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Oncogenic hypophosphataemic osteomalacia: biomarker roles of fibroblast growth factor 23, 1,25-dihydroxyvitamin D₃ and lymphatic vessel endothelial hyaluronan receptor 1

Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Headington, Oxford, OX3 7LJ, UK¹ Department of Pathology, Nuffield Department of Orthopaedic Surgery² Department of Radiology and³ Nuffield Department of Orthopaedic Surgery, Nuffield Orthopaedic Centre, Headington, Oxford, OX3 7LD, UK and⁴ Department of Clinical Biochemistry, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK

(Correspondence should be addressed to R V Thakker; Email: rajesh.thakker{at}ndm.ox.ac.uk)

Abstract

Oncogenic osteomalacia (OOM) is characterised by tumour production of fibroblast growth factor 23 (FGF23) that results in hypophosphataemia and renal phosphate wasting, reduced 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) synthesis and osteomalacia. Here, we demonstrate the roles of serum FGF23 and 1,25(OH)₂D₃, together with the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), as biomarkers for OOM. A previously well 52-year-old man presented with a 2-year history of generalised musculoskeletal pain and proximal myopathy. He had hypophosphataemia, elevated serum alkaline phosphatase activity, low serum 1,25(OH)₂D₃ and a reduced tubular maximum of phosphate/glomerular filtration rate. These findings indicated a diagnosis of OOM, but magnetic resonance imaging (MRI) and octreotide scintigraphy did not identify any tumours. Treatment with oral phosphate and calcitriol resolved the symptoms and biochemical abnormalities within 6 months. Four years later, he relapsed whilst on treatment with oral phosphate and calcitriol. Serum FGF23 concentration was elevated and MRI identified a 2 cm tumour within Hoffa's fat pad of the left knee. Removal of the tumour resulted in a complete resolution of symptoms and normalisation of the serum biochemical abnormalities including serum FGF23. Histology demonstrated a phosphaturic mesenchymal tumour, mixed connective tissue variant (PMTMCT), which revealed immunostaining with anti-LYVE-1 antibody and hence the presence of lymphatic vessels. Serum FGF23 and 1,25(OH)₂D₃ were found to be reliable biomarkers for OOM. In addition, the demonstration of lymphatics in the PMTMCT helps to distinguish this tumour from most typical benign haemangiomas.