Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)

J Clin Endocrinol Metab. 2020 May 1;105(5):1393-1400. doi: 10.1210/clinem/dgaa111.

Abstract

Context: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered 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: The objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1.

Methods: A 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent.

Results: The FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 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 to 2.8 mmol/L (8.0-11.2 mg/dL) and parathyroid hormone of 2.2 pmol/L; normal 1.0 to 9.3 pmol/L, and required treatment with intravenous 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 modeling 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 mobilization and mitogen-activated protein kinase 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 on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.

Keywords: calcium-sensing receptor; hypercalcemia; hypocalcemia; hypoparathyroidism; loss-of-function; mutation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child of Impaired Parents*
  • Female
  • Germ-Line Mutation
  • HEK293 Cells
  • Humans
  • Hypercalcemia / congenital*
  • Hypocalcemia / congenital*
  • Hypocalcemia / genetics
  • Infant
  • Infant, Newborn
  • Infant, Newborn, Diseases / diagnosis
  • Infant, Newborn, Diseases / genetics
  • Models, Molecular
  • Mothers
  • Nuclear Family
  • Pedigree
  • Phenotype
  • Receptors, Calcium-Sensing / chemistry
  • Receptors, Calcium-Sensing / genetics
  • Seizures / congenital*
  • Seizures / diagnosis
  • Seizures / genetics

Substances

  • CASR protein, human
  • Receptors, Calcium-Sensing

Supplementary concepts

  • Hypocalciuric hypercalcemia, familial, type 1