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Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.
Circ Cardiovasc Genet. 2008 Dec; 1(2):133-40.CC

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.

METHODS AND 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.

CONCLUSION

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.

Links

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Authors+Show Affiliations

Rutsch F
Department of General Pediatrics, University Children's Hospital, Münster, Germany. rutschf@mednet.uni-muenster.de
Böyer P
No affiliation info available
Nitschke Y
No affiliation info available
Ruf N
No affiliation info available
Lorenz-Depierieux B
No affiliation info available
Wittkampf T
No affiliation info available
Weissen-Plenz G
No affiliation info available
Fischer RJ
No affiliation info available
Mughal Z
No affiliation info available
Gregory JW
No affiliation info available
Davies JH
No affiliation info available
Loirat C
No affiliation info available
Strom TM
No affiliation info available
Schnabel D
No affiliation info available
Nürnberg P
No affiliation info available
Terkeltaub R
No affiliation info available
GACI Study Group
No affiliation info available

MeSH

AllelesAngiographyArteriesCalcinosisCohort StudiesDiphosphonatesFemaleHeterozygoteHomozygoteHumansHypophosphatemiaHypophosphatemia, FamilialInfantInfant, NewbornMaleMutationPhosphoric Diester HydrolasesPyrophosphatasesSurvival AnalysisUltrasonography

Pub Type(s)

Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

20016754

Clinical Trial Links

Study of People With Generalized Arterial Calcification of Infancy (GACI) or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2)

Citation

Rutsch, Frank, et al. "Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy." Circulation. Cardiovascular Genetics, vol. 1, no. 2, 2008, pp. 133-40.
Rutsch F, Böyer P, Nitschke Y, et al. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008;1(2):133-40.
Rutsch, F., Böyer, P., Nitschke, Y., Ruf, N., Lorenz-Depierieux, B., Wittkampf, T., Weissen-Plenz, G., Fischer, R. J., Mughal, Z., Gregory, J. W., Davies, J. H., Loirat, C., Strom, T. M., Schnabel, D., Nürnberg, P., & Terkeltaub, R. (2008). Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circulation. Cardiovascular Genetics, 1(2), 133-40. https://doi.org/10.1161/CIRCGENETICS.108.797704
Rutsch F, et al. Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy. Circ Cardiovasc Genet. 2008;1(2):133-40. PubMed PMID: 20016754.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. AU - Rutsch,Frank, AU - Böyer,Petra, AU - Nitschke,Yvonne, AU - Ruf,Nico, AU - Lorenz-Depierieux,Bettina, AU - Wittkampf,Tanja, AU - Weissen-Plenz,Gabriele, AU - Fischer,Rudolf-Josef, AU - Mughal,Zulf, AU - Gregory,John W, AU - Davies,Justin H, AU - Loirat,Chantal, AU - Strom,Tim M, AU - Schnabel,Dirk, AU - Nürnberg,Peter, AU - Terkeltaub,Robert, AU - ,, PY - 2009/12/18/entrez PY - 2009/12/18/pubmed PY - 2010/3/3/medline KW - genetics KW - mortality KW - pediatrics KW - prognosis KW - survival SP - 133 EP - 40 JF - Circulation. Cardiovascular genetics JO - Circ Cardiovasc Genet VL - 1 IS - 2 N2 - 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. METHODS AND 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. CONCLUSION: 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. SN - 1942-3268 UR - https://www.unboundmedicine.com/medline/citation/20016754/Hypophosphatemia_hyperphosphaturia_and_bisphosphonate_treatment_are_associated_with_survival_beyond_infancy_in_generalized_arterial_calcification_of_infancy_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCGENETICS.108.797704?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -