Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: A fibroblast growth factor 23 mutation identified by exome sequencing

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. Methods 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. Results 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. Conclusions 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.

Original languageEnglish
Pages (from-to)2235-2243
Number of pages9
JournalNephrology Dialysis Transplantation
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Exome
Hyperphosphatemia
Vascular Calcification
Calcinosis
Mutation
Amputation
Blood Vessels
fibroblast growth factor 23
Siblings
Theoretical Models
Alleles
Bone and Bones

Keywords

  • vascular calcification

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia : A fibroblast growth factor 23 mutation identified by exome sequencing. / Shah, Anuja; Miller, Clinton J.; Nast, Cynthia C.; Adams, Mark D.; Truitt, Barbara; Tayek, John A.; Tong, Lili; Mehtani, Parag; Monteon, Francisco; Sedor, John R.; Clinkenbeard, Erica L.; White, Kenneth; Mehrotra, Rajnish; LaPage, Janine; Dickson, Patricia; Adler, Sharon G.; Iyengar, Sudha K.

In: Nephrology Dialysis Transplantation, Vol. 29, No. 12, 01.12.2014, p. 2235-2243.

Research output: Contribution to journalArticle

Shah, A, Miller, CJ, Nast, CC, Adams, MD, Truitt, B, Tayek, JA, Tong, L, Mehtani, P, Monteon, F, Sedor, JR, Clinkenbeard, EL, White, K, Mehrotra, R, LaPage, J, Dickson, P, Adler, SG & Iyengar, SK 2014, 'Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: A fibroblast growth factor 23 mutation identified by exome sequencing', Nephrology Dialysis Transplantation, vol. 29, no. 12, pp. 2235-2243. https://doi.org/10.1093/ndt/gfu324
Shah, Anuja ; Miller, Clinton J. ; Nast, Cynthia C. ; Adams, Mark D. ; Truitt, Barbara ; Tayek, John A. ; Tong, Lili ; Mehtani, Parag ; Monteon, Francisco ; Sedor, John R. ; Clinkenbeard, Erica L. ; White, Kenneth ; Mehrotra, Rajnish ; LaPage, Janine ; Dickson, Patricia ; Adler, Sharon G. ; Iyengar, Sudha K. / Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia : A fibroblast growth factor 23 mutation identified by exome sequencing. In: Nephrology Dialysis Transplantation. 2014 ; Vol. 29, No. 12. pp. 2235-2243.
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AB - Background Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. Methods 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. Results 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. Conclusions 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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