary osteodystrophy without overt hormone resistance, a condition termed pseudopseudohypoparathyroidism. The molecular defect causing hormone resistance in most, but not all, patients with pseudohypoparathyroidism Ia is a deficiency in a guanine nucleotide-binding protein (Gs) that couples hormone receptors to stimulation of adenylyl cyclase. Distinct heterozygous mutations in the gene encoding the Gs-α subunit have been identified in affected individuals from many families with pseudohypoparathyroidism Ia. The disease is inherited in an autosomal dominant fashion, with evidence for paternal imprinting of the Gs-α gene. Thus, offspring who inherit the mutant gene from their mother are affected with pseudohypoparathyroidism, whereas those who inherit the mutant gene from their father show the pseudopseudohypoparathyroidism phenotype. Some patients with similar mutations present with progressive osseous heteroplasia, a severe disorder of ectopic ossification. A defect in some other general component of the receptor-Gs-αdenylyl cyclase complex is postulated in patients with the identical phenotype of pseudohypoparathyroidism Ia but normal Gs activity.In pseudohypoparathyroidism type Ib, physical appearance is normal, and resistance is generally limited to the renal response to parathyroid hormone. As in pseudohypoparathyroidism Ia, the defect is located proximal to cAMP formation. The disease may be both sporadic and familial. Almost all cases of pseudohypoparathyroidism type Ib are associated with an imprinting defect in the GS-α gene that presumably leads to loss of GS-αexpression in renal proximal tubules. Rarely, this disorder is associated with GS-αmutations that lead to specific uncoupling from the parathyroid hormone receptor.Pseudohypoparathyroidism type II is rarely if ever familial. Resistance is limited to parathyroid hormone and is due to a defect distal to cAMP formation. SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/29 UR - ommbid.mhmedical.com/content.aspx?aid=1181454137 ER -