Oncogenic osteomalacia: A reversible metabolic bone disorder (original) (raw)
Related papers
Hypophosphatemic rickets and osteomalacia
Arquivos Brasileiros de Endocrinologia & Metabologia, 2006
The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomaldominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well. (Arq Bras Endocrinol Metab 2006;50/4:802-813)
Bone, 2013
Although recent studies have established that osteocytes function as secretory cells that regulate phosphate metabolism, the biomolecular mechanism(s) underlying these effects remain incompletely defined. However, investigations focusing on the pathogenesis of X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR), heritable disorders characterized by abnormal renal phosphate wasting and bone mineralization, have clearly implicated FGF23 as a central factor in osteocytes underlying renal phosphate wasting, documented new molecular pathways regulating FGF23 production, and revealed complementary abnormalities in osteocytes that regulate bone mineralization. The seminal observations leading to these discoveries were the following: 1) mutations in FGF23 cause ADHR by limiting cleavage of the bioactive intact molecule, at a subtilisin-like protein convertase (SPC) site, resulting in increased circulating FGF23 levels and hypophosphatemia; 2) mutations in DMP1 cause ARHR, not only by increasing serum FGF23, albeit by enhanced production and not limited cleavage, but also by limiting production of the active DMP1 component, the C-terminal fragment, resulting in dysregulated production of DKK1 and β-catenin, which contributes to impaired bone mineralization; and 3) mutations in PHEX cause XLH both by altering FGF23 proteolysis and production and causing dysregulated production of DKK1 and β-catenin, similar to abnormalities in ADHR and ARHR, but secondary to different central pathophysiological events. These discoveries indicate that ADHR, XLH, and ARHR represent three related heritable hypophosphatemic diseases that arise from mutations in, or dysregulation of, a single common gene product, FGF23 and, in ARHR and XLH, complimentary DMP1 and PHEX directed events that contribute to abnormal bone mineralization.
The Journal of Clinical Endocrinology & Metabolism, 1997
We describe a presentation of Autosomal Dominant Hypophosphatemic Rickets (ADHR) in a 22-year-old female with normal pubertal growth and development and a negative family history in first-degree relatives. The patient presented with a 2-year history of upper and lower extremity proximal muscle pain and weakness and bilateral femoral neck and pubic bone insufficiency fractures. She had a normal serum calcium but a low phosphate as well as 25-hydroxyvitamin D (25(OH)D) levels leading initially to a diagnosis of osteomalacia. Urine phosphate reabsorption was low confirming a phosphate wasting disorder. She had an elevated Fibroblast Growth Factor 23 (FGF23) level. After Tumor-Induced Osteomalacia was ruled out by extensive imaging, she was sent for genetic testing for hereditary rickets which showed a previously reported missense variant in FGF23. Subsequently, she found out that her father's maternal aunt and grandfather had 'bone disorder' and were wheelchair-bound in adulthood. After replenishment of vitamin D, treatment with calcitriol and phosphate leads to complete resolution of patient's symptoms and laboratory abnormalities.
Molecular bases of diseases characterized by hypophosphatemia and phosphaturia: new understanding
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 2006
Serum phosphate levels are regulated in both calcium-dependent and -independent fashions. Active vitamin D increases while PTH decreases serum phosphate levels in association with the elevation of serum calcium. On the other hand, a calcium-independent phosphaturic factor, historically called phosphatonin is believed to exert a physiological function based on findings in hereditary and tumor-induced diseases characterized by hypophosphatemia with normocalcemia. Among them, autosomal dominant hypophosphatemic rickets (ADHR) has contributed greatly to its elucidation because the gene responsible for ADHR encodes fibroblast growth factor 23 (FGF23) that has been found to have a phosphaturic effect. In addition, FGF23 has been proved to be involved in most cases of oncogenic osteomalacia and X-linked hypophosphatemic rickets that are also characterized by hypophosphatemia and normocalcemia. Moreover, familial tumoral calcinosis, which represents the metabolic mirror image of hypophospha...
Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis
Current osteoporosis reports, 2014
Rapid and somewhat surprising advances have recently been made toward understanding the molecular mechanisms causing heritable disorders of hypophosphatemia. The results of clinical, genetic, and translational studies have interwoven novel concepts underlying the endocrine control of phosphate metabolism, with far-reaching implications for treatment of both rare Mendelian diseases as well as common disorders of blood phosphate excess such as chronic kidney disease (CKD). In particular, diseases caused by changes in the expression and proteolytic control of the phosphaturic hormone fibroblast growth factor-23 (FGF23) have come to the forefront in terms of directing new models explaining mineral metabolism. These hypophosphatemic disorders as well as others resulting from independent defects in phosphate transport or metabolism will be reviewed herein, and implications for emerging therapeutic strategies based upon these new findings will be discussed.
Clinical kidney journal, 2012
In oncogenic osteomalacia (OOM), fibroblast growth factor 23 (FGF23) induces renal phosphate wasting and inhibits the appropriate increase of calcitriol. A patient suffering from OOM is described. Serum calcium, phosphate, biointact parathyroid hormone and intact FGF23 as well as the calcitriol and 24,25-vitamin D levels were measured before and after tumour removal. The clinical approach to a patient with hypophosphataemia is discussed and the changes in mineral metabolism after removal of a FGF23-producing tumour are described.