Article Text
PDF
Abstract
A female in her 50s developed a headache, collapsed and was noted to have an acute atraumatic subdural haemorrhage (SDH) requiring surgical evacuation and intracranial pressure-directed therapy. Her background included recurrent epistaxis, severe generalised bone pain and multiple insufficiency fractures and an undifferentiated autoimmune connective tissue disease. Chronic hypophosphataemia, elevated alkaline phosphatase and raised fibroblast growth factor 23 (FGF23) were also noted. An MRI head and subsequent 68Ga CT/positron emission tomography scan demonstrated an intensely avid tumour in the right ethmoid sinus, extending intracranially. Phosphate was aggressively replaced, and alfacalcidol was initiated to circumvent the effects of FGF23 on her kidneys and bone minerals. The tumour was biopsied and then definitively resected via combined endonasal and craniotomy approaches, resulting in good clinical improvement. FGF23 titre and serum phosphate both normalised leaving the diagnosis of a phosphaturic mesenchymal tumour-secreting FGF23, leading to tumour-induced osteomalacia.
- Osteomalacia
- Neuro ITU
- Neurosurgery
- Otolaryngology / ENT
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
Background
Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, commonly driven by ectopic fibroblast growth factor 23 (FGF23) secretion from phosphaturic mesenchymal tumours (PMTs).1 These tumours are usually small and slow growing with misdiagnosis common due to resemblance with other metabolic bone diseases.2 PMTs are typically benign and locally aggressive, but rare malignant transformations have also been reported.3
FGF23 was first discovered in the murine model in 2000 and later found to be secreted by osteoblasts and osteocytes into the systemic circulation.4 FGF23 promotes renal phosphate wasting and inhibits both intestinal phosphate reabsorption and the 1-alpha hydroxylation of vitamin D.5 Renal excretion is the primary method of phosphate clearance and is governed by parathyroid hormone, vitamin D and phosphatonins, such as FGF23.6–8 Excessive FGF23 leads to hypophosphataemia and hyperphosphaturia,9 with chronic secretion affecting bone mineralisation, leading to osteomalacia and a subsequent rise in alkaline phosphatase (ALP).10
PMTs most commonly arise from the extremities (95%), followed by head and neck sites (5%), of which 38–50% have been reported to be of sinonasal origin.3 11 Within sinonasal origin TIO, the ethmoid sinus remains the most common location.12 While PMTs represent the most common pathological diagnosis in TIO, almost 30.7% of TIO tumours have been shown to be other—including haemangiopericytomas and glomangiopericytomas.12
Medical supplementation with phosphate and alfacalcidol is started early to manage the hypophosphataemia. Successful surgical resection of tumour is the definitive management, halting excessive secretion of FGF23, leading to the resolution of symptoms and the restoration of normal phosphate metabolism.13–15 In instances where resection is not feasible or where the tumour cannot be localised, burosumab, a human monoclonal antibody against FGF23, plays a role in treating the abnormal phosphate metabolism and underlying osteomalacia.
Case presentation
A female in her 50s attending hospital for a routine appointment developed a headache, collapsed and became unresponsive. Direct head injury was not witnessed, nor any external signs of head injury seen nor did any history of head trauma transpire in the preceding weeks to months. The patient was not taking any anticoagulants or antiplatelets and was not known to be coagulopathic. Her Glasgow Coma Score was 3, and she was intubated in the emergency department.
Initial CT head with angiography showed a 14 mm thickness right subdural haemorrhage (SDH) with 9 mm of midline shift (figure 1). It also highlighted a right ethmoid sinus mass, extending through the cribriform plates to abut the gyrus rectus. Additionally, a 5 mm contrast-enhancing focus within the mass was suggestive of an intratumoural vessel as the potential source of haemorrhage (figure 2). The CT angiogram was otherwise normal with no further evidence of intracranial aneurysm, vascular malformation, large artery occlusion or stenosis. A digital subtraction angiogram (DSA) was not performed preoperatively owing to the acuity of the presentation. An emergency craniotomy was performed to evacuate the haematoma.
Acute right subdural haemorrhage (red arrow) with 9 mm of midline shift (blue arrow) from the ideal midline (green line) and effacement of the right lateral ventricle.
