What is the phenotypic expression of Hyper IgD (Hyperimmunoglobulinemia D) syndrome?

Phenotypic Expression of Hyper-IgD Syndrome

Hyper-IgD syndrome presents with recurrent febrile attacks beginning in early childhood (typically before age 1 year), characterized by fever lasting 3-7 days recurring every 4-6 weeks, accompanied by abdominal pain, cervical lymphadenopathy, joint involvement, and skin lesions. 1, 2

Core Clinical Manifestations

Fever Pattern

• Recurrent fever episodes lasting 3-7 days with 4-6 week intervals between attacks 3
• Onset typically occurs in infancy (often by 6-12 months of age) 4, 3
• Attack frequency and severity tend to diminish with age, though patients experience episodes throughout life 2, 5

Gastrointestinal Features

• Abdominal pain, vomiting, and diarrhea occur during febrile attacks 1, 2
• Symptoms can mimic inflammatory bowel disease, particularly Crohn's disease 1
• Enlargement of mesenteric lymph nodes may be present 1

Musculoskeletal Involvement

• Arthralgias or frank arthritis manifest during febrile episodes 1, 2
• Joint symptoms are a prominent feature during attacks 6, 5

Lymphatic System

• Massive cervical lymphadenopathy is characteristic, particularly during attacks 4, 5
• Hepatosplenomegaly may be present in severe phenotypes 4

Dermatologic Manifestations

• Skin lesions appear during attacks with variable morphology 1, 2
• Rash may be seen occasionally 4

Neurologic Symptoms

• Headache commonly occurs during febrile episodes 2, 6

Laboratory Phenotype

Immunologic Markers

• Elevated serum IgD (>100 U/mL) is the hallmark finding 2, 5
• Important caveat: Serum IgD is usually normal until 3 years of age, so normal IgD does not exclude the diagnosis in young children 3

Acute Phase Response During Attacks

• Vigorous acute-phase response with elevated C-reactive protein (mean 213 mg/L during attacks) 4, 6
• Elevated erythrocyte sedimentation rate 4
• Elevated serum amyloid A 4
• Leukocytosis 4
• Elevated soluble type-II phospholipase A2 (mean 1,452 ng/mL during attacks) 6

Cytokine Profile

• Elevated IL-6 during attacks (19.7 pg/mL baseline vs 147.9 pg/mL during attacks), correlating with CRP levels 6
• Slightly elevated TNF-alpha concentrations during attacks (104 vs 117 pg/mL) 6
• Increased levels of IL-1, IL-6, and TNF with respective soluble receptors 3
• Elevated antiinflammatory compounds: IL-1 receptor antagonist, soluble TNF receptors p55 and p75 6
• Ex vivo monocyte/macrophage production of TNF-alpha, IL-1 beta, and IL-1ra is significantly higher during attacks, indicating in vivo priming 6

Between-Attack Period

• Clinical and laboratory improvement occurs between attacks 4
• Acute phase reactants normalize during remission 6

Genetic Basis

• Caused by mutations in the MVK gene (mevalonate kinase deficiency) with autosomal recessive inheritance 7, 1
• Novel mutations continue to be identified, such as p.R277G associated with severe phenotype 4

Phenotypic Severity Spectrum

• Severe phenotypes may present with massive lymphadenopathy, hepatosplenomegaly, and poor response to standard therapies 4
• Genotype-phenotype correlations require further study to fully characterize 4

Clinical Pitfalls

• Do not exclude Hyper-IgD syndrome based on normal IgD levels in children under 3 years of age 3
• The disorder occurs in families and should prompt evaluation of siblings 2
• Clinical suspicion should remain high even with normal IgD if the clinical phenotype is consistent 4