Additional Diverse Findings Expand the Clinical Presentation of DOCK8 Deficiency

Abstract

We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1-1 featured sclerosing cholangitis and colitis; patient 2-1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3-1, a fatal metastatic leiomyosarcoma; and patient 4-2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients’ lymphopenia was primarily restricted to CD4+ T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment.

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

“…The gut microbiota may be important in driving colitis in these mice, as in other models of autoimmune enteropathy (77)(78)(79). Together, these findings suggest that Treg dysfunction may play a role in the colitis that develops in patients with DOCK8 deficiency (80).…”

“…However, DOCK8-deficient patients only sporadically develop autoimmune disease (20,(23)(24)(25)(26). We report that mice with selective deficiency of DOCK8 in Tregs, but not Dock8 -/-mice, develop rampant autoimmunity, suggesting that deficient T effector cells (Teff) function may protect DOCK8-deficient patients from autoimmunity.…”

Ten-Year Follow-Up of a DOCK8-Deficient Child With Features of Systemic Lupus Erythematosus

“…It should be considered as early as possible, given the gradual worsening of the disease. [19][20][21][22] Hematopoietic stem cell transplantation has also shown dramatic positive outcomes in various autoimmune diseases, including SLE. 23 …”

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

“…DOCK8-deficient patients are also susceptible to autoimmunity and develop colitis, autoimmune hemolytic anemia, and vasculitis (53)(54)(55). These patients display increased levels of autoantibodies due to defective peripheral B cell tolerance, which was correlated with reduced numbers of Tregs with impaired suppressive function (28).…”