Published online before print December 9, 2008, doi: 10.1161/CIRCGENETICS.108.797704
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Original Articles |
Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy
From the Department of General Pediatrics (F.R., P.B., Y.N., T.W.), University Children’s Hospital, Münster, Germany; Laboratory of Developmental Genetics and Imprinting (N.R.), The Babraham Institute, Cambridge, United Kingdom; Institute of Human Genetics (B.L.-D., T.M.S.), Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics (B.L.-D., T.M.S.), Klinikum rechts der Isar, Technical University, Munich, Germany; Department of Cardiothoracic Surgery (G.W.-P.), University Hospital, Münster, Germany; Department of Medical Informatics and Biomathematics (R.-J.F.), Münster University Hospital, Münster, Germany; Department of Paediatrics (Z.M.), Saint Mary’s Hospital for Women and Children, Manchester, United Kingdom; Department of Pediatric Endocrinology (J.W.G.), Wales School of Medicine, Cardiff University, Cardiff, United Kingdom; Department of Pediatric Endocrinology (J.H.D.), Southampton University Hospital, Southampton, United Kingdom; Department of Pediatric Nephrology (C.L.), Hôpital Robert Debré, Paris, France; Pediatric Endocrinology (D.S.), Otto Heubner Center, Charité, Berlin, Germany; Cologne Center for Genomics (P.N.), University of Cologne, Germany; and Department of Rheumatology Allergy/Immunology (R.T.), VA Medical Center, UCSD, San Diego, Calif.
Correspondence to Dr Frank Rutsch, Klinik und Poliklinik für Kinder-und Jugendmedizin, Universitätsklinikum Münster, Albert-Schweitzer Strasse 33, D-48149 Münster, Germany. E-mail rutschf{at}mednet.uni-muenster.de
Received June 9, 2008; accepted October 15, 2008.
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 
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.
Key Words: genetics • mortality • pediatrics • prognosis • survival
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.797704/DC1.