| DOCK8 deficiency | |
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| Other names | Combined immunodeficiency due to dedicator of cytokinesis 8 protein deficiency, CID due to DOCK8 deficiency |
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| DOCKS deficiency is autosomal recessive | |
DOCK8 deficiency, also called DOCK8 immunodeficiency syndrome, is the autosomal recessive form of hyperimmunoglobulin E syndrome, a genetic disorder characterized by elevated immunoglobulin E levels, eosinophilia, and recurrent infections with staphylococcus and viruses. It is caused by a mutation in the DOCK8 gene.
The signs and symptoms of DOCK8 deficiency are similar to the autosomal dominant form, STAT3 deficiency. However, in DOCK8 deficiency, there is no skeletal or connective tissue involvement, and affected individuals do not have the characteristic facial features of those with autosomal dominant hyper-IgE syndrome. DOCK8 deficient children often have eczema, respiratory and skin staphylococcus infections. [1] [2]
Beyond these, many other recurrent infections have been observed, including recurrent fungal infections and recurrent viral infections (including molluscum contagiosum, herpes simplex, and herpes zoster), recurrent upper respiratory infection (including Streptococcus pneumoniae , Haemophilus influenzae , respiratory syncytial virus, and adenovirus), recurrent sinusitis, recurrent otitis media, mastoiditis, pneumonia, bronchitis with bronchiectasis, osteomyelitis, candidiasis, meningitis (caused by cryptococcus or H. influenzae), pericarditis, salmonella enteritis, and giardiasis. Other dermatologic problems include squamous-cell carcinoma/dysplasia (vulvar, anal, and facial). Immune problems are also common, including autoimmune hemolytic anemia, severe allergies (both food and environmental), asthma, and reactive airway disease. The nervous system may also be affected; observed conditions in DOCK8 deficient people include hemiplegia, ischemic stroke, subarachnoid hemorrhage, and facial paralysis. Vascular complications are common, including aortic aneurysm, cerebral aneurysm, vessel occlusion and underperfusion, and leukocytoclastic vasculitis. [1] [2] [3] [4]
DOCK8, or "dedicator of cytokinesis 8", is a protein involved in regulating the actin skeleton of the cell. It may also be a tumor suppressor, since DOCK8 is lost in many cancers and people with DOCK8 deficiency are prone to developing malignancies. When it is mutated, an incorrect protein is produced, so there is, at most, a trace level of functional DOCK8 protein in the cell. There are a variety of loss-of-function mutations in DOCK8 that can cause deficiency and hyperimmunoglobulin E, including frameshift mutations, nonsense mutations, microdeletions, and, most commonly, large deletions. [3] [4] The low number of T cells (T cell lymphopenia) and other lymphocytes appears to be responsible for the susceptibility to infections, and the poor humoral immunity is responsible for low response to vaccines. However, how DOCK8 is involved in the loss of T cells is not known. [4]
A diagnosis can only be definitively made after genetic testing to look for a mutation in the DOCK8 gene. However, it can be suspected with a high IgE level and eosinophilia. Other suggestive laboratory findings include decreased numbers of B cells, T cells, and NK cells; and hypergammaglobulinemia. [1] It can be distinguished from autosomal dominant hyper-IgE (STAT3 deficiency) because people with DOCK8 deficiency have low levels of IgM and an impaired secondary immune response. [3] IgG and IgA levels are usually normal to high. It can be distinguished from the similar X-linked Wiskott–Aldrich syndrome by the presence of thrombocytopenia and the consequent bloody diarrhea, as well as its pattern of inheritance. WHIM syndrome, caused by a mutation in CXCR4, is associated with similar chronic cutaneous viral infections. [4]
Treatment in DOCK8 deficiency focuses on preventing and treating infections. Broad-spectrum antibiotics are a common mode of treatment when infection is present, though some infections (like lung abscesses) require surgical treatment. Pneumatocele may be treated with surgery, but the benefit is unclear. [3]
Surgical treatment is also recommended for skin abscesses, along with topical and systemic antibiotics and antifungals. [3]
Long-term treatment with systemic antibiotics, including trimethoprim/sulfamethoxazole, penicillins, and cephalosporins, is effective in preventing skin and lung infections. Other treatments used in DOCK8 deficiency include sodium cromoglycate, which improves white blood cell function, and isotretinoin, which improves skin condition. [3]
Sometimes, Intravenous immunoglobulin is used as a treatment, but its benefits have not been proven. Levamisole is also ineffective. Mixed clinical outcomes have been found with interferon gamma and omalizumab. Though early research on hematopoietic stem cell transplantation was equivocal, later research has shown it to improve immune function. [3] Two patients have been cured by bone marrow transplantation. [5] Cyclosporine A is a current topic of research; preliminary results have shown it to be effective. [3]
Children with DOCK8 deficiency do not tend to live long; sepsis is a common cause of death at a young age. CNS and vascular complications are other common causes of death. [3]
DOCK8 deficiency is very rare, [1] estimated to be found in less than one person per million; [2] there have been 32 patients diagnosed as of 2012. [5]
DOCK8 deficiency was first described in 2004. [1] The mutation was discovered in 2009. [5]
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.5×109/l (500/μL). Eosinophils usually account for less than 7% of the circulating leukocytes. A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being some form of allergic reaction or parasitic infection. Diagnosis of eosinophilia is via a complete blood count (CBC), but diagnostic procedures directed at the underlying cause vary depending on the suspected condition(s). An absolute eosinophil count is not generally needed if the CBC shows marked eosinophilia. The location of the causal factor can be used to classify eosinophilia into two general types: extrinsic, in which the factor lies outside the eosinophil cell lineage; and intrinsic eosinophilia, which denotes etiologies within the eosiniphil cell line. Specific treatments are dictated by the causative condition, though in idiopathic eosinophilia, the disease may be controlled with corticosteroids. Eosinophilia is not a disorder (rather, only a sign) unless it is idiopathic.
