Pediatric DOCK8 Deficiency Beyond Infections and Atopy: An Immunoactinopathy with Immune Dysregulation and Multisystem Involvement

Abstract

Highlights What are the main findings? This tertiary-center cohort supports viewing pediatric DOCK8 deficiency as an actin cytoskeleton-related IEI with overlapping infectious, allergic, immune-dysregulatory, and systemic manifestations. Beyond eczema and recurrent infections, the cohort included cytopenias, autoimmunity, organomegaly, hepatobiliary disease, malignancy, and selected vascular/systemic complications. What are the implications of the main findings? Recognizing DOCK8 deficiency as an actin cytoskeleton-related IEI with immune dysregulation may help clinicians interpret severe atopy, viral skin disease, autoimmunity, and systemic findings within a single disease framework. Timely genetic diagnosis and early hematopoietic stem cell transplantation evaluation are critical to prevent cumulative organ damage and improve long-term outcomes. Abstract Background/Objectives: Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive combined immunodeficiency and an actin cytoskeleton-related inborn error of immunity characterized by severe atopy, recurrent infections, and broad immune dysregulation. We aimed to describe the clinical, immunological, genetic, treatment-related, and outcome features of children with genetically confirmed DOCK8 deficiency, emphasizing immune dysregulation and systemic involvement. Methods: We retrospectively reviewed 17 pediatric patients from 14 unrelated kindreds with genetically confirmed DOCK8 deficiency followed at a tertiary pediatric immunology center between 2005 and 2026. Demographic data, infectious and allergic manifestations, autoimmune and hematological findings, organ involvement, malignancy, laboratory parameters, genetic findings, hematopoietic stem cell transplantation (HSCT) status, and survival outcomes were analyzed descriptively. Results: Twelve patients were male (70.6%), and parental consanguinity was present in 13 patients (76.5%). The median age at symptom onset was 5 months (IQR, 3–10), whereas the median age at diagnosis was 44 months (IQR, 23–56). A history of eczema was documented in all patients. Recurrent skin infections occurred in 16 patients (94.1%), recurrent pneumonia in 13 (76.5%), mucocutaneous candidiasis in 10 (58.8%), and cytomegalovirus infection in four (23.5%). Confirmed autoimmune manifestations were documented in two patients, including autoimmune hepatitis and autoimmune hemolytic anemia. Malignancy occurred in two patients: gastrointestinal stromal tumor and cutaneous squamous cell carcinoma. Additional uncommon systemic manifestations included sclerosing cholangitis, giant aortic aneurysm, and chronic pancreatitis. HSCT was performed in 12 patients (70.6%); complete clinical recovery was achieved in 11, whereas one patient died after transplantation. Four of five non-transplanted patients died during follow-up. Conclusions: Pediatric DOCK8 deficiency showed an early-onset, severe, multisystem phenotype. Beyond infections and atopy, immune dysregulation-related and systemic manifestations were clinically important. Favorable HSCT outcomes were consistent with previous evidence supporting early molecular diagnosis and timely transplant evaluation.