title: A hypocalcemic child with a novel activating mutation of the calcium-sensing receptor gene: successful treatment with recombinant human parathyroid hormone.
abstract: BACKGROUND
  Persistent hypercalciuria, with the attendant risk of nephrocalcinosis and eventual renal failure, is common in hypoparathyroid patients, especially those with activating mutations of the calcium-sensing receptor (CASR) gene, being treated with oral calcium and calcitriol. Treatment with replacement PTH may be warranted, although this has yet to be evaluated in children.
  
  
  OBJECTIVE
  The objectives of this study were to identify the cause of the disorder in a young hypocalcemic patient and to assess the efficacy of treatment of the patient with recombinant human PTH(1-34).
  
  
  METHODS
  An infant presenting with hypocalcemia at 3 wk of age was studied.
  
  
  METHODS
  CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The patient was treated with twice-daily administration of recombinant human PTH(1-34) over a 17-month period.
  
  
  RESULTS
  The proband was heterozygous for a de novo novel missense mutation (L727Q), on the border between transmembrane helix 4 and intracellular loop 2 of the CASR. When transiently expressed in a human embryonic kidney 293 cell line, the mutant receptor demonstrated a significant leftward shift in the extracellular calcium/intracellular signaling dose-response curve vs. that for the wild-type receptor [EC(50); mutant, 2.59 +/- 0.11 mm (mean +/- se) vs. wild-type, 3.78 +/- 0.12 mm, P < 0.001]. During treatment with PTH(1-34), the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably.
  
  
  CONCLUSIONS
  PTH should be evaluated further as a treatment of autosomal dominant hypocalcemia in young patients.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Mail Stop Number 61, Los Angeles, California 90027, USA. smittelman@chla.usc.edu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Mittelman
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.forename: Richard A
authors.initials: RA
authors.lastname: Fefferman
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.forename: Irina
authors.initials: I
authors.lastname: Mosesova
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
authors.forename: Linda
authors.initials: L
authors.lastname: Burkett
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Geffner
mesh_terms: D002118:Calcium / Q000652:urine; D002460:Cell Line; D019281:Dimerization; D004622:Embryo, Mammalian; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D006996:Hypocalcemia / Q000188:drug therapy* / Q000235:genetics*; D007223:Infant; D007668:Kidney; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics*; D010281:Parathyroid Hormone / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D044169:Receptors, Calcium-Sensing / Q000737:chemistry / Q000235:genetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014162:Transfection
chemical_list: D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D011994:Recombinant Proteins; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium