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CONTEXT: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), and considered to be a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy. OBJECTIVE: To characterise the range of calcitropic phenotypes in the children of a mother with FHH1. METHODS: A three generation FHH kindred was assessed by clinical, biochemical and mutational analysis following informed consent. RESULTS: The FHH kindred comprised a hypercalcemic male and his daughter who had hypercalcemia and hypocalciuria, and her four children, of whom two had asymptomatic hypercalcemia, one was normocalcemic, and one suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (6.28 mg/dL); normal, 2.0-2.8 mmol/L (8.0-11.2 mg/dL) and PTH of 2.2 pmol/L; normal 1.0-9.3 pmol/L, and required treatment with I-V calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modelling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilisation and MAPK responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation. CONCLUSIONS: Thus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending upon the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.

Original publication




Journal article


J Clin Endocrinol Metab

Publication Date