Rare Diseases That Impersonate One Another:X‐LinkedHypophosphatemia andTumor‐InducedOsteomalacia, a Retrospective Analysis of Discriminating Features

Abstract

Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate‐wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades‐old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X‐linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p < 0.001) and alkaline phosphatase (282.8 versus 118.5 IU/L, p < 0.01) but significantly reduced phosphorus (1.4 versus 2.2 mg/dL, p < 0.05) and 1,25(OH)2 D (16.6 versus 59.8 pg/mL, p < 0.01). By contrast, total vitamin D was similar between the two groups. Dual‐energy X‐ray absorptiometry (DXA) scans reveal lower Z‐scores in the hip (−1.6 versus 0.050, p < 0.01) and spine (0.80 versus 2.35, p < 0.05). TIO patients were more likely to have prior clinical diagnosis of osteoporosis (67% versus 0%), use assistive devices in daily living (100% versus 14%), and have received a knee arthroplasty (33% versus 7%). TIO patients lost an average of 1.5 cm over their disease course and had sustained an average of 8 fractures each, whereas fractures were rare in XLH. The XLH cohort had higher incidence of osteotomy (19% versus 0%), spinal stenosis (12% versus 0%), secondary dental abnormalities (95% versus 44%, p < 0.001), and depression and anxiety (46.5% versus 11%). These results deepen our understanding of the subtle differences present between diseases of phosphate wasting. They suggest several biochemical, clinical, and historical features that effectively distinguish TIO from XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Global guidance for the recognition, diagnosis, and management of tumor‐induced osteomalacia

“…The potential for the biochemical differentiation of TIO with XLH continues to be investigated. One retrospective analysis indicated that patients with TIO had significantly higher levels of FGF23 and alkaline phosphate, significantly lower levels of phosphorus and 1,25(OH) 2 D, but similar levels of 25-hydroxyvitamin D (25[OH]D) compared with patients with XLH [36]. A potential role for sclerostin in the differentiation of TIO and XLH has also been proposed, with one cross-sectional study reporting decreased levels in patients with TIO and increased levels in patients with XLH [49].…”

“…A careful medical history should include the age of onset and accompanying symptoms, which may include bone pain, muscle weakness and pain, fatigue, decreased exercise tolerance, gait disturbance, height loss, increased thoracic kyphosis, pectus carinatum, and fractures [ 30 , 33 , 34 , 35 , 36 , 37 ]. Cases have been reported in individuals as young as 9 months old [ 38 ], with a median age of onset of 46 years and a range of 9 months–90 years [ 7 , 39 ].…”