MedGen

Common variable immunodeficiency (CVID) is a clinically and genetically heterogeneous group of disorders characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections, and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B cells are usually in the normal range, but can be low. Most individuals with CVID have onset of infections after age 10 years. CVID represents the most common form of primary immunodeficiency disorders and is the most common form of primary antibody deficiency. Approximately 10 to 20% of patients with a diagnosis of CVID have a family history of the disorder (reviews by Chapel et al., 2008, Conley et al., 2009, and Yong et al., 2009). Genetic Heterogeneity of Common Variable Immunodeficiency Common variable immunodeficiency is a genetically heterogeneous disorder. See also CVID2 (240500), caused by mutation in the TACI gene (TNFRSF13B; 604907); CVID3 (613493), caused by mutation in the CD19 gene (107265); CVID4 (613494), caused by mutation in the BAFFR gene (TNFRSF13C; 606269); CVID5 (613495), caused by mutation in the CD20 gene (112210); CVID6 (613496), caused by mutation in the CD81 gene (186845); CVID7 (614699), caused by mutation in the CD21 gene (CR2; 120650); CVID8 (614700), caused by mutation in the LRBA gene (606453); CVID10 (615577), caused by mutation in the NFKB2 gene (164012); CVID11 (615767), caused by mutation in the IL21 gene (605384); CVID12 (616576), caused by mutation in the NFKB1 gene (164011); CVID13 (616873), caused by mutation in the IKZF1 gene (603023); CVID14 (617765), caused by mutation in the IRF2BP2 gene (615332); and CVID15 (620670), caused by heterozygous mutation in the SEC61A1 gene (609213). The disorder formerly designated CVID9 has been found to be a form of autoimmune lymphoproliferative disorder; see ALPS3 (615559). [from OMIM]

Activated PI3K-delta syndrome (also known as APDS) is a disorder that impairs the immune system. Individuals with this condition often have low numbers of white blood cells (lymphopenia), particularly B cells and T cells. Normally, these cells recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The severity of activated PI3K-delta syndrome varies widely. Some people may have multiple, severe infections while others show mild symptoms to none at all.

Most commonly, people with activated PI3K-delta syndrome develop recurrent infections that begin in childhood, particularly in the lungs, sinuses, and ears. Over time, recurrent respiratory tract infections can lead to a condition called bronchiectasis, which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. People with activated PI3K-delta syndrome may also have chronic active viral infections, such as Epstein-Barr virus, herpes simplex virus, or cytomegalovirus infections.

Another possible feature of activated PI3K-delta syndrome is abnormal clumping of white blood cells. These clumps can lead to enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly). The white blood cells can also build up to form solid masses (nodular lymphoid hyperplasia), usually in the moist lining of the airways or intestines. While nodular lymphoid hyperplasia is not cancerous (benign), activated PI3K-delta syndrome increases the risk of developing forms of blood cancer called Hodgkin lymphoma and non-Hodgkin lymphoma.

There are two types of activated PI3K-delta syndrome, each with different genetic causes.

Some people with activated PI3K-delta syndrome develop autoimmunity, which occurs when the body attacks its own tissues and organs by mistake. [from MedlinePlus Genetics]

Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive disorder of immune dysregulation. Affected individuals have early childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease. The presentation and phenotype are highly variable, even within families (summary by Lopez-Herrera et al., 2012 and Alangari et al., 2012). Immunologic findings are also variable and may include decreased B cells, hypogammaglobulinemia, and deficiency of CD4+ T regulatory (Treg) cells (Charbonnier et al., 2015). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594). [from OMIM]

Autoinflammation, antibody deficiency, and immune dysregulation (APLAID) is an autosomal dominant systemic disorder characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, the eye, and the gastrointestinal tract. Affected individuals have a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies (summary by Zhou et al., 2012). [from OMIM]

A rare autosomal recessive primary immunodeficiency characterized by infancy onset of severe inflammatory bowel disease with life-threatening diarrhea and failure to thrive, oral aphthous ulcers, and recurrent severe upper and lower respiratory tract infections with finger clubbing. Laboratory examination reveals increased IgE and decreased IgG levels, as well as reduced numbers of circulating CD19+ B-cells including IgM+ naive and class-switched IgG memory B-cells, with a concomitant increase in transitional B-cells, while T-cell numbers and function are normal. [from SNOMEDCT_US]

Autoimmune lymphoproliferative syndrome type III is an autosomal recessive disorder of immune dysregulation. The phenotype is variable, but most patients have significant lymphadenopathy associated with variable autoimmune manifestations. Some patients may have recurrent infections. Lymphocyte accumulation results from a combination of impaired apoptosis and excessive proliferation (summary by Oliveira, 2013). For a general description and a discussion of genetic heterogeneity of ALPS, see 601859. [from OMIM]

Immunodeficiency-75 with lymphoproliferation (IMD75) is an autosomal recessive immunologic disorder characterized by immunodeficiency, immune dysregulation, and the development of lymphoproliferative disorders, including lymphoma. Affected individuals usually present in infancy with severe and recurrent infections, mainly viral and affecting the respiratory tract. Some patients may have autoimmune cytopenias, anemia, or thrombocytopenia. Patients also develop hepatosplenomegaly, lymphadenopathy, lymphoproliferative disorders, and various types of T- or B-cell lymphomas. Immunologic work-up shows decreased class-switched B cells, impaired B-cell terminal differentiation, and hypo- or hypergammaglobulinemia. There is skewed differentiation and dysregulation of T cells, as well as possibly disrupted hematopoiesis. Additional features include failure to thrive and global developmental delay. The phenotype may be reminiscent of ALPS (601859), including laboratory evidence of impaired Fas-dependent T-cell apoptosis. Although hematopoietic stem cell transplantation may be effective treatment, many patients die in childhood (summary by Stremenova Spegarova et al., 2020). [from OMIM]

