Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing.
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.
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Anuja
A
Shah
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Clinton J
CJ
Miller
Division of Pathology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Cynthia C
CC
Nast
J. Craig Venter Institute, San Diego, CA 92121, USA.
Mark D
MD
Adams
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Barbara
B
Truitt
Division of General Internal Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
John A
JA
Tayek
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Lili
L
Tong
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Parag
P
Mehtani
Unidad de Nefrologia y Transplante, Hospital Mexico-Americano, Guadalajara, Jalisco, Mexico.
Francisco
F
Monteon
Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA.
John R
JR
Sedor
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Erica L
EL
Clinkenbeard
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Kenneth
K
White
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Rajnish
R
Mehrotra
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Janine
J
LaPage
Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Patricia
P
Dickson
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Sharon G
SG
Adler
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Sudha K
SK
Iyengar
D000328:Adult; D000483:Alleles; D002114:Calcinosis / Q000097:blood / Q000150:complications / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D059472:Exome; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006958:Hyperostosis, Cortical, Congenital / Q000097:blood / Q000150:complications / Q000235:genetics*; D054559:Hyperphosphatemia / Q000097:blood / Q000150:complications / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D010710:Phosphates / Q000097:blood*; D061205:Vascular Calcification / Q000097:blood / Q000209:etiology / Q000235:genetics*
C000717427:FGF23 protein, human; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D004247:DNA
FGF23; hyperphosphatemia; vascular calcification