XMEN is an X-linked recessive immunodeficiency characterized by CD4 (186940) lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation (Li et al., 2011). Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders. Magnesium supplementation may be therapeutic (summary by Li et al., 2014).

Lymphoproliferative syndrome-1 is an autosomal recessive primary immunodeficiency characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinemia. Autoimmune disorders, such as autoimmune hemolytic anemia or renal disease, may also occur. Patients show a high EBV viral load and decreased invariant natural killer T cells. It is unknown whether patients with ITK mutations are intrinsically susceptible to development of lymphoma or dysgammaglobulinemia in the absence of EBV infection (summary by Stepensky et al., 2011; Linka et al., 2012). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).

Immunodeficiency-110 (IMD110) is an autosomal recessive primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, and autoimmune manifestations. Patients are at risk for developing lymphoproliferative disorders or lymphoma, particularly associated with EBV. Some patients may show cardiac malformations, including atrial septal defect (Abdollahpour et al., 2012; Nehme et al., 2012).

Lymphoproliferative syndrome-2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (summary by van Montfrans et al., 2012). The phenotype can vary significantly, from asymptomatic borderline-low hypogammaglobulinemia, to a full-blown symptomatic systemic inflammatory response with life-threatening EBV-related complications, including hemophagocytic lymphohistiocytosis, a lymphoproliferative disorder, and malignant lymphoma requiring stem cell transplantation (summary by Salzer et al., 2013). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).

Immunodeficiency-7 (IMD7) is an autosomal recessive immunologic disorder characterized by onset of recurrent bacterial and viral infections in infancy or early childhood. Affected individuals may also have features of immune dysregulation, including lymphadenopathy and presence of autoantibodies. Laboratory studies show increased serum IgE, low numbers of T cells, low TCR-alpha/beta cells, and increased TCR-gamma/delta cells. The disorder often results in death in childhood, although bone marrow transplant is effective (summary by Morgan et al., 2011 and Rawat et al., 2021).

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.

IMD23 is an autosomal recessive primary immunodeficiency syndrome characterized by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity (summary by Bjorksten and Lundmark, 1976 and Zhang et al., 2014).

Immunodeficiency-36 with lymphoproliferation (IMD36) is an autosomal dominant primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (Elkaim et al., 2016).

IMD52 is an autosomal recessive primary immunodeficiency with variable manifestations, including severe combined immunodeficiency, hematologic autoimmune disorders, progressive lymphopenia and hypogammaglobulinemia, and lymphoproliferation with splenomegaly. Patients develop severe recurrent infections from infancy, and most die without bone marrow transplantation. The variable clinical features result from a defect in T-cell receptor signaling (summary by Keller et al., 2016 and Bacchelli et al., 2017).

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).

Immunodeficiency-84 (IMD84) is an autosomal dominant primary immunologic disorder characterized by recurrent sinopulmonary infections from childhood associated with low levels of B cells and impaired early B-cell development. There may also be variable T-cell abnormalities. Patients with IMD84 have increased susceptibility to infection with Epstein-Barr virus (EBV) and may develop lymphoma in adulthood (summary by Yamashita et al., 2021).

Immunodeficiency-85 and autoimmunity (IMD85) is an autosomal dominant immunologic disorder characterized by onset of atopic eczema and recurrent respiratory infections in the first decade of life. Affected individuals also develop autoimmune enteropathy with vomiting, diarrhea, and poor overall growth. More variable features may include autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Laboratory studies show hypogammaglobulinemia and abnormal T-cell function, consistent with a combined immunodeficiency (Keskitalo et al., 2019).

Immunodeficiency-87 and autoimmunity (IMD87) is an autosomal recessive immunologic disorder with wide phenotypic variation and severity. Affected individuals usually present in infancy or early childhood with increased susceptibility to infections, often Epstein-Barr virus (EBV), as well as with lymphadenopathy or autoimmune manifestations, predominantly hemolytic anemia. Laboratory studies may show low or normal lymphocyte numbers, often with skewed T-cell subset ratios. The disorder results primarily from defects in T-cell function, which causes both immunodeficiency and overall immune dysregulation (summary by Serwas et al., 2019 and Fournier et al., 2021).

Immunodeficiency-109 with EBV-induced lymphoproliferation (IMD109) is an autosomal recessive primary immune disorder characterized by onset of recurrent sinopulmonary infections in childhood. Affected individuals are susceptible to infection with EBV and develop EBV viremia and EBV-associated lymphoproliferative disease or B-cell lymphoma. Immunologic workup shows normal levels of T, B, and NK cells, with defective CD8+ T cell function after stimulation. Some patients may have hypogammaglobulinemia and poor antibody response to stimulation (Alosaimi et al., 2019).