CT angiogram suggestive of an intratumoural vessel (red arrow) within the right ethmoid sinus tumour.
Her background included a suspected diagnosis of an undifferentiated autoimmune connective tissue disease. The presenting symptoms included myalgia, arthralgia, muscle weakness, fatigue and exertional breathlessness. Autoimmune serology was positive, being antinuclear antibody positive (7.7 units via ELISA, reference range 0.0–0.9), antidouble stranded DNA positive (38 iu/mL via ELISA, range 0–10 iu/mL) and anti-Ro antibody positive (159 u/mL via ELISA, range 0–7 u/mL). The inflammatory markers, creatine kinase, anti-La, anti-Jo-1, anti-Scl-70, anticentromere and C3/C4 levels were normal. There was no suspicion of antiphospholipid syndrome as the anticardiolipin antibodies, beta-2 glycoprotein antibodies, lupus anticoagulant, Activated Partial Thromboplastin Time ratio and dilute Russell viper venom time ratio were all within normal ranges. Further investigations including urinalysis, renal function and a CT thorax did not reveal any evidence of organ-threatening connective tissue disease.
Her presentation, coupled with the above autoantibody profile, resulted in a 6-week trial of prednisolone therapy and the initiation of hydroxychloroquine. There was no discernible improvement while on prednisolone, and it was thus tapered off after 6 weeks. The hydroxychloroquine was discontinued once the eventual diagnosis of TIO was made.
The history of back pain led to an MRI of the whole spine, revealing multiple vertebral fractures and resulted in a referral to the metabolic bone disease clinic. She underwent dual-energy X-ray absorptiometry bone densitometry and a nuclear medicine bone scan 2 years before her collapse (figure 3). These revealed spinal osteoporosis, hip osteopaenia and increased bone turn over across her skeleton, for which she was treated with oral alendronate. On subsequent review of previous CT scans, there were characteristic multilevel vertebral endplate changes, as seen in osteomalacia.
Bone scan showing areas of increased bone turnover across the skeleton due to tumour-induced osteomalacia. In particular, the pelvic region, vertebral column, right humeral head and mid-facial structures.
She was noted to be chronically hypophosphataemic, and alongside an elevated ALP, this raised the suspicion of TIO. Subsequently, serum FGF23 levels were found to be elevated at 160 RU/mL (0–100 RU/mL) 8 months prior to admission.
Separately, the local Ear, Nose and Throat (ENT) department had also been managing her recurrent epistaxis with facial dysaesthesia, while a 68Ga DOTATATE CT/positron emission tomography scan requested by rheumatology was performed 4 months prior to her collapse due to the suspicion of TIO. This identified a lesion in the right ethmoid sinus with intensely avid uptake of tracer along with numerous other sites of mild uptake across her axial skeleton and underlying mild bone sclerosis (figure 4). Contrast-enhanced MRI confirmed that the lesion had not invaded the bony orbit but did extend beyond the cribriform plate (figure 5).
Positron emission tomography/CT fused images demonstrating avid uptake of tracer within the right ethmoidal sinus (red arrow).
Contrast-enhanced MRI, Susceptibility-Weighted Angiography (SWAN) sequence, prior to the patient’s collapse and acute subdural haemorrhage. Evidence of tumour invasion beyond the cribriform plate (red arrow).
It was on the day of her appointment to discuss biopsy and definitive resection of the FGF23-secreting tumour that she collapsed due to the acute SDH.
Treatment
Following her collapse, full blood count revealed a mild pancytopaenia, a normocytic anaemia (haemoglobin of 86 g/L) and platelet count of 88×109/L (150–370×109/L). Both improved as she recovered from critical illness. Initial biochemistry showed a serum phosphate of 0.56 mmol/L (0.8–1.5) (figure 6) and adjusted calcium of 2.73 mmol/L (2.2–2.6 mmol/L). ALP of 243 U/L (30–130 U/L). Total serum 25OH vitamin D was 58.5 nmol/L (above 50 nmol/L considered sufficient). Parathyroid hormone levels, renal function, clotting function and anterior pituitary function tests were all within normal ranges.
