Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis

Familial hypoparathyroidism is an unusual and genetically heterogeneous group of disorders that may be isolated or may be associated with congenital or acquired abnormalities in other organs or glands. We have evaluated a family with a novel syndrome of autosomal dominant hypoparathyroidism, short stature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and one member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 yr. Because of the known association between autosomal dominant hypoparathyroidism and activating mutations of the calcium-sensing receptor (CaR) gene, further studies were performed. Sequencing of PCR-amplified genomic DNA revealed a leucine to valine substitution at position 616 in the first transmembrane domain of the CaR, which cosegregated with the disorder. However, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK-293 cells. In conclusion, a sequence alteration in the coding region of the CaR gene was identified, but is not conclusively involved in the etiology of this novel syndrome. The cosegregation of hypoparathyroidism, short stature, and osteoarthritis in this kindred does suggest a genetic abnormality involving a common molecular mechanism in parathyroid, bone, and cartilage.