T-cell immunodeficiency with thymic aplasia (TIDTA) is an autosomal recessive disorder that is often detected at birth through newborn SCID screening with the finding of decreased T-cell receptor excision circles (TRECs). Affected individuals have selective hypo- or aplasia of the thymus, which results in T-cell immunodeficiency due to impaired T-cell development and increased susceptibility to viral infections. The phenotype is similar to T-/B+/NK+ SCID. Some patients may die in childhood; thymus transplantation may be curative (summary by Du et al., 2019).

Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment (review by Aust et al., 1992).

Mulvihill-Smith syndrome is characterized by premature aging, multiple pigmented nevi, lack of facial subcutaneous fat, microcephaly, short stature, sensorineural hearing loss, and mental retardation. Immunodeficiency may also be a feature. Adult manifestations include the development of tumors, a sleep disorder with severe insomnia, and cognitive decline (summary by Yagihashi et al., 2009).

Immunodeficiency-116 (IMD116) is an autosomal recessive immunologic disorder characterized by the onset of recurrent upper and lower respiratory tract infections in infancy or early childhood. Laboratory studies show absence of CD8+ T cells, whereas other lymphocyte numbers and immunoglobulin levels are normal (Dumontet et al., 2015).

Immunodeficiency-41 is an autosomal recessive complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (summary by Goudy et al., 2013).

With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of EPG5-related disorder represents a continuum. At the most severe end of the spectrum is classic Vici syndrome (defined as a neurodevelopmental disorder with multisystem involvement characterized by the combination of agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive); at the milder end of the spectrum are attenuated neurodevelopmental phenotypes with variable multisystem involvement. Median survival in classic Vici syndrome appears to be 24 months, with only 10% of children surviving longer than age five years; the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure. No data are available on life span in individuals at the milder end of the spectrum.

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes: Severe combined immunodeficiency disease (SCID), often diagnosed by age six months and usually by age 12 months; Less severe "delayed" onset combined immune deficiency (CID), usually diagnosed between age one and ten years; "Late/adult onset" CID, diagnosed in the second to fourth decades; Benign "partial ADA deficiency" (very low or absent ADA activity in erythrocytes but greater ADA activity in nucleated cells), which is compatible with normal immune function. Infants with typical early-onset ADA-deficient SCID have failure to thrive and opportunistic infections associated with marked depletion of T, B, and NK lymphocytes, and an absence of both humoral and cellular immune function. If immune function is not restored, children with ADA-deficient SCID rarely survive beyond age one to two years. Infections in delayed- and late-onset types (commonly, recurrent otitis, sinusitis, and upper respiratory) may initially be less severe than those in individuals with ADA-deficient SCID; however, by the time of diagnosis these individuals often have chronic pulmonary insufficiency and may have autoimmune phenomena (cytopenias, anti-thyroid antibodies), allergies, and elevated serum concentration of IgE. The longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent infection.

Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012).

Immunodeficiency-35 (IMD35) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to localized or disseminated mycobacterial infection after BCG vaccination. Some patients may have increased susceptibility to infection with other intracellular organisms and/or viral infections. Fungal infections are not observed. Laboratory studies show normal levels of immune cells but defective signaling in specific immunologic pathways (summary by Kreins et al., 2015).

Omenn syndrome is an autosomal recessive disorder characterized by severe combined immunodeficiency (SCID) associated with erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire (summary by Ege et al., 2005). Another distinct form of familial histiocytic reticulocytosis (267700) is caused by mutation in the perforin-1 gene (PRF1; 170280) on chromosome 10q22.

