Oncogenic rickets diagnosed at age 8 and the risk of persistent rickets: a rare case of pediatric-onset tumor-induced osteomalacia

Abstract

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excess fibroblast growth factor 23 (FGF23), leading to hypophosphatemia and osteomalacia. It typically manifests in adulthood, with pediatric cases being exceedingly rare. Early diagnosis is critical to prevent irreversible skeletal deformities. We report the case of a 19-year-old man with severe lower limb deformities and loss of ambulation since childhood. Initially misdiagnosed with X-linked hypophosphatemia (XLH) and treated with burosumab, genetic testing ruled out hereditary hypophosphatemic disorders. Further evaluation revealed an FGF23-secreting mesenchymal tumor in the right femur, confirming TIO. Surgical resection of the tumor led to biochemical remission, while burosumab treatment contributed to pain relief, functional improvement, and increased bone mineral density. Histological examination suggested potential tumor modifications linked to burosumab exposure. This case highlights the diagnostic challenge of pediatric-onset TIO, emphasizing the importance of considering oncogenic rickets in cases of early hypophosphatemic osteomalacia with severe deformities. The risk of persistent skeletal abnormalities despite treatment underscores the need for early recognition and intervention. Moreover, burosumab showed clinical efficacy in managing hypophosphatemia and symptoms, suggesting a therapeutic role in TIO when surgery is delayed or inoperable. Pediatric-onset TIO is an underrecognized entity that can lead to severe disability if not diagnosed early. This case underscores the importance of early tumor identification.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00198-025-07469-2.

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic bone disease characterized by hypophosphatemia and hyperphosphaturia induced by an overexpression of fibroblast growth factor 23 (FGF23) [1, 2], a phosphaturic hormone that regulates phosphate metabolism alongside parathyroid hormone and calcitriol [3].

The average age at diagnosis is 45 years, with a balanced sex ratio [4]. The average delay is about 3 years for tumor identification [4]. Pediatric cases are even rarer and poorly documented. Early diagnosis is crucial, as the disease is curable with complete remission in 83% of cases when the tumor is withdrawn previously to the development of irreversible deformities [5]. Furthermore, in pediatric cases, early diagnosis is even more critical as untreated TIO at this age can lead to permanent rachitic deformities. Clinically, patients usually present with diffuse pain, muscle weakness, and multiple bone fractures. Treatment generally involves surgical removal of the tumor [6]. However, in cases where the tumor is inoperable, a humanized monoclonal antibody against FGF23, burosumab, typically used in X-linked hypophosphatemia (XLH) [7], may be considered [8, 9].

The case we report here is original due to the young age of the individual and the long diagnostic delay caused by an initial misdiagnosis. Given the pediatric onset of symptoms, XLH was initially suspected and treated with burosumab. We later identified a TIO that led to surgical removal of the tumor.

Case presentation

We reviewed a 19-year-old man who had recently immigrated from Georgia. He was referred by a healthcare service dedicated to refugees for the evaluation of a complex syndrome of arthralgia, myalgia, short stature, and severe deformities of the lower limbs (Fig. 1). He started walk at a normal age but from age 8 began to experienced walking difficulties. Lower limb deformities appeared at age 12, at which age he began using an electric wheelchair. He had a history of multiple fractures in the lower limbs, with five orthopedic surgeries between the ages of 12 and 16. After the latter surgery, his lower limb pain had worsened, making standing impossible. There was no family history of bone disease and no consanguinity. He had been treated with cholecalciferol (50 drops/day) and been given a presumptive diagnosis of an osteochondrodysplasia.

Fig. 1.

