(20.06) Tumor-Induced Osteomalacia Secondary to Neurofibromatosis Type 1

Introduction : Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with weakness, bone pain, and multiple fractures. Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with multisystem tumors of the skin and central nervous system. NF1 associated with TIO is a rare entity. We present a case of TIO secondary to NF1.

Case(s) Description : A 58-year-old female with a history of NF1 since childhood presented with multiple non-traumatic bone fractures over the preceding two years, leading to her being wheelchair-bound. DXA scan showed severe osteoporosis at multiple locations, with the lowest T-score of -4.5. Her labs showed normal calcium, low phosphorus, low vitamin D, high PTH, and high alkaline phosphatase levels. She was initially diagnosed with osteoporosis and was started on alendronate, vitamin D, and phosphorus (Phos) supplements. In the interim, the patient continued to sustain multiple fractures. Repeat labs continued to show low Phos levels despite supplementation. FGF23 was elevated at 417 RU/ml (normal range: 44-215). A 24-hour urine collection was not done due to urinary incontinence. Genetic testing for hypophosphatemic disorders, including mutations in PHEX, DMP1, and ENPP1 genes, was negative. PET/CT DOTATATE scan showed numerous fractures in various states of healing, but was negative for tumor. She was deemed to have TIO secondary to NF1.
 
The patient was started on burosumab. Alendronate and Phos supplements were eventually discontinued. Her Phos level normalized. She also started to improve clinically and was able to walk with assistance without sustaining any new fractures.

Discussion : TIO is a rare disease with an estimated prevalence of 7 in 1,000,000 persons. It is characterized by FGF23 overproduction by mesenchymal tumors. FGF23 decreases sodium phosphate cotransporter in the renal proximal tubule, leading to low Phos levels that affect bone mineralization, which in turn may lead to fractures. NF1 is another rare disease with a prevalence of 1 in 3,000 persons. It is caused by mutations in the NF1 tumor suppressor gene. Its disease manifestation can occur in any body system, but is most often characterized by multiple neurofibromas, café-au-lait macules, skinfold freckling, and iris Lisch nodules.
 The case above is interesting due to its extreme rarity. Few patients with NF1 have elevated FGF23 from unclear source.
Literature review revealed fewer than 50 case reports showing an association between NF1 and TIO.
There is a significantly increased risk of certain cancers in NF1, including breast cancers, malignant peripheral nerve sheath tumors, and brain tumors. However, no such tumor could be found in our case.