What are the skin manifestations of Hyper-IgD (Hyperimmunoglobulinemia D) syndrome?

Skin Manifestations of Hyper-IgD Syndrome

Skin lesions occur in approximately 79% of patients with Hyper-IgD syndrome during febrile attacks, with erythematous macules being the most common presentation, followed by erythematous papules, urticarial lesions, and erythematous nodules. 1

Primary Cutaneous Manifestations

The skin lesions in Hyper-IgD syndrome appear during febrile episodes and include:

• Erythematous macules are the most frequent cutaneous finding, occurring in approximately 43% of patients with skin involvement 1
• Erythematous papules present in approximately 34% of patients with cutaneous manifestations 1
• Urticarial lesions develop in approximately 26% of patients with skin involvement 1
• Erythematous nodules appear in approximately 20% of patients with cutaneous disease 1

Distribution and Timing

• Skin lesions typically appear during febrile attacks and are considered a true manifestation of the disease rather than an incidental finding 1
• The cutaneous manifestations occur alongside other systemic symptoms including fever, abdominal distress, joint involvement, headache, and lymphadenopathy 1, 2
• Lesions may occasionally present on the distal parts of upper and lower extremities 3

Histopathologic Features

The histologic findings in Hyper-IgD syndrome are variable and often nonspecific:

• Mild vasculitis features are the most common histopathologic finding in skin biopsy specimens 1
• Leukocytoclastic vasculitis pattern can be observed, particularly in lesions on the extremities 3
• Nonspecific inflammatory changes are noted in approximately 50% of biopsy specimens 1
• Sweet-like features (neutrophilic dermatosis pattern) occur in approximately 20% of cases 1
• Cellulitis-like findings and deep vasculitis characteristics are less common presentations 1

Immunopathologic Mechanism

• IgD immune complex deposition has been demonstrated in skin lesions, with perivascular deposits of IgD and C3 found on immunofluorescence examination of early lesional skin 3
• Circulating IgD immune complexes can be detected both during and between clinical attacks, suggesting an IgD immune complex-mediated pathogenesis for the skin lesions 3
• The cytokine network is activated during attacks, with elevated IL-6, TNF-alpha, and acute-phase proteins (CRP and PLA2) that may contribute to the inflammatory skin manifestations 4

Clinical Context and Differential Diagnosis

When evaluating suspected Hyper-IgD syndrome with skin manifestations:

• Confirm elevated serum IgD (>100 U/mL) as this is a defining feature of the syndrome 2, 5
• Document the periodic nature of symptoms, as attacks recur throughout life although frequency and severity may diminish with age 2, 5
• Distinguish from other periodic fever syndromes including Familial Mediterranean Fever, TRAPS, CINCA syndrome, and FAPA syndrome, which may share some cutaneous features but have normal serum IgD levels 2, 5
• Consider skin biopsy when the diagnosis is uncertain, though histopathologic findings are often nonspecific and multiple biopsies may be needed 1