SUMMARY

 

1. DOCK8 Deficiency is an autosomal recessive combined immunodeficiency. Prior to the identification of the molecular defect for this disease, many patients were categorized as having autosomal recessive Hyper IgE syndrome.

 

2. Patients with DOCK8 deficiency are characterized by the following clinical features:

 

- Severe atopic disease (atopic dermatitis, food allergies, asthma)

- Recurrent Staph aureus skin abscesses

- Recurrent pneumonias

- Viral cutaneous infections (Molluscum, Herpes simplex, HPV, VZV)

- Increased risk for malignancies (lymphoma and squamous cell carcinoma)

 

3. Unlike patients with STAT3 deficiency, patients lack coarse facial features, delayed shedding of primary teeth, pathological fractures, and pneumatocele formation.

 

4. It has been postulated that DOCK8 deficiency results in impaired actin reorganization, which is critical for number of key immune functions. 5. Laboratory findings include elevated IgE levels and eosinophilia. T cell lymphopenia and reduced T cell function have been reported. Patients can also have NK and B cell lymphopenia. IgG levels may elevated but specific antibody responses are impaired. IgM and IgA levels may be reduced.

 

6. DOCK8 protein expression and gene sequencing can confirm the diagnosis.

 

7. Antibiotic prophylaxis with trimethoprim-sulfamethoxazole (2.5mg/kg of TMP component) is useful for preventing staphylococcal infections. Patients with specific antibody deficiency require IVIG replacement therapy.

 

8. DOCK8 deficiency is associated with high morbidity and mortality. Stem cell transplantation has been successfully performed in a small number of patients – this treatment should be strongly considered for patients with severe disease.

 

 

 

OVERVIEW

 

          DOCK8 Deficiency is an autosomal recessive combined immunodeficiency. Prior to the identification of the molecular defect for this disease, many patients were categorized as having autosomal recessive Hyper IgE syndrome.

 

          Patients with DOCK8 deficiency are characterized by the following clinical features:

 

- Severe atopic disease (atopic dermatitis, food allergies, asthma)

- Recurrent Staph aureus skin abscesses

- Recurrent pneumonias

- Viral cutaneous infections (Molluscum, Herpes simplex, HPV, VZV)

- Increased risk for malignancies (lymphoma and squamous cell carcinoma)

 

         

 

PATHOGENESIS

 

         Many of the DOCK180-related family members activate RAC and CDC42 to initiate actin reorganization. It has been postulated that DOCK8 deficiency results in impaired actin reorganization (which is critical for a number of immune functions including formation of the immunologic synapse, phagocytosis, chemotaxis, endocytosis, and exocytosis).

 

 

EVALUATION

 

The diagnosis of DOCK8 deficiency should be considered in patients with severe dermatitis, Staph aureus skin infections, pneumonias, and viral skin infections.

 

 

Step 1: Initial screening laboratory studies.

         

                      - CBC with Differential

- Serum IgE levels IgG, IgM, IgA

- Specific antibody responses to vaccines

- Lymphocyte subset enumeration by flow cytometry

 

-Eosinophilia and lymphopenia may be present on CBC with differential.

 

-Serum IgE is typically elevated IgG levels are often elevated but IgM and IgA levels may be low.

 

-Impaired specific antibody responses have been described

 

-Decreased T, B and NK cell numbers have been reported. Patients may also have reduced T cell function.

 

 

Step 2:  Protein expression

 

-DOCK8 protein expression by flow cytomtery is commercially available

 

 

Step 3: Gene sequencing

 

-DOCK8 gene sequencing 

- Genetic confirmation of DOCK8 Deficiency can be achieved by sanger sequencing, whole exome sequencing or whole genome sequencing.

 

 

 

MANAGEMENT

 

1. Skin Care – Eczema should be treated with emollients and topical anti-inflammatory medications. Superinfection of eczema requires treatment with systemic antibiotics. Bleach baths 3 times weekly can be helpful to decrease cutaneous Staphylococcus colonization.

 

2. Prophylactic Antibiotics - Daily trimethoprim-sulfamethoxazole (2.5mg/kg of TMP component twice daily) is useful to decrease skin and lung infections.

 

3. Intravenous Immune Globulin (IVIG) therapy – Patients with impaired specific antibody responses benefit from IVIG replacement therapy. Typical dosing is 400-600mg per kg administered once a month by IV or once a week by subcutaneous infusion.

 

4. Stem Cell Transplantation – There is a case report of this immunomodulator being used to treat severe cutaneous molluscum infection in HIES (see resource section).

 

 

                                                                           

RESOURCES

 

Diagnostic Resources     

 

1. Seattle's Children: DOCK8 Flow cytometry & DOCK8 Gene Sequencing

 

Literature Resources

 

 

1.  Su 2009

     DOCK8 Combined immune deficiency

 

2.  Su 2010

     DOCK8 deficiency