Hypophosphataemia is a common finding in clinical practice with a wide variety of clinical manifestations, some of which can be confused with rheumatological condition. Below are two cases of hypophosphataemia mimicking ankylosing spondylitis.
Case 1:
A 47 years old woman presented to clinic for second opinion on ankylosing spondylitis management. The diagnosis was made four years ago after two decades of chronic back pain. Treatment included anti-inflammatories, adalimumab and etanercept. Etanercept gave excellent therapeutic result. She had hysterectomy two years ago for menorrhagia. Her only other medication is Panadeine Forte.
In the last 12 months, the patient developed new bilateral groin pain. She was referred to orthopedic surgeon and was managed as osteoarthritis of the hips with bilateral total hip replacement. Groin pain improved postoperatively, but back pain recurred with increased nocturnal lumbar pain. She also reported new proximal myopathy in lower limbs.
Examination showed limited lumbar movement and reduced chest expansion but normal cervical and thoracic spine. Hip extension and adduction were markedly reduced bilaterally. There was no synovitis or enthesitis. Lumbar and pelvic xrays showed no ankylosis and normal sacroiliac joints. Subsequent computer tomography (CT) and magnetic resonance imaging (MRI) revealed widespread facet joint arthritis, sclerotic sacrum with thickened trabeculae, and fusion of sacroiliac joints without sacroiliitis. Blood test was incongruent with ankylosing spondylitis: normal inflammatory markers (ESR 12, CRP<3). ANA, ENA and HLAB27 negative. Phosphate was low (0.61), alkaline phosphatase (ALP) 166; calcium and serum 1,25(OH)2D3 were normal. Tubular maximal phosphate reabsorption was reduced. DNA testing for PHEX gene mutation confirmed novel PHEX missense mutation, consistent with clinical diagnosis of X-linked hypophosphatemic rickets (XLH). Patient was started on calcitriol, phosphate sandoz and cholecalciferol intramuscular injection with significant clinical and biochemical improvement. Entanercept was ceased.
Case 2:
A 35 years old previously well Chinese gentleman presented with three-year history of progressive, debilitating pain in lower back, legs and chest wall. He had recurrent falls and required walking-aid to mobilise. He was managed previously as ankylosing spondylitis with Naprosyn, adalimumab and etanercept with minimal benefit. Examination of the upper limbs was normal. Movement of the lumbar spine and lower limbs appeared stiff initially. On closer inspection, the patient was able to demonstrate relatively normal passive range of movement in hips, knees and ankles. There was no evidence of psoriasis, synovitis or enthesitis.
Investigation showed low phosphate (0.47), ALP elevated to 314 but normal 1,25(OH)2D3 32, calcium and parathyroid hormone (PTH). Whole body bone scan revealed widespread insufficiency fractures. PET-CT confirmed single lesion in left upper tibia with increased uptake. Subsequent biopsy showed phosphouric mesenchymal tumour. The patient was diagnosed with tumoral-induced osteomalacia and was managed with surgical resection successfully.
Discussion
Hypophosphataemia is a common finding with a vast number of manifestations affecting cardiovascular, respiratory, musculoskeletal and neurological systems. Common musculoskeletal sequelae include osteopenia, proximal myopathy and osteomalacia causing bone pain, muscle weakness and even enthesopathy1. These symptoms can mimic other conditions such as spondyloarthropathy, polymyalgia rheumatica, polymyositis and osteoporosis2.
Hoshino et al reported a case of progressive back and bilateral leg pain treated as ankylosing spondylitis before being diagnosed with hypophophatemic osteomalacia3. In Siva et al, a 32 year old with sacroiliitis on MRI was treated unsuccessfully with anti-TNF-alpha. Subsequent investigation revealed hypophosphataemic osteomalacia and patient responded to phosphate and active vitamin D replacement. In osteomalacia, non-mineralised osteoid can accumulate in subchondral bones. Its radiological appearance can mimic that of early sacroiliitis2.
Phosphate homeostasis is maintained by a number of key regulators including vitamin D, PTH, and fibroblast-growth-factor 23 (FGF-23). FGF-23 is a bone-derived glycoprotein that response to elevated phosphate and vitamin D levels by suppressing proximal renal tubular phosphate reabsorption. It also decreases active 1,25(OH)2D3. FGF-23 is further regulated by a number of mediators including an endopeptidase encoded by the PHEX gene. A mutation in PHEX impairs endopeptidase function and upregulates FGF-23 activity, causing renal phosphate wasting4.
Hypophosphataemia can be hereditary or acquired. X-linked hypophosphatemic rickets (XLH) is one of the most common hereditary causes and is caused by mutation in PHEX gene, causing up-regulation of FGF-23. Most cases are diagnosed during childhood where the predominant feature is bone deformities, abnormal gait, and short stature. In adults, XLH usually presents as osteomalacia and insufficiency fractures with bone pain and myopathy5. Enthesopathy, another common feature in rheumatological conditions, can also occur in XLH6. Investigation would show hypophosphatemia, renal phosphate wasting, elevated ALP, inappropriately low or normal serum 1,25(OH)2D3 but normal calcium and 25-vitamin D4. Final diagnosis usually confirmed with genetic testing. Conventional treatments include phosphate and active vitamin D replacement. Main treatment complication includes nephrocalcinosis and hyperparathyroidism5.
Tumoral-induced osteomalacia (TIO) is a form of acquired hypophosphatemia. As a paraneoplastic condition, TIO can presents similarly to XLH. Its non-specific symptomatology often leads to delayed diagnosis7. TOI tumours are usually benign and FGF-23 positive. There are four main types: phosphaturic mesenchymal, osteoblastoma-like, non-ossifying fibroma-like, and ossifying fibroma-like variant. Phosphaturic mesenchymal tumours account for 70 – 80% of cases4. Diagnosis is confirmed in a step-wise approach: functional imaging (such as somatostatin analogue, Octreoscan or FDG-PET/CT) should be performed first to confirm lesion. The exact location and extend of the lesion should be confirmed with CT or MRI. Single lesion can be surgically resected. Multiple lesions, or anatomically difficult ones, should be further evaluated with venous sampling. Surgery usually offers definitive treatment8.
Take home message