title: Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.
abstract: BACKGROUND
  Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy.
  
  
  RESULTS
  We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1, were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen.
  
  
  CONCLUSIONS
  ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in approximately 75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment.
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Münster, Germany. rutschf@mednet.uni-muenster.de
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.forename: Petra
authors.initials: P
authors.lastname: Böyer
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nitschke
authors.forename: Nico
authors.initials: N
authors.lastname: Ruf
authors.forename: Bettina
authors.initials: B
authors.lastname: Lorenz-Depierieux
authors.forename: Tanja
authors.initials: T
authors.lastname: Wittkampf
authors.forename: Gabriele
authors.initials: G
authors.lastname: Weissen-Plenz
authors.forename: Rudolf-Josef
authors.initials: RJ
authors.lastname: Fischer
authors.forename: Zulf
authors.initials: Z
authors.lastname: Mughal
authors.forename: John W
authors.initials: JW
authors.lastname: Gregory
authors.forename: Justin H
authors.initials: JH
authors.lastname: Davies
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnabel
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
mesh_terms: D000483:Alleles; D000792:Angiography; D001158:Arteries / Q000000981:diagnostic imaging; D002114:Calcinosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D017674:Hypophosphatemia / Q000150:complications / Q000235:genetics*; D007015:Hypophosphatemia, Familial / Q000150:complications / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014463:Ultrasonography
chemical_list: D004164:Diphosphonates; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases