Severe combined immunodeficiency refers to a genetically and clinically heterogeneous group of disorders with defective cellular and humoral immune function. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms, including Candida albicans, Pneumocystis carinii, ... Severe combined immunodeficiency refers to a genetically and clinically heterogeneous group of disorders with defective cellular and humoral immune function. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms, including Candida albicans, Pneumocystis carinii, and cytomegalovirus, among many others. Laboratory analysis shows profound lymphopenia with diminished or absent immunoglobulins. The common characteristic of all types of SCID is absence of T cell-mediated cellular immunity due to a defect in T-cell development. Without treatment, patients usually die within the first year of life. The overall prevalence of all types of SCID is approximately 1 in 75,000 births (Fischer et al., 1997; Buckley, 2004). SCID can be divided into 2 main classes: those with B lymphocytes (B+ SCID) and those without (B- SCID). Presence or absence of NK cells is variable within these groups. The most common form of SCID is X-linked T-, B+, NK- SCID (300400) caused by mutation in the IL2RG gene (308380) on chromosome Xq13.1. Autosomal recessive SCID includes T-, B+, NK- SCID (600802) caused by mutation in the JAK3 gene (600173) on 19p13.1; T-, B+, NK+ SCID (608971) caused by mutation in the IL7R gene (146661) on 5p13, the CD45 gene (151460) on 1q31-q32, or the CD3D gene (186790) on 11q23; T-, B-, NK- SCID (102700) caused by mutation in the ADA (608958) gene on 20q13.11; T-, B-, NK+ SCID with sensitivity to ionizing radiation caused by mutation in the Artemis gene on 10p; and T-, B-, NK+ SCID caused by mutation in the RAG1 and RAG2 genes on 11p13 (Kalman et al., 2004). Approximately 20 to 30% of all SCID patients are T-, B-, NK+, and approximately half of these patients have mutations in the RAG1 or RAG2 genes (Schwarz et al., 1996; Fischer et al., 1997).
Glanzmann and Riniker (1950) reported 2 pairs of sibs who had severe infections, candidiasis, agammaglobulinemia, and lymphopenia. Hitzig and Willi (1961), Hitzig (1968), and Hitzig et al. (1968) reported ... - Early Descriptions of Autosomal Recessive SCID Glanzmann and Riniker (1950) reported 2 pairs of sibs who had severe infections, candidiasis, agammaglobulinemia, and lymphopenia. Hitzig and Willi (1961), Hitzig (1968), and Hitzig et al. (1968) reported a form of congenital immunodeficiency with agammaglobulinemia and absence or decreased numbers of lymphocytes. At that time, the disorder was termed 'Swiss-type agammaglobulinemia' to distinguish it from the less severe Bruton agammaglobulinemia (300755) in which T lymphocytes are unaffected. Nezelof (1992) noted that 'Swiss-type agammaglobulinemia' is a historic term referring to severe combined immunodeficiency as a disorder with both agammaglobulinemia and T-cell lymphopenia, and does not represent a single disease entity. Tobler and Cottier (1958) reported families with agammaglobulinemia and lymphopenia showing autosomal recessive inheritance. Affected patients had a small thymus with depletion of lymphoid cells, suggesting a failure or arrest in embryologic development of the gland. The findings were consistent with 'thymic dysplasia' (Nezelof, 1992). Good (1963) referred to the recessive form of agammaglobulinemia as the Swiss type. In contrast to X-linked Bruton agammaglobulinemia, patients were unusually susceptible to fungal and viral as well as pyogenic pathogens, lacked delayed hypersensitivity, and showed failure of antibody production. Furthermore, the thymus, which was usually normal in Bruton agammaglobulinemia, was very small with absence of lymphoid cells and Hassall corpuscles. Haworth et al. (1967) reported that 'thymic alymphoplasia,' now known as thymic dysplasia (Nezelof, 1992), was frequent among Mennonites living in southern Manitoba. Lipsey et al. (1967) reported 3 families in which multiple sibs had congenital hypogammaglobulinemia that defied classification. The 3 probands died of pneumonia in the first 3 years of life. - Descriptions of T-, B-, NK+ SCID Stephan et al. (1993) reported 36 patients with T-, B- SCID among 117 patients with SCID. The average age at first hospitalization was 93 days, and at diagnosis, 141 days. All patients showed growth impairment by 3 months of age. The most common presentations were persistent diarrhea, candidiasis, lung infections, fever, and opportunistic infections. The most common organisms were Candida albicans, Pseudomonas, gram-negative species, Pneumocystis, Streptococcus, and Staphylococcus. Profound lymphopenia (less than 1,000 cells/microliter) occurred in 16 of the 36 patients. The disorder was fatal in infancy in all patients who did not undergo hematopoietic stem cell transplantation. Corneo et al. (2001) reported 3 unrelated patients with T-, B- SCID. One of the patients had a sib with Omenn syndrome (de Saint-Basile et al., 1991), and another patient was from a consanguineous family.
In 6 of 14 T-, B-, NK+ SCID patients, Schwarz et al. (1996) identified homozygous or compound heterozygous mutations in the RAG1 (179615.0001-179615.0004) and RAG2 (179616.0001; 179616.0002) genes. Several of the SCID patients had unaffected sibs who were ... In 6 of 14 T-, B-, NK+ SCID patients, Schwarz et al. (1996) identified homozygous or compound heterozygous mutations in the RAG1 (179615.0001-179615.0004) and RAG2 (179616.0001; 179616.0002) genes. Several of the SCID patients had unaffected sibs who were heterozygous with 1 wildtype allele for RAG1 or RAG2, suggesting that 1 wildtype allele is sufficient for normal lymphocyte development. The authors concluded that structural mutations of the RAG genes account for a substantial proportion of human SCID cases. In a patient with T-, B- SCID, Corneo et al. (2001) identified compound heterozygosity for 2 mutations in the RAG2 gene (179616.0002; 179616.0008). A sib with Omenn syndrome had the same genotype. In 2 additional unrelated patients with T-, B- SCID, Corneo et al. (2001) identified mutations in the RAG1 gene (179615.0010; 179615.0015). Both mutations were also identified in patients with Omenn syndrome. The authors concluded that there was an additional factor required for the phenotypic expression of Omenn syndrome. In 4 of 6 patients with T-, B- SCID, Tabori et al. (2004) identified mutations in the RAG2 gene (see, e.g., 179616.0007). In 3 children with T-, B-, NK+ SCID from 2 related families of Athabascan-speaking Dine Indians from the Canadian Northwest Territories, Xiao et al. (2009) identified homozygosity for a missense mutation in the RAG1 gene (179615.0023). As expected, there was no increased sensitivity to ionizing radiation in patient fibroblasts. Xiao et al. (2009) stated that this is the third gene known to cause SCID in Athabascan-speaking Native Americans, in addition to the gene encoding Artemis (DCLRE1C; 605988), which causes SCIDA (602450), and the IL2RG gene (308380), which causes an X-linked form of SCID (300400).