Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.
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.
Rutsch
Frank
F
Department of General Pediatrics, University Children's Hospital, Münster, Germany. rutschf@mednet.uni-muenster.de
Böyer
Petra
P
Nitschke
Yvonne
Y
Ruf
Nico
N
Lorenz-Depierieux
Bettina
B
Wittkampf
Tanja
T
Weissen-Plenz
Gabriele
G
Fischer
Rudolf-Josef
RJ
Mughal
Zulf
Z
Gregory
John W
JW
Davies
Justin H
JH
Loirat
Chantal
C
Strom
Tim M
TM
Schnabel
Dirk
D
Nürnberg
Peter
P
Terkeltaub
Robert
R
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
D004164:Diphosphonates; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases