Anuja Shah1, Clinton J Miller2, Cynthia C Nast3, Mark D Adams4, Barbara Truitt2, John A Tayek5, Lili Tong1, Parag Mehtani1, Francisco Monteon6, John R Sedor7, Erica L Clinkenbeard8, Kenneth White8, Rajnish Mehrotra1, Janine LaPage1, Patricia Dickson9, Sharon G Adler1, Sudha K Iyengar2. 1. Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. 2. Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. 3. Division of Pathology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. 4. J. Craig Venter Institute, San Diego, CA 92121, USA. 5. Division of General Internal Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. 6. Unidad de Nefrologia y Transplante, Hospital Mexico-Americano, Guadalajara, Jalisco, Mexico. 7. Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA. 8. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 9. Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
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.
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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