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Anuja Shah, Clinton J. Miller, Cynthia C. Nast, Mark D. Adams, Barbara Truitt, John A. Tayek, Lili Tong, Parag Mehtani, Francisco Monteon, John R. Sedor, Erica L. Clinkenbeard, Kenneth White, Rajnish Mehrotra, Janine LaPage, Patricia Dickson, Sharon G. Adler, Sudha K. Iyengar, Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing, Nephrology Dialysis Transplantation, Volume 29, Issue 12, December 2014, Pages 2235–2243, https://doi.org/10.1093/ndt/gfu324
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Abstract
Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia.
We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed.
We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function.
This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.
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