Chronic mucocutaneous candidiasis (CMC) includes a group of rare disorders with altered immune responses, selective against Candida, characterized by persistent and/or recurrent infections of the skin, nails, and mucous membranes, caused by organisms of the genus Candida, mainly Candida albicans (Zuccarello et al., 2002). Isolated familial chronic mucocutaneous candidiasis is distinct from candidiasis with endocrinopathy (240300). In myeloperoxidase deficiency (254600), susceptibility to candidiasis may be increased. Genetic Heterogeneity of Candidiasis Familial candidiasis-1 (CANDF1) maps to chromosome 2p. CANDF2 (212050) is caused by mutation in the CARD9 gene (607212) on chromosome 9q34.3. CANDF3 (607644), a form restricted to nails of the hands and feet, maps to chromosome 11. CANDF4 (613108) is caused by mutation in the CLEC7A gene (606264) on chromosome 12p13. CANDF6 (613956) is caused by mutation in the IL17F gene (606496) on chromosome 6p12. CANDF7 (614162) is caused by mutation in the STAT1 gene (600555) on chromosome 2q32. CANDF8 (615527) is caused by mutation in the TRAF3IP2 gene (607043) on chromosome 6q21. CANDF9 (616445) is caused by mutation in the IL17RC gene (610925) on chromosome 3p25. A form of familial candidiasis, previously thought to be isolated and designated CANDF5, has been found to be part of a primary immune deficiency (IMD51; 613953) that includes Staphylococcal skin infections and increased susceptibility to chronic bacterial respiratory infections.

A rare autosomal recessive primary immunodeficiency characterized by absence of HLA class II molecules on the surface of immune cells, leading to severely impaired cellular and humoral immune response to foreign antigens, severe CD4+ T-cell lymphopenia, and hypogammaglobulinemia. The disease clinically manifests with early onset of severe and recurrent infections mainly of the respiratory and gastrointestinal tract, protracted diarrhea with failure to thrive, and autoimmune disease, and is frequently fatal in childhood.

Immunodeficiency-31B (IMD31B) results from autosomal recessive (AR) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (147660)/IFNB (147640) (type I interferon) and IFNG (147570) (type III interferon). AR STAT1 deficiency affects both the IFNA/IFNB and the IFNG pathways, resulting in susceptibility to mycobacteria, Salmonella, and viruses, with a severe disease course and often fatal outcome (review by Al-Muhsen and Casanova, 2008).

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).

This primary immunodeficiency, designated IMD21, DCML, or MONOMAC, is characterized by profoundly decreased or absent monocytes, B lymphocytes, natural killer (NK) lymphocytes, and circulating and tissue dendritic cells (DCs), with little or no effect on T-cell numbers. Clinical features of IMD21 are variable and include susceptibility to disseminated nontuberculous mycobacterial infections, papillomavirus infections, opportunistic fungal infections, and pulmonary alveolar proteinosis. Bone marrow hypocellularity and dysplasia of myeloid, erythroid, and megakaryocytic lineages are present in most patients, as are karyotypic abnormalities, including monosomy 7 and trisomy 8. In the absence of cytogenetic abnormalities or overt dysplasia, hypoplastic bone marrow may initially be diagnosed as aplastic anemia. Bone marrow transplantation is the only cure. Some patients may have an increased risk of miscarriage. Both autosomal dominant transmission and sporadic cases occur. Less common manifestations of GATA2 deficiency include lymphedema and sensorineural hearing loss, a phenotype usually termed 'Emberger syndrome' (614038) (summary by Bigley et al. (2011), Hsu et al. (2011), and Spinner et al. (2014)).

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).

Combined immunodeficiency due to MALT1 deficiency is a rare, genetic form of primary immunodeficiency characterized by growth retardation, early recurrent pulmonary infections leading to bronchiectasis, inflammatory gastrointestinal disease, and other symptoms, such as rash, dermatitis, skin infections.