Immunodeficiency or immunocompromise is a state in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. Most cases of immunodeficiency are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. In the clinical setting, the immunosuppression by some drugs, such as steroids, can be either an adverse effect or the intended purpose of the treatment. Examples of such use is in organ transplant surgery as an anti-rejection measure and in patients suffering from an overactive immune system, as in autoimmune diseases. Some people are born with intrinsic defects in their immune system, or primary immunodeficiency. A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone. Immunodeficiency also decreases cancer immunosurveillance, in which the immune system scans the body's cells and kills neoplastic ones.
Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.
X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.
Hypogammaglobulinemia is a problem with the immune system in which not enough gamma globulins are produced in the blood. This results in a lower antibody count, which impairs the immune system, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as common variable immunodeficiency, or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria. Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of live vaccines, and take precautionary measures when traveling to regions with endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed.
Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Generally symptoms include high susceptibility to foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract. However, symptoms vary greatly between people. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent bacterial infections, increased risk for autoimmune disease and lymphoma, as well as gastrointestinal disease. CVID is a lifelong disease.
Hyperimmunoglobulinemia E syndrome (HIES), of which the autosomal dominant form is called Job's syndrome or Buckley syndrome, is a heterogeneous group of immune disorders. Job's is also very rare at about 300 cases currently in the literature.
Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 x 109/L (i.e. 1,500/μL). This disorder is distinguished from 1) eosinophilia, which is an elevation in this count above normal levels of 0.5 x 109/L (i.e. 500/μl) but below the hypereosinophilia cutoff level and 2) the hypereosinophilic syndrome, which is a sustained elevation in this count above 1.5 x 109/L (i.e. 1,500/μl) that is also associated with evidence of eosinophil-based tissue injury. Informally, blood eosinophil levels are often regarded as mildly elevated at counts of 500–1,500/μL, moderately elevated between 1,500–5,000/μL, and severely elevated when greater than 5,000/μL. Elevations in blood eosinophil counts can be transient, sustained, recurrent, or cyclical.
Hyper IgM syndrome describes a group of primary immune deficiency disorders characterized by defective CD40 signaling; via B cells affecting class switch recombination (CSR) and somatic hypermutation. Immunoglobulin (Ig) class switch recombination deficiencies are characterized by elevated serum Immunoglobulin M (IgM) levels and a considerable deficiency in Immunoglobulins G (IgG), A (IgA) and E (IgE). As a consequence, people with HIGM have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections.
Hyper IgM Syndrome Type 2 is a rare disease. Unlike other hyper-IgM syndromes, Type 2 patients identified thus far did not present with a history of opportunistic infections. One would expect opportunistic infections in any immunodeficiency syndrome. The responsible genetic lesion is in the AICDA gene found at 12p13.
The fifth type of hyper-IgM syndrome has been characterized in three patients from France and Japan. The symptoms are similar to hyper IgM syndrome type 2, but the AICDA gene is intact.
Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency (PID), the cause of the immune deficiency must not be secondary in nature. Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 430 recognized PIDs as of 2019, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, auto-inflammatory disorders, tumors, and disorders of various organs. There are currently limited treatments available for these conditions; most are specific to a particular type of PID. Research is currently evaluating the use of stem cell transplants (HSCT) and experimental gene therapies as avenues for treatment in limited subsets of PIDs.
An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:
DOCK8, also known as Zir3, is a large protein involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins.
Hyper-IgM syndrome type 3 is a form of hyper IgM syndrome characterized by mutations of the CD40 gene. In this type, Immature B cells cannot receive signal 2 from helper T cells which is necessary to mature into mature B cells.
Immunodeficiency with hyperimmunoglobulin M is a rare disorder characterized by recurrent infections, low or absent IgG, IgE, and IgA levels, and normal or elevated levels of IgM and IgD.
Cernunnos deficiency is a form of combined immunodeficiency characterized by microcephaly, due to mutations in the NHEJ1 gene, it is inherited via autosomal recessive manner Management for this condition is antiviral prophylaxis and antibiotic treatment
PGM3 deficiency is a rare genetic disorder of the immune system associated with diminished phosphoglucomutase 3 function. PGM3 is an enzyme which in humans is encoded by gene PGM3. This disorder manifests as severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination. In 2014, Investigators Atfa Sassi at the Pasteur Institute of Tunis, Sandra Lazaroski at the University Medical Center Freiburg, and Gang Wu at the Imperial College London, identified PGM3 mutations in nine patients from four consanguineous families. In the same year, a researchers from the laboratories of Joshua Milner and Helen Su at the National Institute of Allergy and Infectious Disease at the U.S. National Institutes of Health described PGM3 deficiency in eight additional patients from two families.
Nuclear factor-kappa B Essential Modulator (NEMO) deficiency syndrome is a rare type of primary immunodeficiency disease that has a highly variable set of symptoms and prognoses. It mainly affects the skin and immune system but has the potential to affect all parts of the body, including the lungs, urinary tract and gastrointestinal tract. It is a monogenetic disease caused by mutation in the IKBKG gene. NEMO is the modulator protein in the IKK inhibitor complex that, when activated, phosphorylates the inhibitor of the NF-κB transcription factors allowing for the translocation of transcription factors into the nucleus.
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