NEONATAL SEVERE HYPERPARATHYROIDISM, SECONDARY HYPERPARATHYROIDISM, AND FAMILIAL HYPOCALCIURIC HYPERCALCEMIA - MULTIPLE DIFFERENT PHENOTYPES ASSOCIATED WITH AN INACTIVATING ALU INSERTION MUTATION OF THE CALCIUM-SENSING RECEPTOR GENE

Neonatal severe hyperparathyroidism (NSHPT) is considered an autosomal -recessive disorder, attributable in many cases to homozygous inactiva ting mutations of the Ca++-sensing receptor (CASH) gene at 3q13.3-21. Most heterozygotes are clinically asymptomatic but manifest as familia l (benign) hypocalciuric hypercalcemia (FHH) with a laboratory profile that is variably and sometimes only marginally different from normal, In 5 NSHPT cases from 3 Nova Scotian families, we found homoallelic h omozygosity for an insertion mutation in exon 7 of CASH that includes an Alu repeat element with an exceptionally long polyA tract, Four of the 5 NSHPT infants were treated by parathyroidectomy more than a deca de ago and are well now, A fifth went undiagnosed until adulthood and has profound musculoskeletal and neurobehavioral deficits. Among 36 id entified FHH heterozygotes are 3 individuals with an unexpected degree of hypercalcemia and elevated circulating parathyroid hormone levels consistent with secondary hyperparathyroidism, Two are obligately hete rozygous offspring of NSHPT mothers with surgical hypoparathyroidism a nd variable compliance with vitamin D therapy, The other is an adult w ith coexistent celiac disease in whom hyperparathyroidism, probably se condary to vitamin D deficiency, led to surgery. In counseling affecte d families, the heterozygous state should not be considered entirely b enign, since FHH heterozygotes, particularly infants, may be prone to secondary hyperparathyroidism and symptomatic hypercalcemia, In such f amilies, molecular diagnosis will allow for unambiguous identification of at-risk individuals. (C) 1997 Wiley-Liss, Inc.