Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Negative, Nk Cell-Positive

A number sign (#) is used with this entry because T cell-negative (T-), B cell-negative (B-), natural killer cell-positive (NK+) severe combined immunodeficiency (SCID) can be caused by mutation in the recombinase activating genes RAG1 (179615) and RAG2 (179616).

Omenn syndrome (603554), an immunodeficient disorder with a less severe phenotype, is also caused by mutation in the RAG1 and RAG2 genes. See also T-, B-, NK+ SCID with sensitivity to ionizing radiation (602450) caused by mutation in the Artemis gene (DCLRE1C; 605988) and T-, B-, NK+ SCID with microcephaly, growth retardation, and sensitivity to ionizing radiation (611291) caused by mutation in the NHEJ1 gene (611290).

Description

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).

Clinical Features

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 (1964) 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.

Clinical Management

Dror et al. (1993) reported the results of lectin-treated T-cell-depleted haplocompatible parental bone marrow transplantation in patients with SCID. Nineteen of 21 patients had T-cell engraftment by 10 to 12 months posttransplant. B-cell function became normal in 10 of 14 patients 2 to 8 years posttransplant. Fourteen of 24 (58%) patients were alive 7 months to 9.8 years posttransplant.

Stiehm et al. (1996) reported successful bone marrow transplantation in the treatment of autosomal recessive SCID in a 1-month-old girl. The donor was the patient's HLA-mismatched 6-year-old sister, who had previously received a marrow transplant from her father that was mismatched in regard to 1 HLA haplotype to treat the same condition. The graft in the younger girl was not depleted of T cells, and no conditioning regimen was used before transplantation. The prompt engraftment in the infant and her uneventful course after transplantation indicated that the paternal T cells in the older sister's marrow had acquired immunologic tolerance of relevant HLA antigens and thus reconstituted the younger child's immune system without causing graft-versus-host disease (GVHD; see 614395).

Pathogenesis

Cooper et al. (1965, 1965) suggested that both the thymus system responsible for cellular immunity and the tonsillar system responsible for immunoglobulin production were absent in SCID ('Swiss type'), whereas only the latter was affected in Bruton type agammaglobulinemia.

Pyke et al. (1975) found that in vitro incubation of peripheral blood lymphocytes and bone marrow cells from SCID patients on monolayer cultures of normal human thymic epithelium resulted in the SCID lymphocytes forming rosettes with sheep erythrocytes. The same cell preparation yielded synthesis of antigen-specific, complement-dependent antibodies. The findings suggested that the defect in SCID involved a failure of lymphoid precursor cells to differentiate because of a thymic defect rather than a deficiency of these cells.

Schwarz et al. (1991) provided evidence for an abnormal recombination pattern of D-J heavy chain elements in pre-B cells from T-, B- SCID patients, suggesting that human SCID resembles murine scid (see 600899).

Patients with T-, B-, NK+ SCID have mutations in the lymphocyte-specific RAG1 and RAG2 genes, which mediate the initial step of somatic recombination of genes encoding variable (V), diversity (D), and joining (J) segments to generate variable types of immunoglobulins and T-cell receptors required for proper immune function. The lymphocyte-specific RAG genes cleave double-stranded DNA between specific recombination signal sequences and coding joints, producing blunt signal ends and covalently sealed or 'hairpinned' coding ends. Failure of the recombination machinery leads to arrest of both T- and B-cell development, resulting in SCID (Corneo et al., 2001).

Using real-time PCR and immunohistochemistry, Cavadini et al. (2005) analyzed autoimmune regulator (AIRE; 607358) expression in the thymi of 2 Omenn syndrome patients and 1 T-, B-, NK+ SCID patient and found profound reduction of AIRE mRNA and protein compared to a normal control subject. There was no detectable mRNA for the self-antigens insulin (176730), cytochrome P450 1A2 (124060), or fatty acid-binding protein (see 134650) in the immunodeficient patients. Cavadini et al. (2005) concluded that deficiency of AIRE expression occurs in severe immunodeficiencies characterized by abnormal T-cell development and suggested that in Omenn syndrome, the few residual T-cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.

Molecular Genetics

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).

Animal Model

The scid mouse, which shows a similar phenotype to T-, B- SCID, is caused by mutation in the Prkdc gene (600899), which is involved in V(D)J recombination (Bosma et al., 1983; Kirchgessner et al., 1995).