The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

Abstract

Background Mutations in DOCK8 cause a combined immunodeficiency (CID) also classified as autosomal-recessive hyper-IgE syndrome (HIES). Recognizing patients with CID / HIES is of clinical importance due to a difference in prognosis and management. Objectives Define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs; study the mutational spectrum of DOCK8 deficiency; and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of autosomal-recessive HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with 10 AR-HIES patients without a DOCK8 mutation and 64 patients with STAT3 mutations. Results DOCK8-deficient patients had a median IgE of 5,201 IU, high eosinophil levels of usually at least 800/µl (92% of patients), and low levels of IgM (62%). About 20% of patients were lymphopenic, mainly due to low CD4+ and CD8+ T cells. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of five clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels, who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

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

“…DOCK8-deficient patients uniformly suffer from infections and skin inflammation and are on multiple medications, which could potentially affect their Tregs (27). To circumvent these limitations, we examined mice that carry a homozygous knockin c.C1074T mutation, recapitulating a mutation in a DOCK8 null patient (21).…”

“…DOCK8 regulates actin cytoskeleton-dependent functions in T cells, B cells, NK cells, and DCs (14)(15)(16)(17)(18). DOCK8 deficiency in humans is caused by biallelic mutations in DOCK8 that abolish protein expression (19). DOCK8 deficiency is associated with atopic dermatitis, asthma, food allergies, an unusual susceptibility to viral mucocutaneous infections, T cell lymphopenia, reduced proliferative T cell responses, decreased cytokine production, and impaired antibody responses (20,21).…”

Serum IgE Düzeyi ve Eozinofil Sayısı ile Atopik Hastalıklar Hiper IgE Sendromu’ndan Ayırt Edilebilir mi?

“…Primer immün yetmezlik tanısının erken konması, profilaktik tedavilerin başlanması, morbidite ve mortaliteyle ilişkili kronik akciğer hasarını önlemede birincil öneme sahiptir. Bu nedenle birçok skorlama geliştirilmiş (24,26), laboratuvar verileri karşılaştırılarak bu soruya yanıt aranmaya çalışılmıştır (15,27). Çalışmamızda, atopik grupta hem kan eozinofil, hem serum IgE değerleri atopik gruba göre PİY grubunda anlamlı yüksek saptandı.…”

“…Duyarlanma saptananların tümü DOCK8 eksikliği olanlardı. Literatürde de allerjik yakınmalar otozomal resesif formda gözlenirken (%73), en sık gıdalara (%64), ikinci sırada aeroallerjenlere duyarlanma saptanmaktadır (%32) (26). Atopik dermatitli 31 hastamızın ise 12'si ev tozu akarı, 6'sı gıda ve 1 tanesi polenlere karşı duyarlanmıştı.…”

DOCK8 regulates signal transduction events to control immunity

“…7 Patients with DOCK8 deficiency present with clinical characteristics such as eczema, respiratory tract infections, high levels of serum IgE, hyper-eosinophilia, and a failure to clear bacterial, fungal and viral infections (Table 1). 5,8,9 In particular, they suffer from severe cutaneous viral infections with molluscum contagiosum, papilloma virus and herpes simples virus. 8 Since the discovery of DOCK8 mutations as a genetic driver of AR-HIES, the clinical manifestations have pointed to a crucial role for DOCK8 in regulating multiple facets of the immune response.…”