A Man With Pain in His Muscles and Bones

Camilo Jimenez, MD, Sai-Ching Jim Yeung, MDSeries Editor: Ashok Balasubramanyam, MD


April 02, 2003


Hypophosphatemia is the primary biochemical abnormality in patients with oncogenic osteomalacia. Patients invariably have decreased 1,25 (OH)2D3 serum concentrations as a consequence of a possible renal defect in the activation of 25(OH)D 1-hydroxylase. Although Fanconi syndrome also causes hypophosphatemia associated with vitamin D deficiency, the serum 1,25(OH)2D3 level is usually only slightly low or in the normal range ("inappropriately normal" for the degree of hypophosphatemia). In a very small group of patients with inherited Fanconi syndrome, 1,25 (OH)2D3 may even be appropriately elevated.

Fanconi syndrome and tumor-induced osteomalacia have very similar clinical presentations. Both conditions are characterized by a defect in the transport capacity of proximal renal tubule, resulting in impaired reabsorption of glucose, phosphate, and amino acids. The defects are usually more generalized in Fanconi syndrome than in oncogenic osteomalacia. The absorption of bicarbonate, uric acid, citrate, and low-molecular-weight proteins is usually much more impaired in patients with Fanconi syndrome. Diminished urinary excretion of calcium and magnesium and normal blood pH are usually present in both conditions.

Interestingly, both oncogenic osteomalacia and Fanconi syndrome are associated with both benign and malignant neoplasms.

Mesenchymal tumors such as giant-cell granulomas, hemangiopericytomas, hemangiomas, neuromas, and fibromas are typical neoplasms associated with oncogenic osteomalacia. Occasionally, carcinomas of epidermal or endodermal origin (eg, breast and prostate cancers) may be complicated by this paraneoplastic syndrome. In the past, the putative responsible humoral factor was termed phosphatonin. Recently, genetic analysis has shown that in many cases, the mechanistic culprit could be overproduction of fibroblast growth factor 23 (FGF23). This, in turn, could result from mutations in FGF23 that can prevent its proteolytic cleavage, or inactivating mutations in the responsible protease. In nude mice, unregulated FGF23 production results in phosphaturia, hypophosphatemia, and rickets/osteomalacia.[1]

Acquired Fanconi syndrome is associated with hematologic malignancies such as multiple myeloma, lymphomas, and amyloidosis, as well as benign hematologic conditions such as benign monoclonal gammopathy. Excessive production of immunoglobulin light chains can cause light chain nephropathy that may result in bone disease due to defective vitamin D metabolism. Although our patient did not have a frankly low serum level of 1,25(OH)2D3, the 1,25(OH)2D3 concentration was inappropriate for the degree of hypophosphatemia. In the face of marked urinary loss of phosphate, this relatively low level of 1,23 (OH)2D3 would be sufficient to cause severe osteomalacia. This patient probably had acquired Fanconi syndrome associated with B-cell lymphoma.

Regardless of the underlying cause, hypophosphatemic osteomalacia associated with both Fanconi syndrome and oncogenic osteomalacia appears to respond well to treatment with phosphate and vitamin D replacement. Effective treatment of the underlying neoplasm is also essential.


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