Combined immunodeficiency due to DOCK8 deficiency

Combined immunodeficiency due to DOCK8 deficiency, also known as DOCK8 immunodeficiency syndrome or autosomal recessive hyper-IgE syndrome, is a rare primary immunodeficiency disorder caused by loss-of-function mutations in the DOCK8 gene located on chromosome 9p24.3. DOCK8 is a guanine nucleotide exchange factor critical for immune cell signaling, migration, and survival. The disease primarily affects the immune system, leading to a profound susceptibility to viral, bacterial, and fungal infections. Patients typically present in early childhood with recurrent sinopulmonary infections, extensive cutaneous viral infections (including severe herpes simplex, molluscum contagiosum, and human papillomavirus infections), eczema-like dermatitis, and food allergies. A hallmark laboratory finding is markedly elevated serum IgE levels, along with eosinophilia, lymphopenia (particularly of T cells), and impaired T-cell and NK-cell function. The disease follows an autosomal recessive inheritance pattern and is more frequently observed in populations with higher rates of consanguinity. Affected individuals are at significantly increased risk for developing malignancies, particularly squamous cell carcinomas and lymphomas, often at a young age. Autoimmune manifestations, including vasculitis and hemolytic anemia, may also occur. Without treatment, the disease is associated with significant morbidity and early mortality. The only curative treatment currently available is hematopoietic stem cell transplantation (HSCT), which has shown favorable outcomes when performed early, ideally before the development of severe infections or malignancies. Supportive management includes prophylactic antiviral and antifungal medications, immunoglobulin replacement therapy, and aggressive treatment of infections. Interferon-alpha has been used in some cases to manage viral infections. Early diagnosis through genetic testing and prompt referral for transplant evaluation are critical for improving long-term outcomes.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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