Long phase of hypophosphataemia (black arrow), followed by notable efforts to supplement phosphate in hospital (dark blue arrow), followed by resolution of hypophosphataemia at the 4-month clinic follow-up (light blue arrow). Reference range of serum phosphate concentration represented by the shaded region.
A craniotomy was performed on the first day of admission, and the acute SDH was evacuated down to the cribriform plate. A breach in the dura was noted, with the tumour seen infiltrating intracranially. The tumour appeared hypervascular and was the source of strong bleeding until multiple tumour vessels were ligated. She received intracranial pressure (ICP)—directed therapy while the peri-haematoma oedema settled, alongside basic intensive care in the neurosciences critical care unit. The post-SDH evacuation head MRI showed further increasing size of the right ethmoidal sinus tumour. The patient was tracheostomised 1 month into her admission due to a prolonged neurological recovery/ventilator wean.
Right-sided endonasal debulking and biopsy were performed at 11 weeks, resulting in a partial resection of the tumour. The mass was seen in the right ethmoid sinus, extending into the superior meatus and heading intracranially through the cribriform plate. The debulking involved both middle and superior turbinate resection with complete spheno-ethmoidectomy, exposing intact dura above. The sphenoid and frontal sinuses were confirmed free of disease.
Immunohistochemical staining of the biopsy sample taken at 11 weeks into admission was used to confirm the diagnosis of a phosphaturic mesenchymal tumour. The sample was sent for whole-genome sequencing but did not show FN1-FGFR1 gene fusion. In a study by Lee et al, only 16 out of 39 (41%) of FGF23-secreting PMTs were shown to bear the aforementioned FN1 rearrangement.16
She received alfacalcidol 500 ng once daily, calcium carbonate/colecalciferol 1.5g+10 µg two times per day and folic acid and intravenous replacement of phosphate. The alfacacidol was eventually exchanged for calcitriol due to higher oral bioavailability and better absorption.17 Burosumab had also been considered if the definitive resection was unsuccessful or if the patient failed to improve.
8 months after her initial collapse, the patient returned for definitive tumour resection involving a combined approach left-sided endoscopic craniofacial resection with craniotomy. A preoperative DSA showed slight arterial blush from the tumour, but embolisation was not attempted. Endonasal resection involved left-sided spheno-ethmoidectomy, middle plus superior turbinate resection and a septectomy. Clearing the right and left sinonasal regions over the course of two operations aimed to create a wide area of resection to prevent recurrence. The final macroscopic elements of the tumour were removed via craniotomy with resection of the cribriform plate from the scarred gyrus recti followed by closure with a tensor fascia lata flap.
Outcome and follow-up
After spending 3 months in the hospital, the patient was seen in clinic 4 months after her discharge and successful decannulation of her tracheostomy. She had recovered well and was able to walk a few steps with a frame, and her pain driven by her profound osteomalacic myopathy had improved. At further review, she remained cognitively intact and was able to walk 50 yards from the waiting room to the clinic room. Serum phosphate continued to remain stable within reference ranges 10 months following admission, and the FGF23 graph showed full resolution of excess tumour product, from 160 RU/mL 8 months before admission to 77 RU/mL 7 months after admission (figure 7).
Resolution of fibroblast growth factor 23 concentration following resection of tumour. Reference range indicated by the shaded region.
Discussion
Formulating the diagnosis of TIO is challenging and involves tumour localisation alongside a search for ectopic phosphatonin secretion. Occasionally, the primary disease process is obvious, as seen in secondary TIO. Secondary TIO can be caused by prostate, lung and haematological malignancies, and treatment of the underlying cancer is the main aim, followed by treatment of the hypophosphataemic syndrome.6 The hallmark elevation of FGF23 itself can also be due to genetic pathologies, such as hereditary forms of hypophosphataemic rickets and McCune–Albright syndrome, often with a younger presentation.18 19
The most unusual element of the case is that the haemorrhagic source of the acute SDH was likely a spontaneously bleeding tumour vessel rather than secondary to trauma. Often tumours that extend, in part, intracranially, present with altered consciousness and/or focal neurological deficit. This is often due to the direct compression of local structures or localised cerebral oedema but less commonly due to spontaneous haemorrhage from the tumour. In addition, the patient was not inherently coagulopathic, and a negative anterior pituitary function test excluded any endocrinopathy that may have been contributing to the presentation.
