Background

X-linked hypophosphataemia (XLH), caused by pathogenic PHEX gene variants, leads to excess fibroblast growth factor 23 (FGF23) activity and hypophosphataemic osteomalacia with lifelong complications such as fractures, osteoarthritis, pain, and impaired function. Approximately 10% of adults with clinically diagnosed XLH lack an identifiable PHEX variant, which may contribute to delayed diagnosis and preventable morbidity. Emerging evidence suggests burosumab, an anti-FGF23 antibody, improves biochemical and functional outcomes versus conventional therapy in adults with XLH.

Presentation

A 53-year-old Tibetan male presented with a 15-year history of hypophosphataemic osteomalacia with profound skeletal fragility, multiple fractures, and persistent myalgias despite oral phosphate and calcitriol therapy. At age 30, while in India, he developed progressive lethargy and difficulty ambulating, requiring walking aids by age 34, and sustained bilateral atraumatic hip fractures at age 37. Investigations demonstrated severe osteoporosis with persistent hypophosphataemia, renal phosphate wasting, and elevated serum FGF23, in the absence of syndromic features. Medical therapy improved biochemical parameters, but he continued to experience functional disability and ultimately resigned from work. Although tumour-induced osteomalacia (TIO) was suspected, ⁶⁸Ga-DOTANOC PET/CT and 14-site selective venous sampling for FGF23 failed to identify a causative lesion.

At age 43, he migrated to Australia and required surgical management of subacute insufficiency fractures, followed by extensive rehabilitation. It took over 10 years to initiate evaluation for PBS-subsidised burosumab; although no PHEX variant was identified, he met clinical criteria for XLH. During this period, repeated investigations for TIO were negative. Following transition to burosumab therapy, he experienced sustained improvement in musculoskeletal symptoms and wellbeing and was able to undertake all-day hiking in Tibet. At 18 months after starting burosumab, he remains biochemically and symptomatically stable, without no further fractures and improvements in bone mineral density and functional measures of pain and mobility.

Discussion

There is often a substantial delay between symptom onset and diagnosis in adults with XLH, particularly in those with less typical presentations, including individuals without identifiable PHEX variants. Despite prolonged conventional therapy and delayed diagnosis, burosumab produced marked functional improvement in this PHEX-negative adult with XLH, supporting it as a key therapeutic consideration in suspected FGF23-mediated hypophosphataemic disease.