Oncogenic osteomalacia (ORPHA:352540)
A rare paraneoplastic syndrome characterized by renal phosphate wasting and bone demineralization due to a phosphaturic mesenchymal tumor of the mixed connective tissue variant. It causes osteomalacia in adults with bone pain and pathological fractures, and rickets in children.
Epidemiology
The prevalence of the disease is not known. Since the association between phosphate reabsorption and tumor was first made, approximately 400 cases of oncogenic osteomalacia have been reported in the literature.
Clinical description
Disease onset typically is in adulthood, with mean age of 45 years of age, although a few pediatric cases have been reported. Typical features are chiefly related to chronic hypophosphatemia caused by hyperphosphaturia. The causative tumors are typically small and benign, occur in either bone or soft tissue, and cause no local symptoms. Patients usually present with symptoms of isolated hypophosphatemia. This means that the diagnosis is usually made late, and even when it is, the tumors are often not found. Typically, both calcium and parathyroid hormone levels are normal, as is the serum 25 hydroxyvitamin D (25OH vitamin D) concentration. Osteomalacia causes bone pain and can lead to pathological fractures or rickets in young patients where the epiphyses have not matured. Severe hypophosphatemia can cause muscle weakness.
Etiology
This syndrome is caused by phosphatonin secretion by the causative tumor. Classically the phosphatonin is FGF-23 (Fibroblast Growth Factor 23), other phosphatonins (Matrix Extracellular Phosphoglycoprotein - MEPE and secreted frizzled-related protein 4 - sFRP4) appear to have the same biochemical effect, and were, in fact discovered by examination of patients with these tumors. FGF-23 causes urinary phosphate wasting by downregulating the main renal phosphate reabsorption transporter, the type 2 sodium-phosphate cotransporter (NaPi2a), localized in the proximal tubule. FGF-23 overexpression may also affect bone mineralization by suppressing osteoblast differentiation.
Diagnostic methods
The finding of isolated hypophosphatemia, urinary phosphate wasting in the absence of the renal Fanconi syndrome and without hereditary hypophosphatemic rickets, should prompt the search for a causative tumor. As these mesenchymal tumors generally express somatostatin receptors, they can be demonstrated by somatostatin/octreotide scanning. All imaging should be whole body (vertex to toes).
Differential diagnosis
Differential diagnosis may include other forms of hypophosphatemic osteomalacia (X-linked, autosomal dominant or recessive hypophosphatemic rickets) as well as primary or acquired renal Fanconi syndrome.
Management and treatment
Definitive treatment is with surgical resection of the tumor. If the tumor cannot be found or removed, medical treatment involves the supplementation of phosphate and active vitamin D (e.g. alfacalcidol). Radiotherapy may be helpful if the tumor is located but is non-resectable for anatomical reasons. A new anti-FGF23 monoclonal antibody has been promising in the treatment of X-linked hypophosphatemic rickets, and may therefore be effective in FGF-23 mediated oncogenic osteomalacia; however, this remains to be proven.
Prognosis
Excellent recovery after complete tumor excision with complete resolution of symptoms and biochemical abnormalities. Long term monitoring is required as local recurrence and metastases have been reported, even if rarely.

                            Last update: 
                            May 2019


                            - Expert reviewer(s): 
                            Dr Laura CESCA  - Pr T. [Tom] NIJENHUIS | ERKNet* - Dr Stephen WALSH | ERKNet*


                                * European Reference Network