DOCK8 deficiency is a rare immune disorder named after the mutated gene responsible for the disease. NIAID researchers discovered the cause of DOCK8 deficiency in 2009. People with this syndrome have lower-than-normal numbers of immune cells, which have a diminished capacity to move through dense tissues like the skin. These abnormalities lead to recurrent viral infections of the skin and respiratory system. People with DOCK8 deficiency also typically have allergies, asthma, and an increased risk for some types of cancer.

DOCK8 deficiency is associated with very high levels of an antibody called immunoglobulin E, or IgE. The syndrome formerly was known as autosomal recessive hyper-IgE syndrome, or AR-HIES. DOCK8 deficiency is one of many hyper-IgE syndromes.

In 2014, NIAID scientists discovered that the DOCK8 protein is required for certain immune cells to move through dense tissues without fragmenting and dying. When the DOCK8 protein is mutated, immune cells cannot reach and clear viral infections in the skin, likely accounting for the distinct skin infections seen in people with DOCK8 deficiency.

DOCK8 immunodeficiency syndrome is a disorder of the immune system. The condition is characterized by recurrent infections that are severe and can be life-threatening. The infections can be caused by bacteria, viruses, or fungi. Skin infections cause rashes, blisters, accumulations of pus (abscesses), open sores, and scaling. People with DOCK8 immunodeficiency syndrome also tend to have frequent bouts of pneumonia and other respiratory tract infections. Other immune system-related problems in people with DOCK8 immunodeficiency syndrome include an inflammatory skin disorder called eczema, food or environmental allergies, and asthma.

DOCK8 immunodeficiency syndrome is characterized by abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood; the levels can be more than 10 times higher than normal for no known reason. IgE normally triggers an immune response against foreign invaders in the body, particularly parasitic worms, and plays a role in allergies. It is unclear why people with DOCK8 immunodeficiency syndrome have such high levels of this protein. People with DOCK8 immunodeficiency syndrome also have highly elevated numbers of certain white blood cells called eosinophils (hypereosinophilia). Eosinophils aid in the immune response and are involved in allergic reactions.

Some people with DOCK8 immunodeficiency syndrome have neurological problems, such as paralysis that affects the face or one side of the body (hemiplegia). Blockage of blood flow in the brain or abnormal bleeding in the brain, both of which can lead to stroke, can also occur in DOCK8 immunodeficiency syndrome.

People with DOCK8 immunodeficiency syndrome have a greater-than-average risk of developing cancer, particularly cancers of the blood or skin.

DOCK8 immunodeficiency syndrome is also commonly called autosomal recessive hyper-IgE syndrome. However, researchers have identified several conditions that feature elevated levels of IgE and that follow an autosomal recessive pattern of inheritance. Each of these conditions has its own set of additional signs and symptoms and a different genetic cause. Some doctors consider these conditions forms of hyper-IgE syndrome, while others consider them independent disorders.

DOCK8 immunodeficiency syndrome is a rare disorder whose prevalence is unknown.

DOCK8 immunodeficiency syndrome is caused by mutations in the DOCK8 gene. The protein produced from this gene plays a critical role in the survival and function of several types of immune system cells. One of the functions of the DOCK8 protein is to help maintain the structure and integrity of immune cells called T cells and NK cells, which recognize and attack foreign invaders, particularly as these cells travel to sites of infection within the body. In addition, the DOCK8 protein is involved in chemical signaling pathways that stimulate other immune cells called B cells to mature and produce antibodies, which are specialized proteins that attach to foreign particles and germs, marking them for destruction.

DOCK8 gene mutations result in the production of little or no functional DOCK8 protein. Shortage of this protein impairs normal immune cell development and function. It is thought that T cells and NK cells lacking DOCK8 protein are abnormal and die too easily, particularly when moving through the layers of skin. A shortage of these immune cells impairs the immune response to foreign invaders, accounting for the severe skin infections common in DOCK8 immunodeficiency syndrome. A lack of DOCK8 protein also impairs B cell maturation and the production of antibodies. Impairment of this type of immune response leads to recurrent respiratory tract infections in people with this disorder. It is unclear how DOCK8 gene mutations are involved in other features of DOCK8 immunodeficiency syndrome, such as the elevation of IgE levels, and neurological problems.

