What is the diagnosis and treatment for a male child with a family history of X-linked hypophosphataemic rickets, presenting with bowed legs, short stature, and bone pain?

X-Linked Hypophosphataemic Rickets: Diagnosis and Treatment

Diagnostic Approach

In a male child with family history of XLH presenting with bowed legs, short stature, and bone pain, confirm the diagnosis through biochemical testing showing hypophosphataemia with renal phosphate wasting, followed by genetic testing of the PHEX gene. 1

Clinical Presentation

The classic triad in pediatric XLH includes:

• Growth failure and disproportionate short stature 1, 2
• Lower limb deformities (bowing of legs, genu varum or valgum) 1, 2
• Bone pain and waddling gait 2, 3
• Dental abnormalities including spontaneous abscesses 1, 4

Essential Biochemical Work-Up

The diagnostic biochemical profile is characterized by a specific pattern that distinguishes XLH from nutritional rickets: 1, 5

• Serum phosphate: Below age-related reference range (typically <2.5 mg/dL) 1, 5
• Renal phosphate wasting: Confirmed by TmP/GFR calculation showing fractional phosphate excretion >15% 1, 5
• Alkaline phosphatase: Markedly elevated, indicating active rickets 1, 5
• Serum calcium: Normal or low-normal range 1, 5
• PTH: Upper limit of normal or slightly elevated (distinguishing it from calcipenic rickets) 1, 5
• 25(OH) vitamin D: Normal (excluding nutritional rickets) 1, 5
• 1,25(OH)₂ vitamin D: Low or inappropriately normal in the setting of hypophosphataemia 1, 5
• Urinary calcium: Low 1

Critical pitfall: Always use age-related reference ranges for serum phosphate, as normal adult ranges will miss the diagnosis in children. 5

Excluding Other Causes

Rule out Fanconi syndrome by testing urine for abnormal losses of bicarbonate, amino acids, glucose, uric acid, and low molecular mass proteinuria. 1, 5 Non-selective renal tubular phosphate wasting suggests Fanconi syndrome rather than isolated XLH. 1

Genetic Confirmation

Confirm the clinical diagnosis with genetic analysis of the PHEX gene whenever feasible. 1 This is particularly important given:

• The X-linked dominant inheritance pattern means affected males will pass the mutation to all daughters but no sons 1
• De novo mutations occur and may explain cases without obvious family history 3
• Genetic counseling should be offered, especially during transition to adult care and for family planning 1

If genetic testing is unavailable, elevated intact FGF23 levels and positive family history support the diagnosis. 1 However, FGF23 levels should be measured before initiating treatment, as they are influenced by phosphate intake and vitamin D therapy. 1, 5

Radiographic Assessment

Obtain radiographs of wrists and knees to assess rickets severity using the Rickets Severity Score (RSS). 6 Typical findings include:

• Widened, frayed, and cupped metaphyses 2, 3
• Coarse trabecular pattern 2
• Lower limb deformities on long bone films 2, 3

Treatment Strategy

First-Line Therapy: Burosumab

For pediatric patients ≥6 months of age with confirmed XLH, burosumab (CRYSVITA) is now the preferred treatment, demonstrating superior efficacy compared to conventional therapy. 6

Dosing regimen:

• Starting dose: 0.8 mg/kg subcutaneously every 2 weeks 6
• May titrate up to 1.2 mg/kg based on serum phosphorus response 6

Evidence of superiority: In a randomized controlled trial of 61 pediatric patients (ages 1-12 years), burosumab demonstrated: 6

• Mean serum phosphorus increased from 2.4 to 3.3 mg/dL at 40 weeks (vs. 2.3 to 2.5 mg/dL with conventional therapy)
• TmP/GFR increased from 2.2 to 3.4 mg/dL (vs. decreased from 2.0 to 1.8 mg/dL with conventional therapy)
• RSS decreased from 3.2 to 1.1 (vs. 3.2 to 2.5 with conventional therapy)
• 72% achieved substantial radiographic healing (RGI-C score ≥+2.0) vs. 6% with conventional therapy

Alternative: Conventional Therapy

If burosumab is unavailable or contraindicated, use oral phosphate supplementation combined with active vitamin D metabolites: 1, 6

• Oral phosphate: 20-60 mg/kg/day divided into multiple doses (typically 4-5 times daily) 6
• Active vitamin D: Calcitriol 20-30 ng/kg/day OR alfacalcidol 40-60 ng/kg/day 6

Critical monitoring with conventional therapy:

• Risk of nephrocalcinosis and secondary hyperparathyroidism 1
• Monitor urinary calcium:creatinine ratio regularly 1
• Adjust doses to maintain serum phosphorus in low-normal range while avoiding hypercalciuria 1

Treatment Pitfalls

Common errors to avoid:

• Do not use standard vitamin D supplementation alone—this is ineffective in XLH and delays appropriate treatment 2, 3
• Do not assume all patients with family history are aware of their diagnosis—62% of affected individuals in one study knew they had bone problems, but only 22.6% were told they had rickets 4
• Lifelong treatment is required; discontinuation leads to recurrence of biochemical and clinical abnormalities 7, 2
• Multidisciplinary care is essential as complete phenotypic rescue is rarely achieved even with optimal treatment 8

Monitoring During Treatment

Regular follow-up should include: 1

• Serum phosphate, calcium, alkaline phosphatase, PTH, and creatinine
• Urinary calcium:creatinine ratio (especially with conventional therapy)
• Growth velocity and anthropometric measurements
• Radiographic assessment of rickets healing and skeletal deformities
• Dental evaluation for abscesses and enamel defects
• Assessment for craniosynostosis in young children