Immunodeficiency-31A (IMD31A) results from autosomal dominant (AD) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (147660)/IFNB (147640) (type I interferon) and IFNG (147570) (type III interferon). AD STAT1 deficiency selectively affects the IFNG pathway, but not the IFNA/IFNB pathway, and confers a predisposition to mycobacterial infections. Pathogens reported in IMD31A patients include bacillus Calmette-Guerin (BCG) and Mycobacterium avium complex, as well as Mycobacterium tuberculosis. IMD31A has low penetrance and a mild clinical phenotype with good prognosis for recovery (review by Al-Muhsen and Casanova, 2008). Two patients with heterozygous STAT1 mutations have been reported with increased susceptibility to adult-onset herpes simplex encephalitis (HSE) without a history of other significant infections (Mork et al., 2015).

IMD24 is an autosomal recessive immunodeficiency characterized by the impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. Patients have early onset of severe chronic viral infections, mostly caused by herpesviruses, including Epstein-Barr virus (EBV) and varicella zoster virus (VZV); they also suffer from recurrent encapsulated bacterial infections, a spectrum typical of a combined deficiency of adaptive immunity (CID) (summary by Martin et al., 2014).

IMD38 predisposes individuals to severe clinical disease upon infection with weakly virulent mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines (Bogunovic et al., 2012). Patients do not experience severe disease in response to viral infection. Affected individuals have intracranial calcification (Zhang et al., 2015).

Common variable immunodeficiency-13 (CVID13) is an autosomal dominant primary immunodeficiency disorder characterized by recurrent bacterial infections, mainly affecting the respiratory tract, and associated with hypogammaglobulinemia and decreased numbers of B cells. The age at onset of clinical features can range from infancy to adulthood, and some patients may have a mild disorder or even remain clinically asymptomatic (summary by Kuehn et al., 2016). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

BDPLT21 is a hematologic disorder characterized by increased risk of bleeding resulting from a functional platelet defect. Platelets have decreased or even absent dense bodies and abnormally enlarged and fused alpha-granules, and they show defective secretion and aggregation responses to agonists. Platelets are usually enlarged, and some patients may have mild to moderate thrombocytopenia (summary by Saultier et al., 2017).

Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060. See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006).

Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is an autosomal dominant disorder with onset in early infancy. Affected individuals develop severe inflammatory neutrophilic dermatitis, autoimmunity, and variable immunodeficiency (summary by Poli et al., 2018). For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040).

Immunodeficiency-65 (IMD65) is an autosomal recessive immunologic disorder characterized by onset of recurrent and severe viral infections from early infancy. Affected individuals have impaired ability to fight viral infections, resulting in clinically significant disease, including pneumonia, bronchiectasis, and septic shock. Laboratory studies may show lymphopenia or hypogammaglobulinemia, particularly during infection; more detailed studies show an impaired cellular type I interferon response. Treatment with intravenous immunoglobulin (IVIg) is beneficial. Important features of this disorder include the rapid development of septic shock, as well as poor outcomes after vaccination with live attenuated vaccines; such vaccines should never be administered to patients with known impaired interferon responses (summary by Hernandez et al., 2018 and Bravo Garcia-Morato et al., 2019).

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (NEDHRIT) is a severe autosomal recessive disorder characterized by neonatal respiratory distress, poor feeding, and impaired global development. Affected individuals are unable to walk or speak and have poor or absent eye contact. Some patients may develop seizures (summary by Wagner et al., 2020).

Autoinflammation, immune dysregulation, and eosinophilia (AIIDE) is an autosomal dominant disorder characterized by onset of severe atopic dermatitis and chronic gastrointestinal inflammation, mainly involving the colon, in infancy or early childhood. Affected individuals tend to have asthma and food or environmental allergies, as well as poor overall growth with short stature. Severe liver involvement has also been reported (Takeichi et al., 2021). Laboratory studies show increased eosinophils with normal or increased IgE levels, as well as evidence of a hyperactive immune state, including increased erythrocyte sedimentation rate and C-reactive protein. Treatment with JAK inhibitors, such as ruxolitinib and tofacitinib, results in dramatic clinical improvement (summary by Gruber et al., 2020).

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-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).