DOCK8 Deficiency

DOCK8 deficiency is an autosomal recessive combined immunodeficiency from loss-of-function variants in DOCK8. It presents in early childhood as severe eczema, food allergy, raised IgE and recurrent viral skin infections.

Pathophysiology. DOCK8 controls cytoskeletal movement in lymphocytes, so T, B and NK cells die when they migrate through tight tissue. T cell numbers and memory function decline over time, which leads to severe cutaneous viral infection and cancer.

It is rare and is more common where consanguineous marriage is frequent.

Without definitive treatment, survival is poor, mainly from infection, malignancy and vasculitis.

• Severe, early onset eczema, with food allergy, asthma and allergic rhinitis
• Extensive warts, molluscum contagiosum and recurrent herpes simplex and zoster
• Recurrent sinopulmonary infection and bronchiectasis
• Chronic mucocutaneous candidiasis and Staphylococcus aureus skin abscesses
• Cryptosporidium infection with sclerosing cholangitis
• Cutaneous squamous cell carcinoma, EBV-associated lymphoma, and leukaemia
• Vasculitis and cerebral aneurysm
• No skeletal or dental abnormalities (unlike STAT3 hyper IgE syndrome)

• Serum IgE often over 2000 kU/L, with eosinophilia; IgM low, IgG and IgA variable.
• Lymphocyte subsets: progressive CD4 and CD8 T lymphopenia, low B and NK cells.
• DOCK8 protein expression by flow cytometry, confirmed by sequencing.
• Specific antibody responses to tetanus and pneumococcal vaccines.
• Viral PCR for EBV, CMV and herpes simplex, and skin biopsy for atypical lesions.
• Liver ultrasound and cholangiography with raised cholestatic enzymes.
• Skin and mucosal surveillance every 6 months.

Differential diagnosis.

• STAT3 hyper IgE syndrome (skeletal and dental features, pneumatoceles)
• Wiskott-Aldrich syndrome and PGM3 deficiency
• CARD11 and other atopic type combined immunodeficiencies
• Severe atopic dermatitis
• IPEX syndrome
• Omenn syndrome
• Epidermodysplasia verruciformis

• Definitive treatment is haematopoietic stem cell transplantation. Refer early, before malignancy or end organ damage, since outcomes are best in younger patients without active infection or cancer.
• Infection prophylaxis:
  • Co-trimoxazole 960 mg orally three times weekly in adults (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week, maximum 320 mg trimethoprim daily).
  • Fluconazole 100 to 200 mg orally daily for recurrent mucocutaneous candidiasis (maximum 400 mg daily; children 3 to 6 mg/kg daily). Check liver enzymes and avoid QT-prolonging drugs.
  • Aciclovir 400 mg orally twice daily for recurrent herpes simplex or zoster in adults (reduce at creatinine clearance under 25 mL/min; children weight based by a specialist).
• Immunoglobulin replacement for low IgG or poor antibody responses: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Skin care: emollients daily; topical corticosteroid mometasone 0.1% ointment once daily for flares (hydrocortisone 1% on the face and skin folds); treat staphylococcal infection by culture.
• Warts and molluscum: cryotherapy, curettage or imiquimod 5% cream three times weekly at night for up to 16 weeks. These respond poorly and recur until immune reconstitution.
• Food allergy: strict avoidance, with an adrenaline auto injector (0.3 mg for weight 30 kg or more; 0.15 mg for 15 to 30 kg) and a written action plan.
• Malignancy: dermatology review every 6 months, early biopsy, and treatment by stage.

Special groups.

• Children: weight based doses of all prophylactic drugs, and plan transplantation donor search at diagnosis.

Monitoring. Lymphocyte subsets and full blood count every 3 to 6 months. Liver enzymes and creatinine every 3 to 6 months. Trough IgG every 3 to 6 months. Skin and mucosal examination every 6 months.

Referral and escalation. Refer to a transplant immunology centre at diagnosis. Urgent for cerebral symptoms, cholestasis, sepsis, or rapidly growing skin lesions.