Clinical and radiological deformities of the lower limbs. A Photographs of the lower limbs. B Radiograph of the individual’s left femur. C Deformation of the pelvis like a playing card, coxofemoral destruction. D Joint destruction of the left knee

Clinical presentation revealed lower limb deformities (Fig. 1) with a bowing appearance, a gibbosity, foot drop, and severe pain with minimal mobilization (bone and muscle pain of the appendicular skeleton). Height was 130 cm (> − 3 standard deviations) and weight was 43 kg, with a BMI of 25. Pubertal development was normal for his age, corresponding to Tanner stage 5 P5. Dentally, there were no infectious foci, but agenesis of teeth 12, 22, and 42 was noted. Otolaryngological examination revealed mixed deafness. Cone-beam CT showed bilateral low bone mass of the malleus and incus, predominantly on the left side, involving the head of the malleus and the body of the incus, potentially causing conductive hearing loss (a finding reported in XLH). Cardiological evaluation showed no ventricular hypertrophy.

Biological investigations showed hypophosphatemia at 0.32 mmol/L (0.8–1.4 mmol/L) with renal phosphate loss characterized by a TmP/GFR of 0.24 mmol/L (0.84–1.23 mmol/L), as well as a marked increase in alkaline phosphatase (ALP) to 875 IU/L (40–150 IU/L), notably the bone alkaline phosphatase isoform at 376 ng/mL (5–23 ng/mL). Calcitriol levels were 27 pg/mL (20–79 pg/mL).

Radiographic evaluation revealed severe lower limb deformities, cortical bone thinning, diffuse low bone density with a blurred trabecular pattern, and joint destruction in the hips, knees, and ankles (Fig. 1).

Based on these findings, we initiated supplementation with cholecalciferol (7500 IU/day) and phosphoneuros (1200 mg/day) and measured FGF23, which returned at 248 pg/mL (normal: 10–50 pg/mL).

Given the clinical presentation, X-linked hypophosphatemia (XLH) was suspected. While awaiting genetic results, treatment with burosumab (40 mg SC, one injection per month, first injection in October 2022) was initiated because of the unhealed femoral fracture. Genetic results received in October 2022 showed no mutations in the SLC34A1, SLC9A3R1, FGF23, PHEX, SLC34A3, DMP1, and ENPP1 genes, ruling out diagnostic hypotheses of XLH, autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR). In the absence of a genetic anomaly explaining the elevated FGF23, we reconsidered the diagnosis.

The primary differential diagnosis was a mesenchymal tumor secreting FGF23 (TIO), which is extremely rare at this age. An 18 FDG PET-CT scan performed in November 2022 confirmed diffuse low bone density with multiple rib fractures and revealed a hypermetabolic lesion (SUV 9.4) limited by a cortical rim in the posterior part of the distal third of the femur. MRI of the right femur in December 2022 revealed the same lesion of the right femur, measuring 12 mm. DOTATOC scintigraphy in February 2023 confirmed a solitary mesenchymal tumor in the right femur (figure in supplementary material).

Burosumab treatment was continued (four injections) despite the TIO diagnosis for several reasons: first, striking clinical improvement, including pain resolution, increased upper limb muscle strength, self-mobilization in the wheelchair, and normalization of serum phosphate levels to approximately 1 mmol/L. Additionally, the orthopedic surgeon recommended continuing burosumab treatment to allow for surgery on less fragile bone.

In February 2023, surgical removal of the right femoral tumor was performed. The procedure was complicated by a fracture at the resection site, requiring plate fixation. Six weeks post-surgery, the individual was pain-free and showed significant functional improvement with ongoing rehabilitation.

Post-surgical blood tests showed phosphorus at 1.42 mmol/L without supplementation, ALP at 454 IU/L, BAP at 152 ng/mL, 1–25 OH vitamin D at 348 pg/mL, and intact FGF23 at 10,080 pg/mL. At week 7 post-surgery, intact FGF23 was 6020 pg/mL and 489 pg/mL at week 12, still far from the normal range (18.6–59.8 pg/mL). Concerned, we contacted the burosumab manufacturer. The FGF23 assay does not distinguish between free FGF23 and FGF23 bound to burosumab. However, the latest test in June 2024 was normal at 40 pg/mL (16 months post-surgery and 20 months after the first burosumab injection). There is no need to monitor FGF23 levels under burosumab.

