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

Abstract

Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present 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). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A ⁶⁸Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving 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. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several 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.

Graphical abstract

Fig. 1

Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.

Fig. 2

Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.

Fig. 3

Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).

Fig. 4

Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.

Fig. 5

Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.

Fig. 6

FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).

Fig. 7

Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.