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

Abstract

BackgroundNSHPT 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. ObjectiveTo describe a case of NSHPT unresponsive to cinacalcet. Patient and ResultsA 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 4.75mmol/l (N: 2.10–2.62), P: 0.83mmol/l (1.55–2.64), PTH: 1096pg/ml (9–52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10IU/kg×4/day), and then 2days later, pamidronate (0.5mg/kg) for 2days. Doses of cinacalcet were given daily from day 28 of life starting at 30mg/m2 and increasing to 90mg/m2 on day 43. On day 33, 6days after pamidronate, serum Ca levels had fallen to 2.5mmol/l but, thereafter, rose to 5mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18days. At 3months, the girl was mildly hypercalcemic, with no supplementation, and at 6months, 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. ConclusionThe 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.