Neurofibromatosis type 1 associated with hypophosphatemic osteomalacia due to hypersecretion of fibroblast growth factor 23: a case report

Abstract

Background: Neurofibromatosis type 1 is characterized by multiple café au lait spots and cutaneous and plexiform neurofibromas, and is one of the most common autosomal dominant hereditary disorders caused by mutations of the neurofibromatosis type 1 tumor suppressor gene. Osteomalacia in neurofibromatosis type 1 is very rare and is characterized by later onset in adulthood. In humans, fibroblast growth factor 23, which is a causative factor of tumor-induced osteomalacia, is not only a paracrine and autocrine factor, but is also a physiological regulator of phosphate balance in normal serum. Case presentation: Our patient was a 65-year-old Japanese woman whose neurofibromas began to appear when she was in elementary school. At age 28, she was diagnosed as having neurofibromatosis type 1. A spinal compression fracture and multiple rib fractures were identified in 2012 and 2017, respectively. Her laboratory findings revealed hypophosphatemia due to renal phosphate wasting and a high serum level of fibroblast growth factor 23. Neurofibromas located on the surface of her right forearm and left upper arm, in which a slight abnormal accumulation of tracers was observed on 111 indium-pentetreotide scintigraphy, were surgically removed, but there was no improvement in hypophosphatemia or serum fibroblast growth factor 23 after surgery. Therefore, we administered eldecalcitol, which also failed to produce improvement in abnormal data. Subsequent combination with dibasic calcium phosphate hydrate led to improvement in some of the abnormalities, including hypophosphatemia. Immunohistochemical staining using anti-human fibroblast growth factor 23 antibody revealed slightly positive results, however, only one out of three amplifications of the fibroblast growth factor 23 gene was observed by real-time polymerase chain reaction, and no clear fibroblast growth factor 23 gene expression in the resected neurofibromas could be confirmed. Conclusions: We here describe a first rare case of a 65-year-old woman with neurofibromatosis type 1 associated with hypophosphatemic osteomalacia in which a high serum fibroblast growth factor 23 level was confirmed.

Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance

“…Information on 99 patients (70.2%) was collected in the secondary survey. Eleven patients were excluded from the analysis: one patient was counted twice, one patient had neurofibromatosis 1 associated with FGF23-related hypophosphatemic osteomalacia, (25,26) and nine patients did not meet the eligibility criteria regarding the time of the first visit to the hospital. As a result, 88 patients who were definite or clinically diagnosed with TIO were selected for the study.…”

Hypophosphatemic osteomalacia in neurofibromatosis 1 associated with intracranial gliomas and congenital renal agenesis: A rare case report and review of the literature

“…In the same study, micro-ct examination, also, demonstrated thinner and porous cortical bones with disorganized osteocyte dendrites that exhibited reduced strength in mechanical forces leading to spontaneous fractures [ 34 ]. This was supported by the clinical findings of increased circulating levels of FGF-23 in two patients with NF1 that appeared severe HO [ 23 , 25 ]. A possible explanation was that the increased serum concentration of FGF-23 inhibited renal reabsorption of phosphorus and decreased the production of 1,25--dihydroxyvitamin D leading to increased phosphate wasting and lower levels of phosphorus in the serum [ 34 ].…”

“…Multiple myelomas, hemangiopericytomas, osteosarcomas, chondroblastomas, chondrofibroid myxomas, malignant fibrous histiocytomas, giant cell tumors, and prostatic cancers are entities that were associated with adult-onset HO [ 20 , 21 ]. NF1 has been implicated with HO very rarely ( Table 1 ) [ 22 , 23 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Despite the fact, that the association between NF1 and HO was described by Gould in 1918, <50 cases have been referred in the international literature [ 28 ].…”

“…It has been reported that NF1 patients display several skeletal manifestations and deformities [ 10 ]. Bone pains, located on the feet and lower limbs as well as muscle weakness, bowing of long bones, pseudofractures, fractures, kyphoscoliosis, and triradiate pelvis, were the most common described defects ( Table 1 ) in NF1 patients with HO [ 22 , 23 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. In our case, generalized bone pains, weakness of the proximal muscles, thoracic scoliosis, mild bowing of long bones of lower limbs, stress fractures, and old healed fractures accompanied by altered bone remodeling serum markers were observed.…”