MedGen

X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifest as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, and more liberal use of antibiotics. [from GeneReviews]

The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities. [from GeneReviews]

X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with failure to thrive. Neutropenia is common; thrombocytopenia and anemia are less commonly seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of affected males. Liver disease, a serious complication of HIGM1 once observed in more than 80% of affected males by age 20 years, may be decreasing with adequate screening and treatment of Cryptosporidium infection. [from GeneReviews]

G6PC3 deficiency is characterized by severe congenital neutropenia which occurs in a phenotypic continuum that includes the following: Isolated severe congenital neutropenia (nonsyndromic). Classic G6PC3 deficiency (severe congenital neutropenia plus cardiovascular and/or urogenital abnormalities). Severe G6PC3 deficiency (classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines, additional extra-hematologic features, and pulmonary hypertension; known as Dursun syndrome). Neutropenia usually presents with recurrent bacterial infections in the first few months of life. Intrauterine growth restriction (IUGR), failure to thrive (FTT), and poor postnatal growth are common. Other findings in classic and severe G6PC3 deficiency can include inflammatory bowel disease (IBD) resembling Crohn's disease, and endocrine disorders (growth hormone deficiency, hypogonadotropic hypogonadism, and delayed puberty). [from GeneReviews]

Severe combined immunodeficiency (SCID) due to DCLRE1C deficiency is a type of SCID (see this term) characterized by severe and recurrent infections, diarrhea, failure to thrive, and cell sensitivity to ionizing radiation. [from ORDO]

Netherton syndrome (NETH) is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by Bitoun et al., 2002). [from OMIM]

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). [from OMIM]

Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (116920)-like immune deficiency and Glanzmann thrombasthenia (GT; 273800)-like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with beta-integrins in hematopoietic cells. In LAD3, the adhesive functions of integrins on both leukocytes and platelets are disrupted, most likely due to defects in activation-dependent alterations of surface integrins that enable high-avidity binding to ligands on target cells, a process termed 'inside-out signaling' (Svensson et al., 2009; Zimmerman, 2009). For a discussion of genetic heterogeneity of leukocyte adhesion deficiency, see 116920. [from OMIM]

Immunodeficiency-10 (IMD10) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta (summary by Parry et al., 2016). [from OMIM]

Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 14 (CG14, equivalent to CGJ) have mutations in the PEX19 gene. For information on the history of PBD complementation groups, see 214100. [from OMIM]

Reticular dysgenesis, the most severe form of inborn severe combined immunodeficiency (SCID), is characterized by absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immune functions, leading to fatal septicemia within days after birth (summary by Pannicke et al., 2009). [from OMIM]

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]

The Currarino syndrome is an autosomal dominant form of hereditary sacral dysgenesis that classically consists of the triad of sacral malformation, presacral mass, and anorectal malformations. However, other features include neonatal-onset bowel obstruction, chronic constipation, recurrent perianal sepsis, renal/urinary tract anomalies, female internal genital anomalies, tethered spinal cord, and anterior meningocele. There is marked inter- and intrafamilial variability, and up to 33% of patients are asymptomatic (summary by Wang et al., 2006). [from OMIM]

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). [from OMIM]

Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL) is an autosomal dominant complex immune disorder with highly variable presentation and clinical manifestations. Prominent features include recurrent infections often associated with hypogammaglobulinemia, autoimmune features such as autoimmune cytopenias, and abnormal lymphocytic infiltration of nonlymphoid organs, including the lungs, brain, and gastrointestinal tract, resulting in enteropathy. Laboratory studies often show lymphopenia and abnormal T and B cell subsets. The variable features are a result of impaired function of Treg cells, which play a role in immune homeostasis (summary by Kuehn et al., 2014; Schwab et al., 2018, and Lopez-Nevado et al., 2021). The disorder shows overlapping features with autoimmune lymphoproliferative syndrome (ALPS); for a general description and a discussion of genetic heterogeneity of ALPS, see 601859. [from OMIM]

MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported. [from GeneReviews]

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). [from OMIM]

Heme oxygenase-1 deficiency (HMOX1D) is a rare autosomal recessive disorder with a complex clinical presentation including direct antibody negative hemolytic anemia, low bilirubin, and hyperinflammation (summary by Chau et al., 2020). Other features may include asplenia and nephritis (Radhakrishnan et al., 2011). [from OMIM]

Immunodeficiency-73B with defective neutrophil chemotaxis (IMD73B) is an autosomal dominant immunologic disorder characterized by onset of recurrent infections in infancy or early childhood. Affected individuals develop respiratory infections, cellulitis, and severe invasive infections or sepsis; organisms include bacteria such as Staphylococcus, as well as viruses, fungi, and mycobacterial species. Laboratory studies show variable abnormalities, including B- and T-cell lymphopenia, decreased immunoglobulin subsets, decreased TRECs and dysfunctional T cells, decreased NK cells, neutropenia, and impaired neutrophil chemotaxis. Hematopoietic stem cell transplantation is curative (summary by Hsu et al., 2019; review by Lougaris et al., 2020). In a review of autosomal forms of chronic granulomatous disease (see 306400 for genetic heterogeneity of CGD), Roos et al. (2021) noted that patients with RAC2 mutations may manifest CGD-like symptoms due to defects in neutrophil NADPH oxidase activity. [from OMIM]

Immunodeficiency-68 (IMD68) is an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, although other organisms may be observed. IMD68 is life-threatening in infancy and early childhood. The first invasive infection typically occurs before 2 years of age, with meningitis and upper respiratory infections being common manifestations. The mortality rate in early childhood is high, with most deaths occurring before 8 years of age. Affected individuals have an impaired inflammatory response to infection, including lack of fever and neutropenia, although erythrocyte sedimentation rate (ESR) and C-reactive protein may be elevated. General immunologic workup tends to be normal, with normal levels of B cells, T cells, and NK cells. However, more detailed studies indicate impaired cytokine response to lipopolysaccharide (LPS) and IL1B (147720) stimulation; response to TNFA (191160) is usually normal. Patients have good antibody responses to most vaccinations. Viral, fungal, and parasitic infections are generally not observed. Early detection is critical in early childhood because prophylactic treatment with IVIg or certain antibiotics is effective; the disorder tends to improve naturally around adolescence. At the molecular level, IMD68 results from impaired function of selective Toll receptor (see TLR4, 603030)/IL1R (see IL1R1; 147810) signaling pathways that ultimately activate NFKB (164011) to produce cytokines (summary by Picard et al., 2010). See also IMD67 (607676), caused by mutation in the IRAK4 gene (602170), which shows a similar phenotype to IMD68. As the MYD88 and IRAK4 genes interact in the same intracellular signaling pathway, the clinical and cellular features are almost indistinguishable (summary by Picard et al., 2010). [from OMIM]