Immunodeficiency-59 and hypoglycemia (IMD59) is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocytopenia and B-cell and dendritic cell deficiency are present (Haapaniemi et al., 2017). [from OMIM]

Immunodeficiency-81 (IMD81) is an autosomal recessive complex immunologic disorder with onset of symptoms in infancy. The phenotype is highly variable and may include both immunodeficiency with recurrent infections, including bacterial and fungal infections, as well as autoimmune features, including autoimmune hemolytic anemia, pancytopenia, thrombocytopenia, and inflammatory bowel disease. Immunologic workup shows immune dysregulation with abnormalities affecting multiple immune cell lineages, including T cells, B cells, NK cells, and neutrophils, which may be decreased or increased and demonstrate functional deficits. There is a wide range of hematologic abnormalities. Affected individuals may be susceptible to severe EBV infection. The disorder is caused by a defect in intracellular immune signaling pathways (summary by Lev et al., 2021; Edwards et al., 2023). [from OMIM]

Familial autoinflammatory syndrome with or without immunodeficiency (AISIMD) is characterized by onset of various autoimmune features usually in the first decades of life, although later onset has been reported. Typical features include autoimmune cytopenia, hemolytic anemia, thrombocytopenia, and lymphadenopathy. More variable features may include autoimmune thyroiditis, psoriasis or eczema, nephritis, hepatitis, and symptoms of systemic lupus erythematosus (SLE; see 152700). Some patients may have recurrent infections or exacerbation of the disease with acute infection. Laboratory studies show variable findings, often decreased numbers of naive B cells, lymphopenia with skewed subsets, hypogammaglobulinemia, presence of autoantibodies, and a hyperinflammatory state. The disorder shows autosomal dominant inheritance with incomplete penetrance (summary by Hadjadj et al., 2020). [from OMIM]

Hyper-IgE syndrome-5 with recurrent infections (HEIS5) is an autosomal recessive immunologic disorder characterized by onset of recurrent sinopulmonary and deep skin infections in early childhood. The infections are mostly caused by bacteria, including H. influenza and Staphylococcus aureus. Additional features include atopic dermatitis, impaired inflammatory responses during infection, increased serum IgE, and increased IL6 (147620) (summary by Spencer et al., 2019). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060). [from OMIM]

Immunodeficiency-93 and hypertrophic cardiomyopathy (IMD93) is an autosomal recessive disorder characterized by onset of recurrent viral and bacterial infections, particularly with encapsulated bacteria, and hypertrophic cardiomyopathy in the first months or years of life. Immunologic workup typically shows decreased circulating B cells and hypo- or agammaglobulinemia, sometimes with neutropenia or T-cell lymphocytosis, although laboratory findings may be variable among patients. Ig replacement therapy is beneficial. Cardiac involvement can also include atrial septal defect, valvular insufficiency, and pre-excitation syndrome. Rare myopathic or neurologic involvement has been reported, but these features are not consistently part of the disorder and may be related to other genetic defects (summary by Niehues et al., 2020 and Saettini et al., 2021). [from OMIM]

Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets. Hematopoietic stem cell transplantation may be curative (summary by Beaussant-Cohen et al., 2019 and Levy et al., 2021). [from OMIM]

Immunodeficiency-112 (IMD112) is an autosomal recessive primary immunologic disorder with variable manifestations beginning in early childhood. Some patients have recurrent bacterial, viral, and fungal infections, including disseminated bacillus Calmette-Guerin (BCG)-related infections, whereas at least 1 patient only presented with BCG-related infections. Immunologic workup shows variable abnormalities affecting lymphoid immunity, including hypogammaglobulinemia, lymphopenia or paradoxical lymphocytosis, and defects in B, T, and NK cell differentiation and function mainly due to disruption of the noncanonical NFKB (see 164011) signaling pathway (Willmann et al., 2014; Schlechter et al., 2017). [from OMIM]

Immunodeficiency-99 with hypogammaglobulinemia and autoimmune cytopenias (IMD99) is an autosomal recessive immunologic disorder characterized by the onset of recurrent sinopulmonary infections in early childhood. Laboratory studies reveal hypogammaglobulinemia with decreased memory B cells that show impaired class-switch recombination (CSR) and decreased somatic hypermutation (SHM). Due to abnormal antibody production and impaired self-tolerance, patients may develop autoimmune cytopenias, such as thrombocytopenia, or autoimmune features, such as vitiligo. There are also defects in the T-cell compartment (Kuhny et al., 2020). [from OMIM]

A reduction in the normal proportion of class-switched memory B cells (CD19+/CD27+/IgM+/IgD+) relative to the total number of B cells. Marginal zone B cells undergo limited somatic hypermutation and produce high-affinity IgM and some IgG, whereas class-switched memory B cells synthetize IgG, IgM, and IgA. [from HPO]