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 inactivating mutations of the Ca++-sensing receptor (CASR) gene at 3q13.3-21. Most heterozygotes are clinically asymptomatic but manifest as familial (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 homozygosity for an insertion mutation in exon 7 of CASR 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 decade ago and are well now. A fifth went undiagnosed until adulthood and has profound musculoskeletal and neurobehavioral deficits. Among 36 identified FHH heterozygotes are 3 individuals with an unexpected degree of hypercalcemia and elevated circulating parathyroid hormone levels consistent with secondary hyperparathyroidism. Two are obligately heterozygous offspring of NSHPT mothers with surgical hypoparathyroidism and variable compliance with vitamin D therapy. The other is an adult with coexistent celiac disease in whom hyperparathyroidism, probably secondary to vitamin D deficiency, led to surgery. In counseling affected families, the heterozygous state should not be considered entirely benign, since FHH heterozygotes, particularly infants, may be prone to secondary hyperparathyroidism and symptomatic hypercalcemia. In such families, molecular diagnosis will allow for unambiguous identification of at-risk individuals.