Cutaneous Manifestations of <emph type="ital">DOCK8</emph> Deficiency Syndrome

Abstract

Background: Mutations in the dedicator of cytokinesis 8 gene (DOCK8) cause a combined primary immunodeficiency syndrome that is characterized by elevated serum IgE levels, depressed IgM levels, eosinophilia, sinopulmonary infections, cutaneous viral infections, and lymphopenia. Many patients with DOCK8 deficiency were previously thought to have a variant of Job's syndrome. Distinguishing between DOCK8 deficiency and Job's syndrome, also referred to as autosomal dominant hyper-IgE syndrome, on the basis of clinical findings alone is challenging. The discovery of the DOCK8 mutation has made it possible to differentiate the cutaneous manifestations of these hyper-IgE syndromes.Observations: Twenty-one patients from 14 families with confirmed homozygous or compound heterozygous mutations in DOCK8 were evaluated. Clinical findings included dermatitis, asthma, food and environmental allergies, recurrent sinopulmonary infections, staphylococcal skin abscesses, and severe cutaneous viral infections. Malignant neoplasms, including aggressive cutaneous T-cell lymphoma, anal and vulvar squa-mous cell carcinomas, and diffuse large B-cell lymphoma, developed in 5 patients during adolescence and young adulthood.Conclusions: DOCK8 deficiency and Job's syndrome share several clinical features, including elevated serum IgE levels, dermatitis, recurrent sinopulmonary infections, and cutaneous staphylococcal abscesses. However, the presence of recalcitrant, widespread cutaneous viral infections, asthma, and food and environmental allergies, as well as the absence of newborn rash and coarse facies, favors the clinical diagnosis of DOCK8 deficiency. Rates of malignancy and overall mortality in patients with DOCK8 deficiency were higher than in those with Job's syndrome, highlighting the value of distinguishing between these conditions and the importance of close monitoring for neoplasia.

Mendelian Genetics of Human Susceptibility to Fungal Infection

“…Therefore, DOCK8 deficiency leads to impaired Th17 differentiation and T-cell priming, the latter because of defective dendritic cell migration to lymph node (Harada et al 2012). Similar to autosomal dominant STAT3 deficiency, CMC develops in DOCK8 deficiency, but with lower frequency and severity (Chu et al 2012). Defects in T lymphocyte IL-17 production also occurs in DOCK8 deficiency (Fig.…”

DOCK8 is critical for the survival and function of NKT cells

“…45,46 There are parallels between XLP and DOCK8 deficiency, with defects in both B-and NKT-cell immunity, as well as viral susceptibility and an increased incidence of B lymphoma. 20 As previously indicated, a related DOCK protein DOCK2 is required for NKT cell development. DOCK2-deficient mice show a selective loss of NKT cells during positive selection.…”

“…18,19 Patients also have increased susceptibility to cancer, including metastatic squamous carcinoma 18 and B-cell lymphoma. 20 Given that NKT cells are important in immunity to infection and cancer and that NKT-cell development is dependent on the related DOCK2 protein, 21 this raises the question of whether defects in NKT-cell development and/or function could contribute to an increased risk of infectious disease or malignancy in the absence of DOCK8.…”

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

“…However, these viruses can reemerge from latency to cause disease in up to 30% of the population (Higgins et al, 1993;Kilkenny and Marks, 1996;Harpaz et al, 2008). In contrast to normal individuals, DOCK8-deficient patients with autosomalrecessive loss-of-function mutations in DOCK8 have impaired cellular and humoral immunity (Engelhardt et al, 2009;Zhang et al, 2009;Su et al, 2011;Jing et al, 2014) that manifests as extreme susceptibility to skin and other infections (Chu et al, 2012). Patients often suffer from disseminated and persistent viral skin infections including those caused by HSV, varicella-zoster virus, human papillomavirus, and molluscum contagiosum.…”