DOCK8 deficiency

Overview

DOCK8 deficiency is a rare inherited disorder of the immune system. It typically causes problems with the body's ability to fight off infections, particularly those caused by viruses, bacteria and fungi. Individuals with DOCK8 deficiency often experience severe and persistent eczema, respiratory issues, and may develop allergies or asthma. The condition makes people more vulnerable to certain cancers, especially lymphomas and skin cancers [PMID:19420360]. Symptoms usually begin in infancy or early childhood and can vary in severity between individuals.

Symptoms & clinical features

The symptoms of DOCK8 deficiency are wide-ranging, primarily affecting the skin and immune system. Severe, chronic eczema is a hallmark feature, often appearing in infancy and covering large areas of the body. Recurrent infections are common, including skin infections (warts, molluscum contagiosum), lung infections leading to pneumonia, and ear or sinus infections [PMID:19420360]. These infections can be unusually severe or difficult to treat. Some individuals may also have food allergies, asthma, or a heightened risk of autoimmune conditions. Neurological issues, such as seizures or developmental delays, have also been reported in some cases [PMID:21206126].

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Affected organs

DOCK8 deficiency primarily impacts the immune system, leading to widespread effects throughout the body. The skin is severely affected, manifesting as chronic eczema and recurrent infections. The lungs are often susceptible to persistent or severe respiratory infections, and the ears and sinuses are also commonly affected. The gastrointestinal tract may be impacted by allergies or infections. In some instances, the central nervous system can show abnormalities, and there is a higher lifetime risk of certain cancers affecting the blood cells (lymphoma) or skin.

Immune cells

Immune system dysfunction

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of DOCK8 deficiency can vary, but it is generally considered a severe condition that significantly impacts health. Untreated, individuals can experience life-threatening infections and complications from severe eczema. There is a substantially increased lifetime risk of developing certain cancers, particularly B-cell lymphomas and squamous cell carcinomas of the skin [PMID:21206126]. Symptoms typically begin in early childhood, although diagnosis may sometimes be delayed. Exact prevalence is not well established, but it is certainly a rare condition.

Genetic causes

DOCK8 deficiency is caused by pathogenic variants in the DOCK8 gene. This gene provides instructions for making a protein called dedicator of cytokinesis 8, or DOCK8. The DOCK8 protein is particularly important in immune system cells, such as T cells, B cells, and natural killer (NK) cells. It helps these cells to migrate, survive, and function correctly, playing a crucial role in the body's immune response [PMID:21206126]. When the DOCK8 gene has a pathogenic variant, it can lead to a non-functional or absent DOCK8 protein. This disrupts the normal development and function of immune cells, weakening the body's defence against infections and contributing to the severe eczema and cancer risk seen in DOCK8 deficiency.

• DOCK8
  dedicator of cytokinesis 8
  The DOCK8 gene provides instructions for a protein crucial for immune cell development, survival, and movement, particularly within T cells, NK cells, and B cells.

Inheritance pattern

DOCK8 deficiency is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of the pathogenic DOCK8 gene variant - one from each parent - to develop the condition. Individuals who inherit only one pathogenic variant are called carriers. Carriers typically do not show symptoms of DOCK8 deficiency themselves but can pass the variant on to their children. If both parents are carriers of a DOCK8 pathogenic variant, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two copies and be affected by the condition, a 1 in 2 (50%) chance that their child will be a carrier, and a 1 in 4 (25%) chance that their child will inherit two unaffected copies and not be a carrier.

Diagnosis & testing

Diagnosing DOCK8 deficiency often begins with recognising the characteristic clinical features, such as severe eczema combined with recurrent infections. A definitive diagnosis is confirmed through genetic testing, which looks for specific pathogenic variants in the DOCK8 gene. In the UK, genetic testing for immunodeficiencies is part of the NHS Genomic Medicine Service (GMS) and is typically requested by a clinical immunologist or a clinical geneticist. The relevant NHS National Genomic Test Directory R-code for primary immunodeficiency is R157. Blood tests may also show abnormalities in the number and function of certain immune cells, which can support the diagnosis.

Management & lifestyle

Management of DOCK8 deficiency focuses on treating symptoms, preventing infections, and, where possible, correcting the underlying immune defect. This often involves regular treatment for eczema, such as topical steroids and moisturisers, and prompt treatment of infections with antibiotics, antifungals, or antivirals. Immunoglobulin replacement therapy may be used to provide antibodies to help fight infections. For some individuals, a haematopoietic stem cell transplant (HSCT) may be considered, as this can potentially cure the immune defect [PMID:25725736]. This complex procedure would be discussed in detail by a multidisciplinary team. Regular monitoring for the development of cancers is also an important part of long-term care. All management plans are highly individualised and should be developed in consultation with specialists.

UK care pathway

In the UK, individuals suspected of having DOCK8 deficiency would typically be referred to a clinical immunologist or paediatric immunologist within the NHS. If genetic testing is indicated, it can be accessed through the NHS Genomic Medicine Service (GMS) via the National Genomic Test Directory (R-code R157 for primary immunodeficiencies). Referral to a clinical genetics service is also common, especially to discuss the genetic aspects, inheritance patterns, and for genetic counselling. Genetic counsellors play a vital role in helping families understand the condition, testing options, and implications for relatives.

Related conditions

DOCK8 deficiency shares some symptoms with other primary immunodeficiency disorders, particularly those involving severe eczema and recurrent infections, such as Omenn syndrome or forms of severe combined immunodeficiency (SCID). It can also be clinically mistaken for severe atopic dermatitis (eczema) if the immunodeficiency component is not initially recognised. Genetic testing is crucial to distinguish DOCK8 deficiency from these other conditions and ensure accurate diagnosis and appropriate management.

Frequently asked questions

References

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