Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia

Bone Rep. 2020 Dec 24;14:100744. doi: 10.1016/j.bonr.2020.100744. eCollection 2021 Jun.

PMID: 33490314

Juan M Colazo, Joseph A DeCorte, Erin A Gillaspie, Andrew L Folpe, Kathryn M Dahir

Summary: This case study presents a 41-year-old female with FGF23-mediated hypophosphatemia, with a 26-year delay in TIO (tumor-induced osteomalacia) diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). The study emphasizes the importance of innovative methods for clinicians, such as gene panels, CISH, and RNA sequencing, in characterizing TIO and associated tumors in the form of many phenotypically similar diseases.

Abstract

Objective: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic condition characterized by repeated bone fractures, bone pain, muscle weakness, and altered gait. It is caused by phosphaturic mesenchymal tumors (PMTs). Fibroblastic Growth Factor 23 (FGF23) is a hormone secreted by these tumors that works on the kidney to induce hypophosphatemia, which impairs bone mineralization. This case study presents a 41-year-old female with FGF23-mediated hypophosphatemia, with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH).

Results: Given the lack of a family history of hypophosphatemia, a 13-gene hypophosphatemia panel, including the XLH (PHEX gene), was conducted which came back negative, prompting a diagnostic search for a PMT causing TIO. She underwent rib resection after a 68Ga-DOTATATE PET/CT scan confirmed the existence of a 9th right rib lesion. The patient's laboratory values (particularly serum phosphorus, calcium, and vitamin D) returned to normal after surgery, with FGF23 levels decreasing immediately and symptoms disappearing over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors.

Conclusion: This case highlights that rare and diagnostically complex disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine laboratory analysis. It also emphasizes the value of innovative methods for clinicians, such as gene panels, CISH, and RNA sequencing, in characterizing TIO and associated tumors in the form of many phenotypically similar diseases.

Keywords: 68Ga-DOTATATE; Burosumab; Chromogenic in situ hybridization; FGF23; FGFR1; FN1; FN1-FGFR1; Fibroblast growth factor 23; Fibroblast growth factor receptor 1; PHEX; Paraneoplastic; Phosphaturic mesenchymal tumor; RNA sequencing; TIO; Tumor-induced osteomalacia; X-linked hypophosphatemic rickets; XLH; fibronectin; phosphate wasting disorders; phosphorous.