title: Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatric Endocrinology, Marmara University, Pendik, Istanbul 34899, Turkey. Electronic address: atay.zeynep@yahoo.com.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Atay
authors.affiliation: Department of Pediatric Endocrinology, Marmara University, Pendik, Istanbul 34899, Turkey.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
authors.affiliation: Department of Pediatric Endocrinology, Marmara University, Pendik, Istanbul 34899, Turkey.
authors.forename: Belma
authors.initials: B
authors.lastname: Haliloglu
authors.affiliation: Department of Pediatric Endocrinology, Marmara University, Pendik, Istanbul 34899, Turkey.
authors.forename: Saygin
authors.initials: S
authors.lastname: Abali
authors.affiliation: Department of Neonatology, Marmara University, Pendik, Istanbul 34899, Turkey.
authors.forename: Tutku
authors.initials: T
authors.lastname: Ozdogan
authors.affiliation: Department of Neonatology, Marmara University, Pendik, Istanbul 34899, Turkey.
authors.forename: Emel
authors.initials: E
authors.lastname: Altuncu
authors.affiliation: Department of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec H3A 0G4, Canada; Calcium Research Laboratory and Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.affiliation: Department of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec H3A 0G4, Canada; Department of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Tatiane
authors.initials: T
authors.lastname: Vilaça
authors.affiliation: Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics, University of Toronto, Toronto, Ontario M5G IL5, Canada.
authors.forename: Betty Y L
authors.initials: BY
authors.lastname: Wong
authors.affiliation: Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics, University of Toronto, Toronto, Ontario M5G IL5, Canada.
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
authors.affiliation: Department of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec H3A 0G4, Canada; Calcium Research Laboratory and Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.affiliation: Department of Pediatric Endocrinology, Marmara University, Pendik, Istanbul 34899, Turkey.
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
mesh_terms: D000069449:Cinacalcet; D005260:Female; D006720:Homozygote; D006801:Humans; D006961:Hyperparathyroidism / Q000188:drug therapy* / Q000235:genetics; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008297:Male; D009154:Mutation; D009281:Naphthalenes / Q000627:therapeutic use*; D010375:Pedigree; D044169:Receptors, Calcium-Sensing / Q000235:genetics*
chemical_list: D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing; D000069449:Cinacalcet
keywords: Calcimimetic; Calcium-sensing receptor; Mutation; Neonatal severe hyperparathyroidism