What is the diagnostic approach for Hyper IgD syndrome?

Diagnosing Hyper IgD Syndrome (HIDS)

Hyper IgD syndrome (HIDS) should be diagnosed through genetic testing for mutations in the mevalonate kinase (MVK) gene, along with measurement of serum IgD levels >100 U/ml and characteristic clinical presentation of recurrent fever episodes.

Clinical Presentation and Initial Evaluation

HIDS is an autoinflammatory disorder characterized by:

• Recurrent episodes of fever (typically 3-7 days duration, occurring monthly or bimonthly)
• Early onset (median age 0.5 years, often in first weeks of life) 1
• Associated symptoms during attacks:
  • Abdominal complaints (pain, vomiting, diarrhea)
  • Lymphadenopathy (particularly cervical)
  • Joint involvement (arthralgias/arthritis, non-destructive)
  • Skin lesions (often vasculitic)
  • Headache
  • Splenomegaly

Diagnostic Algorithm

1. Laboratory Testing:

   • Measure serum IgD levels (diagnostic threshold >100 U/ml) 2, 1
   • Measure serum IgA levels (often elevated) 3
   • Check inflammatory markers during attacks (elevated C-reactive protein, IL-6, TNF-alpha, IFN-gamma) 2

2. Genetic Testing:

   • Confirm diagnosis with genetic analysis for mutations in the MVK gene 4
   • HIDS is transmitted by autosomal recessive inheritance 2

3. Imaging Studies:

   • Abdominal ultrasonography to detect mesenteric lymphadenopathy 3
   • Consider abdominal leukocyte scintigraphy which may show diffuse mild to moderate signals 3

4. Rule Out Other Conditions:

   • Inflammatory bowel disease (particularly Crohn's disease)
   • Familial Mediterranean Fever (different genetic basis) 2
   • Other periodic fever syndromes:
     • CINCA (chronic inflammatory, neurological, cutaneous and articular syndrome)
     • FAPA (periodic fever, adenopathies, pharyngitis, and aphthous stomatitis) 2

Diagnostic Pitfalls and Considerations

• Gastrointestinal Focus: HIDS can mimic inflammatory bowel disease, leading to unnecessary invasive investigations. When recurrent fever is accompanied by mesenteric adenopathy and gastrointestinal complaints, consider HIDS 3.

• IgD Measurement Specificity: While elevated IgD is characteristic of HIDS, it's important to note that IgD levels are not elevated in other periodic fever syndromes like CINCA and FAPA 2.

• Geographic Distribution: Most reported cases are from Europe, with very few from other regions, which may lead to underdiagnosis in non-European populations 1.

• Age Considerations: Although typically presenting in early childhood, onset can rarely occur later in life (reported up to age 53) 1.

• Family History: About 40% of patients have a family history of periodic fever, but not necessarily of hyper-IgD 1.

Treatment Implications of Diagnosis

While treatment is not part of the diagnostic process, it's worth noting that:

• No standardized treatment protocols exist 5
• Colchicine has shown some benefit in case reports 6
• Targeted biologic therapies such as anti-IL-6 receptor antibodies have shown promise in severe cases 5
• The disease tends to diminish in frequency and severity with age 2

By following this diagnostic approach, clinicians can accurately identify HIDS and distinguish it from other conditions with similar presentations, avoiding unnecessary invasive procedures and providing appropriate management.