Albright’s hereditary osteodystrophy

Pseudohypoparathyroidism is characterized by end-organ resistance to parathyroid hormone (98,108). This disease takes various forms, including Albright s hereditary osteodystrophy, which has unusual physical features and a generalized resistance to G-protein-linked hormones that function through cAMP as a second messenger. This defect is associated with a deficiency in the levels of the a-subunit of (109). Because this defect may be generalized, such patients also have olfactory dysfunction (110). 

Inactivating G a variants lead to Albright s hereditary osteodystrophy (AHO) in the heterozygote, snggesting that G a haploinsnfficiency canses the disorder. AHO is characterized by short statnre, obesity, brachydactyly (shortening of metacarpal and metatarsal bones), snbcntaneous ossifications, and mental or developmental deficits (86,87). The severity of the phenotype is variable. Some patients with G a mutations have few or no symptoms. 

Other causes of low serum calcium are less common. Hypoparathyroidism is due most commonly to parathyroid gland destruction during neck surgery (90%), and less commonly is idiopathic. Pseudohypoparathyroidism is biochemically similar to hypoparathyroidism however, these patients have inherited resistance to PTH and elevated concentrations of PTH. The molecular basis for the most common form, pseudohypoparathyroidism type I (Albright s hereditary osteodystrophy), is a reduction in guanine nucleotide regulatory complex. Ns, in the adenylate cyclase complex. 

Gs, alpha (GNAS) 20ql3.2 Insertions/deletions and SNPs, 20 % in exon 7 Haploinsufficiency Albright s hereditary osteodystrophy (AHO), short stature, obesity, brachydactyly, subcutaneous ossifications, developmental deficits Inactivating Gas variants lead to variable phenotype related to insufficient parathyroid hormone receptor (PTHR1) in chondrocytes [96-99]... 

Spiegel AM (1990) Albright s hereditary osteodystrophy and defective G proteins. N Engl J Med 322 1461-1462... 

An example of decreased function due to impaired activation or loss of Gsa and resistance to hormone action is pseudohypoparathyroidism Albright s hereditary osteodystrophy). Patients with this syndrome exhibit generalized resistance to the action of those hormones dependent on Gsq, for their function despite elevated serum hormone levels. Several dysmorphic features are also characteristic of these patients. 

Warner, D. R., Weng, G., Yu, S., Matalon, R., and Weinstein, L. S. (1998). A novel mutation in the switch 3 region of Gsa in a patient with albright hereditary osteodystrophy impairs GDP binding and receptor activation. J. Biol. Chem. 273,... 

---