What are the presentation symptoms and management of Hyper IgD syndrome?

Hyper-IgD Syndrome: Clinical Presentation and Symptoms

Hyper-IgD syndrome (HIDS) presents with recurrent febrile attacks accompanied by abdominal pain, joint involvement, lymphadenopathy, and skin lesions, with onset typically in early childhood. 1, 2

Core Clinical Features

Fever Pattern

• Recurrent periodic fevers are the hallmark, beginning in early childhood (often infancy) 2, 3
• Febrile episodes are self-limited but recurrent throughout life, though frequency and severity may diminish with age 2
• Attacks are accompanied by acute-phase response with markedly elevated C-reactive protein 2, 4

Gastrointestinal Manifestations

• Abdominal complaints occur during attacks, including vomiting, abdominal pain, and diarrhea 1, 2
• Symptoms can mimic inflammatory bowel disease, particularly Crohn's disease 3
• Ultrasonography during attacks typically shows enlargement of mesenteric lymph nodes 3
• Abdominal leucocyte scintigraphy may display diffuse signals of mild to moderate degree 3

Musculoskeletal Involvement

• Joint involvement manifests as arthralgias or frank arthritis during febrile episodes 1, 2
• These symptoms are prominent during attacks but resolve between episodes 2

Lymphatic and Dermatologic Features

• Bilateral cervical lymphadenopathy is common, though swollen lymph nodes can occur more diffusely 2, 5
• Skin lesions appear during attacks, with variable morphology 1, 2
• The rash is typically non-urticarial and evanescent 1

Neurologic Symptoms

• Headache is a frequent accompaniment of febrile attacks 2, 5

Laboratory Hallmarks

Immunologic Markers

• Elevated serum IgD levels (>100 U/mL) are the diagnostic cornerstone 2, 5, 3
• IgA levels are often elevated as well (in 3 out of 4 patients in one series) 3
• The IgD elevation is polyclonal 5

Inflammatory Markers During Attacks

• Markedly elevated C-reactive protein (mean 213 mg/L during attacks) 4
• Elevated soluble type-II phospholipase A2 (mean 1,452 ng/mL during attacks) 4
• Significantly increased IL-6 concentrations (19.7 pg/mL at baseline vs 147.9 pg/mL during attacks) 4
• Elevated TNF-alpha, IL-1ra, and soluble TNF receptors (p55 and p75) during attacks 4

Genetic and Diagnostic Considerations

Molecular Basis

• Autosomal recessive inheritance pattern 2
• Caused by mutations in the MVK gene (mevalonate kinase deficiency) 1
• When febrile attacks are associated with abdominal or joint pains or rash, mutation analysis of MVK should be undertaken 1

Differential Diagnosis Pitfalls

• The gene for HIDS is distinct from the familial Mediterranean fever gene 2
• Must be distinguished from CINCA syndrome (chronic inflammatory, neurological, cutaneous and articular syndrome) and FAPA syndrome (periodic fever, adenopathies, pharyngitis, and aphthous stomatitis), both of which have normal serum IgD 2
• Critical caveat: IgD levels in Crohn's disease patients are not elevated compared to healthy controls, making this a specific marker for HIDS 3

Management Approach

Therapeutic Options

• No definitive cure exists, and patients experience attacks throughout life 2
• Colchicine has shown benefit in some cases 5
• Anti-IL-6 receptor therapy (monoclonal antibody) has demonstrated impressive clinical improvement and reduction in hospital admissions in severe, refractory cases 6
• Anti-inflammatory biologicals such as TNF or IL-1 antagonists may be useful, along with corticosteroids 1

Clinical Course

• Frequency and severity of attacks tend to diminish with advancing age 2
• The cytokine network activation during attacks (elevated IL-6, TNF-alpha, and acute-phase proteins) suggests these inflammatory mediators contribute directly to symptoms 4