The broader differential of skull base lesions includes meningiomas, haemangiopericytomas, schwannomas, fibrous dysplasia, primary tumours of bone/cartilage, skull base metastases, extension of head and neck malignancy and, rarely, invasive fungal sinusitis. Specific tumours that more commonly occupy the anterior cranial fossa include esthesioneuroblastomas, orbital tumours, nasopharyngeal angiofibromas (more often found in adolescent males) and forms of sinonasal carcinoma. An esthesioneuroblastoma would be a close morphological mimic of the patient’s tumour, given its location and locally aggressive nature; however, the biopsy examination, Immunohistochemistry staining and genetic profile were suggestive of a PMT. Haemorrhagic lesion differentials included arteriovenous fistulae or haemangiopericytomas that may resemble the enhancing intracranial portion of the CT angiogram, but both MRI and histological evidence showed this was not the case.
Gulwani et al reported a case of a 40-year-old female with chronic osteomalacia, found to have a diffuse subarachnoid haemorrhage with intraventricular extension, stemming from an extra-axial tumour dorsal to the sella.20 Histology revealed a haemangiopericytoma—another rare cause of TIO. Shand et al reported a case of a 40-year-old female with a similar insidious presentation with an extra-axial, frontal, dural-based PMT, without any intracerebral haemorrhage, which was treated with curative resection.21
Another interesting element regarded iatrogenic causes of her disease. She was given high-dose steroids long prior to admission due to her underlying rheumatological conditions. This was followed by multiple symptomatic osteomalacic vertebral insufficiency fractures, which were seen on MRI. She subsequently lost trunk height due to the permanent vertebral fractures.22
In addition, oral alendronate was used in the earlier stages of her disease to manage the osteoporosis, before TIO was considered. The patient was in fact due to be infused with intravenous zoledronate. Long-term bisphosphonate use is associated with osteomalacia, with particular concern regarding zoledronate. This is known to induce severe hypocalcaemia in patients with known osteomalacia, owing to its 100–1000 times higher potency when compared with oral alendronate.23–25 3 mg of ibandronate, a less potent bisphosphonate, was administered before the team recognised the underlying features of TIO, after which it was discontinued.
The prolonged critical care admission provided a platform to directly correct the phosphate losses with daily intravenous infusion and remineralise the osteomalacic bone with alfacalcidol (active 1.25 D3). The former is difficult to achieve orally due to chronic supplementation being unpalatable and causing gastrointestinal upset. The latter promoted hardening of bone, leading to healing of the multiple painful insufficiency fractures.
The combination of alfacalcidol, phosphate supplementation and the partial rection achieved success. The tumour was then definitively resected, leading to normalisation of FGF23 and phosphate levels, alongside marked symptom improvement.
The case highlights the length of time taken to establish a diagnosis of TIO and to locate the culprit tumour. It is unique in its presentation as an acute, atraumatic SDH and shows how both medical and surgical treatments act in synergy to alleviate the burden of this rare condition.
Learning points
Tumour-induced osteomalacia should be suspected in patients with chronic bone pain, insufficiency fractures and hypophosphataemia.
The osteomalacia is driven by fibroblast growth factor 23 (FGF23) secretion—inhibiting the 1-alpha hydroxylation of vitamin D and increasing renal phosphate wasting.
Tumours with dural infiltration can lead to acute subdural haemorrhage, as in this case with a sinonasal tumour, but also in other lesions such as haemangiopericytoma, metastases and aggressive meningiomas.
Functional imaging with 68Ga DOTATATE positron emission tomography/CT currently offers the highest sensitivity and specificity for localising FGF23-secreting tumours.
Phosphaturic mesenchymal tumours are commonly benign—resection with curative intent is advised alongside alfacalcidol supplementation and phosphate replacement.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation of the results, drawing original diagrams and algorithms and critical revision for important intellectual content: SSB, PSM, KP and AM. The following authors gave final approval of the manuscript: SSB, PSM, KP and AM.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.