Identification and functional characterization of a homozygous, inactivating CaSR mutation in a patient with rickets

Context: Over 200 mutations in the human calcium-sensing receptor (CaSR) gene have been reported. Heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH), whereas homozygous inactivating mutations lead to neonatal severe hyperparathyroidism (NSHPT).

Subjects and Results: A 16 year old Lebanese female presented with valgus deformity. Laboratory studies showed severe vitamin D deficiency, low normal serum calcium levels and significantly elevated PTH levels. 6 months after commencement of vitamin D treatment for rickets elevated calcium levels and inappropriately normal PTH were found. A low urinary calcium to creatinine ratio suggested FHH. Genomic testing revealed a mutation in the CaSR gene (Q459R), which surprisingly was homozygous in the index patient and heterozygous in both parents. In vitro studies showed a mild functional inactivation of the Q459R mutant. The calcimimetic NPS R-568 was able to sensitize the mutated receptor to calcium and improve its signaling function.

Conclusions: Homozygous inactivating mutations of the CaSR usually result in severe hypercalcemia in neonates. Homozygosity for a mildly inactivating CaSR mutation can however result in a much less severe phenotype resembling FHH. When FHH and rickets coincide, vitamin D deficiency and CaSR inactivation may mutually compensate and mask their effects on serum calcium but may worsen the skeletal complications.