What is the management approach for Familial Hypocalciuric Hypercalcemia (FHH)?

Management of Familial Hypocalciuric Hypercalcemia (FHH)

Familial hypocalciuric hypercalcemia (FHH) is a benign condition that typically requires observation only and no specific treatment in most cases. This approach differs significantly from other hypercalcemic disorders like primary hyperparathyroidism.

Diagnostic Approach

Before establishing management, proper diagnosis is essential:

1. Laboratory evaluation:

   • Serum calcium (elevated)
   • Parathyroid hormone (normal or mildly elevated)
   • 24-hour urine calcium (low)
   • Calculate calcium/creatinine clearance ratio:
     • Ratio ≤0.020 strongly suggests FHH 1

2. Genetic testing:

   • Confirm diagnosis with genetic testing for mutations in:
     • CASR gene (FHH1 - most common)
     • GNA11 gene (FHH2 - rare)
     • AP2S1 gene (FHH3 - may have more pronounced phenotype) 2

Management Algorithm

1. Asymptomatic Patients (Most Common Scenario)

• Observation only
• No specific treatment required
• Avoid parathyroidectomy (surgery is ineffective) 3
• Regular monitoring of calcium levels
• Patient education about benign nature of condition

2. Symptomatic Patients

For patients with:

• Symptoms of hypercalcemia
• Serum calcium >1 mg/dL (0.25 mmol/L) above normal
• Risk of cardiac arrhythmias (shortened QTc)

Consider:

• Calcimimetic therapy (cinacalcet) 4
  • Has shown promise in reducing serum calcium and PTH levels
  • Can normalize shortened QTc interval
  • Generally well-tolerated

3. Special Populations

Pregnant Women

• Monitor calcium levels during pregnancy
• Usually no specific intervention required
• Consult with maternal-fetal medicine specialist

Children/Infants

• Rare severe presentations (especially FHH3) may require:
  • Low-calcium formula
  • Calcimimetic therapy (cinacalcet) 2
• Consultation with pediatric endocrinologist

Neonatal Severe Primary Hyperparathyroidism

• Rare homozygous CASR mutations
• May require more aggressive management
• Specialist consultation essential

Important Considerations

Avoiding Common Pitfalls

1. Misdiagnosis as primary hyperparathyroidism

   • Critical to differentiate as management differs dramatically
   • FHH patients should NOT undergo parathyroidectomy 3

2. Unnecessary treatment

   • Most patients require no intervention
   • Avoid unnecessary medications or procedures

3. Family screening

   • Autosomal dominant inheritance with high penetrance
   • Screen first-degree relatives to prevent misdiagnosis

Monitoring Recommendations

• Annual serum calcium and PTH levels
• Renal function tests
• Bone mineral density (typically normal despite mild hypercalcemia) 1

Potential Barriers to Treatment (when needed)

• Cost of calcimimetic therapy
• Need for indefinite treatment
• Potential side effects of medication 4

Patient Education

• Explain benign nature of condition
• Emphasize normal life expectancy
• Discuss autosomal dominant inheritance pattern
• Provide genetic counseling when appropriate
• Explain importance of avoiding unnecessary surgery

By following this management approach, patients with FHH can be appropriately diagnosed and managed, avoiding unnecessary interventions while addressing any symptoms or complications when they do occur.