DOCK8 Deficiency: Extended Clinical Phenotypes and the Impact of Somatic Reversions

Introduction DOCK8 deficiency is a rare combined immunodeficiency characterized by atopy, recurrent oto-sinopulmonary infections, viral skin infections, and malignancy. Mortality is approximately 50% by age 20 without curative hematopoietic cell transplantation (HCT). We clinically phenotyped our cohort and assessed whether somatic reversions in lymphocytes impacted clinical severity. Methods We reviewed the clinical characteristics, laboratory studies, and outcomes of 59 patients with DOCK8 deficiency evaluated at the NIH Clinical Center. Twenty-one anti-cytokine autoantibodies were screened using a multiplex particle-based assay. Somatic reversions restoring DOCK8 protein expression in lymphocytes were assessed by flow cytometry in 49 patients. Results The median age at initial evaluation was 10 years (range 0.5-42), with 54% female. The most common clinical findings were sinopulmonary infections (96.6%), recurrent or chronic viral skin infections (96.6%), and eczema (93.2%). End-organ damage included bronchiectasis (44.1%), liver disease (primarily Cryptosporidium-related) (28.1%), and vasculopathy (17.9%). Malignancies (27.1%) included squamous cell carcinoma (13.6%) and lymphoma (23.7%). Laboratory findings showed elevated serum IgE (87.9%), low serum IgM (62.1%), and lymphopenia-affecting CD4 (64.9%), CD8 (43.9%), and NK cells (52.6%). The overall survival was 64% (age of death 7-45 years; median 18). Forty-five patients (76.3%) underwent HCT with a survival rate of 75.6%; 14 (23.7%) did not undergo HCT with a survival rate of 21.4%. Neutralizing autoantibodies against type I/II interferons were not detected in 57 patients. Forty-nine patients were assessed for lymphocyte somatic reversions; 23 had reversions in lymphocytes, while 26 either did not have reversions or had mutations (e.g., large homozygous deletions) that could not be reverted. Patients with reversions had milder eczema, an increased incidence of warts, older age at HCT, and less CD8 lymphopenia; other clinical features, including malignancy and mortality did not differ from those without reversions. Conclusions DOCK8 deficiency is associated with a high incidence of morbidity and mortality by early adulthood without curative HCT. Neutralizing autoantibodies against type I/II interferon were not present despite a high burden of viral infections. Somatic reversions were common but did not preclude life-threatening complications, including malignancy.