Chapter 69: Disorders of Phosphate Homeostasis Mary D. Ruppe and Suzanne M. Jan de Beur

Table 1. Clinical Consequences of Hypophosphatemia From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition. www.asbmrprimer.org Table 1. Clinical Consequences of Hypophosphatemia © 2008 American Society for Bone and Mineral Research

Table 2. Causes of Hypophosphatemia From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition. www.asbmrprimer.org Table 2. Causes of Hypophosphatemia © 2008 American Society for Bone and Mineral Research

Table 3. Characteristics of Renal Phosphate Wasting Disorders From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition. www.asbmrprimer.org Table 3. Characteristics of Renal Phosphate Wasting Disorders © 2008 American Society for Bone and Mineral Research

Table 4. Causes of Hyperphosphatemia From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition. www.asbmrprimer.org Table 4. Causes of Hyperphosphatemia © 2008 American Society for Bone and Mineral Research

From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition. www.asbmrprimer.org Figure 1 Figure 1 Molecular mechanisms of disorders of phosphate homeostasis. Three major mechanisms of hypophosphatemia are FGF23 excess caused by ectopic production as in TIO, excess bone production seen in XLH, ARHR, ADHR, FD, and OGD, and mutation in the FGF23 gene that renders the protein resistant to inactivation. Hypophosphatemia may also be secondary to excess KLOTHO, the co-factor necessary for FGF23 signaling as seen in a patient with hypophosphatemic rickets with hyperparathyroidism. Finally, homozygous inactivating mutations in SLC34A3, which encodes NaPiIIc, or dominant negative mutations in SLC34A2 that encodes NaPiIIa result in phosphate wasting caused by the absence of sodium-phosphate co-transporters. Hyperphosphatemia is caused by FGF23 deficiency, either through inactivating mutations in FGF23, aberrant glycosylation of FGF23 caused by GALNT3 mutations, or FGF23 resistance caused by inactivating KLOTHO mutations. Figure 1 Molecular mechanisms of disorders of phosphate homeostasis. Three major mechanisms of hypophosphatemia are FGF23 excess caused by ectopic production as in TIO, excess bone production seen in XLH, ARHR, ADHR, FD, and OGD, and mutation in the FGF23 gene that renders the protein resistant to inactivation. Hypophosphatemia may also be secondary to excess KLOTHO, the co-factor necessary for FGF23 signaling as seen in a patient with hypophosphatemic rickets with hyperparathyroidism. Finally, homozygous inactivating mutations in SLC34A3, which encodes NaPiIIc, or dominant negative mutations in SLC34A2 that encodes NaPiIIa result in phosphate wasting caused by the absence of sodium-phosphate co-transporters. Hyperphosphatemia is caused by FGF23 deficiency, either through inactivating mutations in FGF23, aberrant glycosylation of FGF23 caused by GALNT3 mutations, or FGF23 resistance caused by inactivating KLOTHO mutations. © 2008 American Society for Bone and Mineral Research

From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition. www.asbmrprimer.org Figure 2 Figure 2 Radiographic and histologic features in TIO. (A) Octreotide scan showing small mesenchymal tumor in the head of the humerus. (B) Hemiangiopericytoma with with numerous pericytes and vascular channels (H&E strain). (C) Bone biopsy with Goldner stain. Excessive osteoid or unmineralized bone matrix composed mainly of collagen stains pink. Minerlized bone stains blue. This bone biopsy shows severe osteomalacia. Figure 2 Radiographic and histologic features in TIO. (A) Octreotide scan showing small mesenchymal tumor in the head of the humerus. (B) Hemiangiopericytoma with with numerous pericytes and vascular channels (H&E strain). (C) Bone biopsy with Goldner stain. Excessive osteoid or unmineralized bone matrix composed mainly of collagen stains pink. Minerlized bone stains blue. This bone biopsy shows severe osteomalacia. © 2008 American Society for Bone and Mineral Research