What are the diagnostic steps and treatment options for Hyper IgD syndrome?

Diagnostic Steps and Treatment Options for Hyper IgD Syndrome

Genetic testing for mutations in the mevalonate kinase (MVK) gene is the definitive diagnostic approach for Hyper IgD Syndrome, accompanied by measurement of serum IgD levels and evaluation of characteristic clinical presentation. 1

Clinical Presentation and Diagnostic Approach

Key Clinical Features to Recognize

• Recurrent fever episodes (typically lasting 3-7 days, recurring every 4-6 weeks)
• Onset typically in infancy, though later onset cases have been reported 2
• Associated symptoms during attacks:
  • Lymphadenopathy (particularly cervical)
  • Arthralgia
  • Abdominal pain and diarrhea
  • Skin rash
  • Headache
  • Aphthous ulcers

Diagnostic Algorithm

1. Clinical suspicion: Consider HIDS in patients with recurrent fever episodes with the constellation of symptoms above

2. Laboratory testing:

   • Serum IgD levels: Often elevated but not diagnostic in isolation
   • Note: Normal IgD levels do not exclude HIDS (sensitivity of elevated IgD is approximately 79%) 3
   • Polyclonal increase in IgD is characteristic 4
   • IgA levels may also be elevated 5

3. Genetic testing:

   • Confirmation requires identification of mutations in the MVK gene 1
   • Transmitted by autosomal recessive inheritance

4. Additional workup to exclude other conditions:

   • Abdominal imaging may show mesenteric lymphadenopathy 5
   • Consider inflammatory markers during attacks (elevated ESR, CRP)
   • Rule out inflammatory bowel disease, which can present with similar gastrointestinal symptoms 5

Treatment Options

FDA-Approved Treatment

• Canakinumab (ILARIS): FDA-approved IL-1β blocker for HIDS/MKD 6
  • Dosing:
    • For patients >40 kg: 150 mg subcutaneously every 4 weeks
    • For patients ≤40 kg: 2 mg/kg subcutaneously every 4 weeks
  • Dose can be increased if clinical response is inadequate:
    • For patients >40 kg: up to 300 mg every 4 weeks
    • For patients ≤40 kg: up to 4 mg/kg every 4 weeks

Alternative Treatment Options

• Anakinra: Another IL-1 receptor antagonist that has shown efficacy 2
• Colchicine: Some case reports suggest benefit 4

Important Considerations

Diagnostic Pitfalls

• Relying solely on IgD levels is insufficient for diagnosis, as:
  • Some patients with MVK mutations have normal IgD levels 3
  • Some patients with elevated IgD levels do not have MVK mutations 3
  • Likelihood ratios indicate IgD measurement alone has poor diagnostic value 3

Differential Diagnosis

• Inflammatory bowel disease (particularly Crohn's disease)
• Other autoinflammatory syndromes (e.g., Familial Mediterranean Fever)
• Recurrent infections

Multidisciplinary Management

• Referral to a clinical immunologist or rheumatologist with experience in autoinflammatory disorders is recommended 7
• Genetic counseling for families due to autosomal recessive inheritance pattern

Monitoring

• Regular assessment of disease activity and treatment response
• Monitoring for treatment-related adverse effects
• Long-term follow-up for potential complications

The diagnosis of HIDS requires a high index of suspicion in patients presenting with recurrent fever episodes and associated symptoms. While elevated IgD levels were historically considered diagnostic, genetic confirmation through MVK mutation analysis is now the gold standard. Treatment with IL-1 inhibitors, particularly canakinumab, has demonstrated efficacy in controlling disease manifestations and improving quality of life.