Normal Function

The DOCK8 gene provides instructions for making a member of the DOCK family of proteins. The proteins in this family act as guanine nucleotide exchange factors (GEFs). GEFs turn on (activate) proteins called GTPases, which play an important role in chemical signaling within cells. Signaling stimulated by DOCK family proteins are typically involved in the arrangement of the structural framework inside cells (the cytoskeleton). By controlling the shape of the cytoskeleton, DOCK family proteins play a role in cell structure and movement (migration).

The DOCK8 protein is found most abundantly in cells of the immune system. This protein plays a critical role in the survival and function of several types of immune system cells, including T cells, NK cells, and B cells. T cells and NK cells recognize and attack foreign invaders, such as viruses, to prevent infection. B cells produce proteins called antibodies, which attach to foreign particles and germs and mark them for destruction.

Through its function as a GEF, the DOCK8 protein helps maintain the structure and integrity of T cells and NK cells. It also aids in the movement of these immune system cells to sites of infection, particularly the skin. The DOCK8 protein is also involved in chemical signaling pathways that stimulate B cells to mature and produce antibodies. The protein is also involved in the normal development and survival of other types of immune system cells.

Health Conditions Related to Genetic Changes

DOCK8 immunodeficiency syndrome

More than 130 mutations in the DOCK8 gene have been found to cause DOCK8 immunodeficiency syndrome (also called autosomal recessive hyper-IgE syndrome or AR-HIES). DOCK8 immunodeficiency syndrome is an immune system disorder that causes recurrent severe infections of the skin and respiratory tract. Affected individuals may have other immune system problems, such as allergies, asthma, or an inflammatory skin disorder called eczema. Most of the mutations involved in DOCK8 immunodeficiency syndrome delete regions of DNA from the DOCK8 gene. These deletions and other DOCK8 gene mutations lead to production of an abnormally short protein or production of no protein. As a result, affected individuals have little or no functional DOCK8 protein.

A shortage of DOCK8 protein impairs normal immune cell development and function. It is thought that T cells lacking DOCK8 protein cannot maintain their shape as they move through dense spaces, such as those found within the skin. The abnormal cells die too easily, resulting in reduced numbers of these cells. A shortage of T cells impairs the immune response to foreign invaders, accounting for the severe skin infections common in DOCK8 immunodeficiency syndrome. A lack of DOCK8 protein also impairs B cell maturation and the production of certain antibodies. Impairment of this type of immune response leads to recurrent respiratory tract infections in people with this disorder.

For unknown reasons, a reduction of DOCK8 protein results in higher-than-normal production of an immune system protein known as immunoglobulin E (IgE), which plays a role in allergic reactions. As a result, people with DOCK8 immunodeficiency syndrome have an increased risk of food and environmental allergies.

Other Names for This Gene

• 1200017A24Rik
• dedicator of cytokinesis protein 8 isoform 1
• dedicator of cytokinesis protein 8 isoform 2
• dedicator of cytokinesis protein 8 isoform 3
• epididymis luminal protein 205
• FLJ00026
• FLJ00152
• FLJ00346
• HEL-205
• MRD2
• ZIR8

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

DOCK8 immunodeficiency syndrome is characterized by recurrent infections, allergies, and certain cancers. Nearly all patients have recurrent or chronic upper and lower respiratory tract infections.

Recurrent lung infections may lead to destruction and widening of the large airways called bronchiectasis. In addition, many patients need sinus surgery or placement of ear tubes (myringotomy tubes) to help with their sinus and ear infections.

Cutaneous, or skin, infections in people with DOCK8 immunodeficiency syndrome are distinctive and may include the following:

• Severe and difficult-to-treat infections with viruses such as herpes simplex virus, human papillomavirus, and molluscum contagiosum virus
• Infections with bacteria such as Staphylococcus aureus
• Fungal infections of the mouth or skin, which are often caused by the fungus Candida

Eczema, a condition that causes the skin to become inflamed or irritated, also is common in people with DOCK8 immunodeficiency syndrome. Eczema can be quite severe and may be further complicated by bacterial infections. In some cases, the skin problems present in people with DOCK8 immunodeficiency syndrome can become disfiguring.

