Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis

Familial hypoparathyroidism is an unusual and genetically heterogeneous gro up of disorders that may be isolated or may be associated with congenital o r acquired abnormalities in other organs or glands. We have evaluated a fam ily with a novel syndrome of autosomal dominant hypoparathyroidism, short s tature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroidism, a move ment disorder secondary to ectopic calcification of the cerebellum and basa l ganglia, and a history of knee and hip replacements for osteoarthritis. T wo members of generation II and one member of generation III were also docu mented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 yr. Because of the known association between autosomal dominant hypoparathyroid ism and activating mutations of the calcium-sensing receptor (CaR) gene, fu rther studies were performed. Sequencing of PCR-amplified genomic DNA revea led a leucine to valine substitution at position 616 in the first transmemb rane domain of the CaR, which cosegregated with the disorder. However, this amino acid sequence change did not affect the total accumulation of inosit ol phosphates as a function of extracellular calcium concentrations in tran sfected HEK-293 cells. In conclusion, a sequence alteration in the coding region of the CaR gene w as identified, but is not conclusively involved in the etiology of this nov el syndrome. The cosegregation of hypoparathyroidism, short stature, and os teoarthritis in this kindred does suggest a genetic abnormality involving a common molecular mechanism in parathyroid, bone, and cartilage.