title: Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey.
abstract: OBJECTIVE
  Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment.
  
  
  METHODS
  Nationwide retrospective collaborative study.
  
  
  METHODS
  We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases.
  
  
  METHODS
  Activating CaSR mutations and clinical and biochemical findings were evaluated.
  
  
  RESULTS
  Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 μg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%).
  
  
  CONCLUSIONS
  This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.
authors.affiliation: Endocrine Practice and Molecular Laboratory, Heidelberg, Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Raue
authors.forename: Josef
authors.initials: J
authors.lastname: Pichl
authors.forename: Helmuth-G
authors.initials: HG
authors.lastname: Dörr
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnabel
authors.forename: Peter
authors.initials: P
authors.lastname: Heidemann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hammersen
authors.forename: Cornelia
authors.initials: C
authors.lastname: Jaursch-Hancke
authors.forename: Reinhard
authors.initials: R
authors.lastname: Santen
authors.forename: Christof
authors.initials: C
authors.lastname: Schöfl
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Christine
authors.initials: C
authors.lastname: Haag
authors.forename: Egbert
authors.initials: E
authors.lastname: Schulze
authors.forename: Karin
authors.initials: K
authors.lastname: Frank-Raue
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003625:Data Collection; D005260:Female; D005799:Genes, Dominant; D005858:Germany / Q000453:epidemiology; D006801:Humans; D006996:Hypocalcemia / Q000453:epidemiology / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D044169:Receptors, Calcium-Sensing / Q000737:chemistry / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D044169:Receptors, Calcium-Sensing