How should a PHEX gene variant of uncertain significance be evaluated and managed?

Management of PHEX Gene Variant of Uncertain Significance

When a PHEX gene variant of uncertain significance (VUS) is identified, the diagnosis of X-linked hypophosphatemia (XLH) must rely entirely on clinical and biochemical criteria, and you should consider re-interpretation of the variant in the future through specialized laboratories. 1, 2

Diagnostic Approach When VUS is Present

Confirm Clinical Diagnosis Independent of Genetics

The presence of a VUS does not confirm or exclude XLH. You must establish the diagnosis based on:

Biochemical Profile Required:

• Serum phosphorus: Low for age due to renal phosphate wasting
• TmP/GFR (tubular maximum reabsorption of phosphate): Low
• Serum calcium: Normal (albumin-adjusted or ionized)
• Parathyroid hormone: Normal or mildly elevated
• Alkaline phosphatase: Elevated
• 25-hydroxyvitamin D: Normal (unless concurrent deficiency)
• 1,25-dihydroxyvitamin D: Normal or inappropriately low
• FGF23: Elevated or inappropriately normal (critical finding) 1

Clinical Manifestations to Document:

• Lower limb deformity (genu varum/valgum, tibial torsion)
• Below average stature
• Bone pain
• Muscle weakness and fatigue
• Dolichocephaly and craniosynostosis
• Dental abscesses (prominent feature)
• Tinnitus, hearing loss 1

Imaging Findings:

• Rachitic growth plates at wrists, knees, ankles
• Lateral femoral bowing
• In adults: pseudofractures, enthesopathies, ligamentous ossification 1, 2

Critical Pitfall: Rule Out Nutritional Rickets

This is essential before attributing symptoms to a VUS. Nutritional rickets presents with:

• Low 25-hydroxyvitamin D (key differentiator)
• Markedly elevated PTH (more than mild elevation)
• Hypocalcemia
• Biochemical abnormalities correct with vitamin D3/D2 supplementation 1

Management of the VUS Itself

Immediate Actions

1. Request variant re-interpretation through the testing laboratory or a specialist in variant interpretation 1, 2

   • Technologies exist to evaluate if a VUS is damaging, though typically research-based and difficult to access
   • Variant classifications change over time as new information accumulates

2. Consider advanced genetic testing if standard sequencing was performed:

   • Deep intronic sequencing (conventional PHEX sequencing may miss deep intronic variants, mosaicism, or chromosomal rearrangements) 2, 3, 4, 5
   • Whole genome sequencing combined with RNA sequencing if clinical suspicion remains high 4, 5
   • Approximately 12-16% of clinically diagnosed XLH cases have no detectable variant with standard approaches 6, 5

3. Family cascade testing if appropriate:

   • Test at-risk relatives to determine if the VUS segregates with disease
   • This provides critical evidence for reclassification 7

Longitudinal Management

Periodic re-evaluation is essential because:

• Disease manifestations vary by age—repeat clinical or biochemical evaluation may be necessary if initial testing is negative 1
• VUS reclassification takes time: mean 30.7 months to benign/likely benign, 22.4 months to pathogenic/likely pathogenic 8
• 80% of reclassified VUSs ultimately become benign or likely benign 8

Establish a tracking system:

• Keep detailed records of the VUS for future re-interpretation
• Schedule periodic follow-up (specific intervals depend on clinical severity)
• Maintain patient contact to enable notification if reclassification occurs 9

Treatment Decisions with VUS Present

If the clinical and biochemical profile is consistent with XLH, treat as XLH regardless of the VUS. The genetic test does not make the diagnosis—it supports it. 1

• Standard treatment options include phosphate supplementation with active vitamin D or burosumab (anti-FGF23 antibody)
• Do not withhold treatment waiting for genetic confirmation when clinical diagnosis is clear
• Conversely, do not treat based on a VUS alone without supporting clinical/biochemical evidence 1

Key Algorithmic Summary

1. VUS identified → Does NOT confirm or exclude XLH
2. Establish clinical diagnosis → Complete biochemical workup + clinical manifestations + imaging
3. Rule out nutritional rickets → Check 25-OH vitamin D, PTH levels
4. If clinical diagnosis clear → Treat as XLH
5. Simultaneously pursue → Variant re-interpretation, consider advanced sequencing, family testing
6. Long-term → Track VUS, schedule re-evaluation, maintain patient contact

The most common error is either over-interpreting a VUS as diagnostic or dismissing XLH entirely because of a VUS result. Clinical judgment supersedes genetic uncertainty in this scenario.