Oncogenic osteomalacia,also known as tumor-induced osteomalacia or oncogenic hypophosphatemicosteomalacia,is an uncommon disorder resulting in increased renalphosphateexcretion,hypophosphatemiaand osteomalacia. It may be caused by a phosphaturic mesenchymal tumor. Symptoms typically include crushing fatigue, severe muscle weakness and brain fog due to the low circulating levels of serum phosphate.
| Oncogenic osteomalacia/tumor induced osteomalacia | |
|---|---|
| Other names | Tumor-induced osteomalacia |
Signs and symptoms
editAdult patients may present with worsening musculoskeletal symptoms,muscle weakness,[1]myalgia,bone painandfatiguewhich are followed by recurrentbone fractures.Children present withdifficulty in walking,stunted growthand deformities of the skeleton (features ofrickets).[2]There can also be a significant delay between the beginning of symptoms to diagnosis, which research reflects as being between 2.5 and 28 years.[3][1]
Cause
editTumor-induced osteomalacia is usually referred to as aparaneoplasticphenomenon, however, the tumors are usuallybenignand the symptomatology is due to osteomalacia or rickets.[4]A benignmesenchymalor mixedconnective tissue tumor(usuallyphosphaturic mesenchymal tumor[5]andhemangiopericytoma) are the most common associated tumors.[6]Association with mesenchymal malignant tumors, such asosteosarcomaandfibrosarcoma,has also been reported.[6] Locating the tumor can prove to be difficult and may require whole bodyMRI.Some of the tumors expresssomatostatinreceptors and may be located byoctreotidescanning.
A phosphaturic mesenchymal tumor is an extremely rarebenignneoplasmofsoft tissueandbonethat inappropriately producesfibroblast growth factor23. Thistumormay cause tumor-induced osteomalacia, aparaneoplastic syndrome,by the secretion of FGF23, which has phosphaturic activity (byinhibitionofrenaltubular reabsorptionofphosphateand renal conversion of25-hydroxyvitamin Dto1,25-dihydroxyvitamin D). The paraneoplastic effects can be debilitating and are only reversed on discovery andsurgical resectionof the tumor.[6]
Pathogenesis
editFGF23 (fibroblast growth factor 23), and likely other phosphatonins, inhibit phosphate transport in the renal tubule and reduce calcitriol production by thekidney.Tumor production of FGF23,[7]Secreted frizzled-related protein 4[8]andmatrix extracellular phosphoglycoprotein(MEPE)[9]have all been identified as possible causative agents for the hypophosphatemia.
Diagnosis
editBiochemical studies reveal hypophosphatemia (low blood phosphate), elevatedalkaline phosphataseand low serum1,25 dihydroxyvitamin Dlevels. Routine laboratory tests may not include serum phosphate levels and this can result in considerable delay in diagnosis. Even when low phosphate is measured, its significance is often overlooked. The next most appropriate test is measurement of urine phosphate levels. If there is inappropriately high urine phosphate (phosphaturia) in the setting of low serum phosphate (hypophosphatemia), there should be a high suspicion for tumor-induced osteomalacia. FGF23 (see below) can be measured to confirm the diagnosis but this test is not widely available.
Once hypophosphatemia and phosphaturia have been identified, begin a search for the causative tumor, which may be small and difficult to detect. Gallium-68 DOTA-Octreotate (DOTA-TATE) positron emission tomography (PET) scanning is the best way to locate these tumors.[10]If this scan is not available, other options include Indium-111 Octreotide (Octreoscan) SPECT/CT, whole body CT or MRI imaging.
Differential diagnosis
editSerum chemistries are identical in tumor-induced osteomalacia,X-linked hypophosphatemic rickets(XHR) andautosomal dominant hypophosphatemic rickets(ADHR). A negative family history can be useful in distinguishing tumor induced osteomalacia from XHR and ADHR. If necessary,genetic testingfor PHEX (phosphate regulating gene with homologies to endopeptidase on the X-chromosome) can be used to conclusively diagnose XHR and testing for the FGF23 gene will identify patients with ADHR.