People with DOCK8 immunodeficiency syndrome frequently have food allergies, environmental allergies, and asthma. Some patients also may experience autoimmune problems, such as autoimmune hemolytic anemia (the body destroys its own red blood cells), vasculitis (blood vessel inflammation), or vasculopathy (blood vessel damage).

Patients also are at increased risk for developing squamous cell carcinoma, a type of skin cancer, and lymphoma, a cancer of the lymphatic system. Some, but not all, of these lymphomas are associated with infections with Epstein-Barr virus, a cancer-causing virus. The cancer risks in people with DOCK8 immunodeficiency syndrome are significant, and patients should be monitored closely for signs of cancer.

DOCK8 immunodeficiency syndrome is considered a combined immunodeficiency because it includes both decreased numbers of immune cells and defective immune cell function. It also can be classified as a type of autosomal recessive hyperimmunoglobulinemia E syndrome, which means that people with the disease have too much of a type of immunoglobulin, or antibody, called IgE.

Laboratory findings in people with DOCK8 immunodeficiency syndrome show progressive decreases in the number of lymphocytes (a type of immune cell), which is referred to as lymphopenia. Lymphopenia primarily affects certain T cell subsets and can reduce B cell and/or natural killer cell numbers in some patients. Other common laboratory findings include an increase in immune cells called eosinophils (eosinophilia) and a variety of immunoglobulin abnormalities. People with DOCK8 immunodeficiency syndrome frequently have poor antibody responses to vaccines. Production of the DOCK8 protein can be measured using a technique called flow cytometry testing. Loss of production of the DOCK8 protein indicates a problem with the DOCK8 gene and suggests DOCK8 immunodeficiency syndrome.

Once a diagnosis is made, treatment for DOCK8 immunodeficiency syndrome is based on a person’s clinical condition and may include medications and other strategies for managing specific infections, allergies, and asthma. Doctors may recommend the prophylactic, or preventive, use of antimicrobial drugs to prevent infections. Doctors also may consider using immunoglobulin replacement therapy if immunoglobulin levels are low. In some patients, a drug called interferon alpha has been used to control serious viral infections, such as widespread warts or herpes.

Bone marrow transplants, also called hematopoietic stem cell transplants, can cure many genetic immunodeficiency diseases. This therapy has been used to cure patients with DOCK8 immunodeficiency syndrome and resolve most of their clinical symptoms and laboratory abnormalities. Families must carefully consider the risks and benefits before pursuing bone marrow transplant or other treatment options.

DOCK8 immunodeficiency syndrome is a difficult disease to have for many reasons. It is important for families to talk openly about DOCK8 immunodeficiency syndrome and about how the family is dealing with it so misconceptions can be identified and corrected and children can learn to identify and cope with their reactions. Some children with DOCK8 immunodeficiency syndrome have to work hard to develop their self-confidence and sense of security. Everyone benefits from being reminded that they have many positive characteristics, but this is especially important when a child’s appearance attracts attention (for example, due to warts or severe eczema).

Some children who have siblings with the disease feel anxious about their brother or sister being in pain or even dying from the disease. Some think that they may develop symptoms because they look or act like a sibling who has the disease or that the disease is contagious. Some children struggle with how much time their parents spend with their sick sibling. Many families benefit from meeting or talking to other families affected by the same rare disease. The Koch family blog (www.kjkdancingthroughtherain.blogspot.com) chronicles one family’s experiences with DOCK8 immunodeficiency syndrome. Patient organizations such as the Immune Deficiency Foundation (www.primaryimmune.org) or Be The Match (www.bethematch.org), operated by the National Marrow Donor Program, are also great resources for providing useful information and support. Counseling can also help families cope with the challenges of DOCK8 immunodeficiency syndrome.

At the same time, many families say that the disease has brought them closer together. Through their experiences with the disease and its treatment, family members learn about controllable and uncontrollable aspects of life. Although certain aspects of the disease cannot be controlled, how a family responds to the stress of any illness is controllable and an important aspect of managing DOCK8 immunodeficiency syndrome. Children also learn who they can turn to for support and how to solve problems. Acknowledging both the challenges and opportunities that DOCK8 immunodeficiency syndrome presents helps children develop resilience.