Endocrine Abstracts

JOINT3708

X-linked hypophosphatemia (XLH) is a rare genetic disorder caused by PHEX mutations, leading to excessive FGF23 activity, renal phosphate wasting, and chronic hypophosphatemia, resulting in rickets and skeletal deformities. Management has evolved from phosphate and calcitriol supplementation to burosumab, a targeted therapy blocking FGF23.

Case report: A 3 y 4 mo girl presents with mild facial dysmorphia (narrow forehead, low anterior hairline, bilateral epicanthus, short neck) and general rachitic signs (flaring thorax at the basis, rachitic rosary, thickened wrists and ankles, short stature and bilateral genu varum -intercondylar distance=19 cm), with normal dental status. Blood tests showed normal serum Calcium, PTH, and 25-OH-Vitamin D, low serum phosphate and very high ALP. Normal renal and liver function. Lower limbs X-Ray show widened and cup-shaped with irregular margins distal femoral metaphysis. Delayed bone age: 2 y (-1.4 y delay). Thatcher score=9. Normal 24-h urine analysis (particularly normal urinary phosphate and calcium) and normal TRP and TmP/GFR. The available Cento Metabolic panel excluded autosomal dominant and autosomal recessive hypophosphatemic rickets. Abdominal ultrasound, nephrology and neurology consult - normal. The suspicion of XLH was high, but genetic testing of the PHEX gene was lacking. We dosed FGF-23 (high) and 1,25-(OH)2-Vitamin D (low). We started conventional treatment, initially with Joulie solution (phosphate supplements are not available in Romania), 1 g of elemental phosphorus/day (divided in 5 doses) for a year, then managed to procure effervescent phosphate (2 × 500 mg/day, increasing adherence to therapy). Treatment also included Calcitriol (2 × 0.25 mg/day). Bilateral orthoses and physiotherapy were recommended. Over 2 years of conventional treatment, intercondylar distance worsened (19 cm to 20.5 cm). Phosphate levels were always low, ALP levels very high, Thatcher score still 9. At 5 yo, sequencing analysis discovered a nonsense variant in heterozygous status (NM_000444.5:c.264G>A) in the PHEX gene (Xp22.11), with a coverage of 339X at the variant site, confirming the XLH diagnosis. Burosumab treatment was initiated. Under the treatment, the intercondilar distance slowly decreased and the stature improved. Serum phosphate normalized and ALP levels decreased gradually. After 3.5 y of treatment with Burosumab (8 y 3 mo), the Thatcher score is 4.5, and intercondilar distance is 13 cm. No nephrocalcinosis and no other complications.

Conclusions: In severe XLH, conventional therapy often fails to correct hypophosphatemia and skeletal deformities. This case underscores Burosumab’s superior efficacy, significantly improving phosphate homeostasis, bone health, and overall quality of life.