Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet

Bone. 2014 Jul:64:102-7. doi: 10.1016/j.bone.2014.04.010. Epub 2014 Apr 13.

Abstract

Background: NSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice.

Objective: To describe a case of NSHPT unresponsive to cinacalcet.

Patient and results: A 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9-52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation.

Conclusion: The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

Keywords: Calcimimetic; Calcium-sensing receptor; Mutation; Neonatal severe hyperparathyroidism.

Publication types

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

MeSH terms

  • Cinacalcet
  • Female
  • Homozygote*
  • Humans
  • Hyperparathyroidism / drug therapy*
  • Hyperparathyroidism / genetics
  • Infant, Newborn
  • Infant, Newborn, Diseases / genetics*
  • Male
  • Mutation*
  • Naphthalenes / therapeutic use*
  • Pedigree
  • Receptors, Calcium-Sensing / genetics*

Substances

  • Naphthalenes
  • Receptors, Calcium-Sensing
  • Cinacalcet