Osteodensitometry showed an improvement in bone mineral density, initially under Burosumab treatment and further post-surgery. Detailed results, including BMD and Z-scores at different time points, are available in supplementary material (Table 1).

The surgical specimen was sent for pathological examination. Histological sections revealed an infiltrating intraosseous tumor partially replacing the marrow spaces. The tumor cells were epithelioid to spindle-shaped, with large pleomorphic nuclei, variably prominent nucleoli and frequent intranuclear pseudoinclusions. The stroma was rich in capillaries with hyalinized walls and showed an abundant chronic inflammatory infiltrate; calcifications were absent. Other areas showed an abundant fibrous matrix with an osteoid-like appearance surrounding the tumor cells. Mitotic activity was low (0.5 mitosis/mm²), and tumor necrosis was absent. On immunohistochemistry, the tumor was positive for SATB2 and SSTR2. RNA sequencing revealed a FN1::FGFR1 gene fusion and high expression levels of FGF23 mRNA. Based on these findings, a diagnosis of a phosphaturic mesenchymal tumor with atypical histology potentially linked to burosumab treatment was rendered. Representative microphotographs of the tumor are available in Fig. 2.

Fig. 2.

Histopathological and immunohistochemical findings of burosumab-treated phosphaturic mesenchymal tumor. A At low magnification (2.5 ×), the tumor showed poorly defined margins and irregularly infiltrated the marrow spaces; note the low density of trabecular bone. B At higher power (20 ×), the tumor cells were epithelioid to spindle-shaped and had atypical pleomorphic nuclei. The cells were dispersed in an inflammatory stroma rich in lymphocytes, histiocytes, and capillaries with hyalinized walls. The inset shows SSTR2 immunohistochemical expression by tumor cells. C, D In other areas, an abundant hyalinized extracellular matrix resembling osteoid was present, reminiscent of the changes seen in denosumab-treated giant cell tumor of bone

Discussion

This observation of TIO is original for two main reasons: the exceptionally young age of onset, and the use of burosumab in this pathology. Indeed, reported cases of oncogenic osteomalacia beginning in childhood are very rare, and their prevalence is difficult to establish due to the paucity of documented cases. This presentation should be referred to as oncogenic rickets. Early diagnosis is critical, as our case demonstrates. While surgical treatment of TIO in adults often leads to recovery, this is not necessarily the case in pediatric patients. Major risks include loss of height, bone deformities, joint destruction, loss of ambulation, dental issues, and ENT involvement, all of which are irreversible even after treatment, resulting in persistent rickets. Only pain and function improve under burosumab and after surgery. Given this poor prognosis and the possibility of rapid treatment with early diagnosis, vigilance is crucial for this rare disease. In our case, the hallmark sign that should have alerted us was the loss of ambulation at age 8.

The individual’s height loss can be attributed to the prepubertal onset of symptoms and probable defective growth plate modeling, common in childhood rickets, compounded by lower limb deformities.

In our case, XLH was initially suspected due to early symptom onset. The young man was treated with burosumab, which proved highly effective clinically and biologically, consistent with the literature [9]. Bone density improved rapidly under burosumab and post-surgery. Such improvements have been reported following surgery [10] and burosumab treatment [11] One interesting finding was the histological aspect of the tumor, which showed abundant areas of fibrosis. This finding was similar to what is observed in giant-cell tumor of bone treated with denosumab, raising the possibility of a potential direct effect of burosumab on tumor morphology. However, additional studies are needed to confirm this observation, as we did not have pre- and post-therapy tumor samples for comparison. Our experience shows that burosumab can also treat TIO, for cases with inoperable tumors or patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Conflict of interest

Nadia Mehsen-Cetre: Advisory Board Kyowa Hakko Kirin. The other authors declare no competing interests.