Treatment
editResectionof the tumor is the ideal treatment and results in correction of hypophosphatemia (and low calcitriol levels) within hours of resection. Resolution of skeletal abnormalities may take many months.
If the tumor cannot be located, begin treatment with calcitriol (1–3 μg/day) and phosphate supplementation (1–4 g/day in divided doses). Tumors that express somatostatin receptors may respond to treatment with octreotide. If hypophosphatemia persists despite calcitriol and phosphate supplementation, administration ofcinacalcethas been shown to be useful.[11]
References
edit- ^abKaur T, Rush ET, Bhattacharya RK (March 2019)."Phosphaturic Mesenchymal Heel Tumor Presenting with Tumor-Induced Osteomalacia".AACE Clinical Case Reports.5(2): e138–e141.doi:10.4158/ACCR-2018-0300.PMC6873860.PMID31967019.
- ^Jan de Beur SM (September 2005). "Tumor-induced osteomalacia".JAMA.294(10): 1260–1267.doi:10.1001/jama.294.10.1260.PMID16160135.
- ^Chong WH, Molinolo AA, Chen CC, Collins MT (June 2011)."Tumor-induced osteomalacia".Endocrine-Related Cancer.18(3): R53–R77.doi:10.1530/ERC-11-0006.PMC3433741.PMID21490240.
- ^Carpenter TO (April 2003). "Oncogenic osteomalacia--a complex dance of factors".The New England Journal of Medicine.348(17): 1705–1708.doi:10.1056/NEJMe030037.PMID12711747.
- ^Wasserman JK, Purgina B, Lai CK, Gravel D, Mahaffey A, Bell D, Chiosea SI (September 2016)."Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis".Head and Neck Pathology.10(3): 279–285.doi:10.1007/s12105-015-0678-1.PMC4972751.PMID26759148.
- ^abcZadik Y, Nitzan DW (February 2012). "Tumor induced osteomalacia: a forgotten paraneoplastic syndrome?".Oral Oncology.48(2): e9-10.doi:10.1016/j.oraloncology.2011.09.011.PMID21985764.
- ^Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. (May 2001)."Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia".Proceedings of the National Academy of Sciences of the United States of America.98(11): 6500–6505.Bibcode:2001PNAS...98.6500S.doi:10.1073/pnas.101545198.PMC33497.PMID11344269.
- ^Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, et al. (September 2003)."Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent".The Journal of Clinical Investigation.112(5): 785–794.doi:10.1172/JCI18563.PMC182208.PMID12952927.
- ^Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL (July 2000). "MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia".Genomics.67(1): 54–68.doi:10.1006/geno.2000.6235.PMID10945470.
- ^Clifton-Bligh RJ, Hofman MS, Duncan E, Sim I, Darnell D, Clarkson A, et al. (February 2013)."Improving diagnosis of tumor-induced osteomalacia with Gallium-68 DOTATATE PET/CT".The Journal of Clinical Endocrinology and Metabolism.98(2): 687–694.doi:10.1210/jc.2012-3642.PMID23295468.
- ^Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT (June 2007)."Cinacalcet in the management of tumor-induced osteomalacia".Journal of Bone and Mineral Research.22(6): 931–937.doi:10.1359/jbmr.070304.PMID17352646.
Further reading
edit- Chong WH, Molinolo AA, Chen CC, Collins MT (June 2011)."Tumor-induced osteomalacia".Endocrine-Related Cancer.18(3): R53–R77.doi:10.1530/ERC-11-0006.PMC3433741.PMID21490240.
- Wasserman JK, Purgina B, Lai CK, Gravel D, Mahaffey A, Bell D, Chiosea SI (September 2016)."Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis".Head and Neck Pathology.10(3): 279–285.doi:10.1007/s12105-015-0678-1.PMC4972751.PMID26759148.