Severe Combined Immunodeficiency, X-Linked; D81.4

X-linked SCID was formerly referred to as "Swiss-type agammaglobulinemia" or thymic epithelial hypoplasia (Nezelof 1992). The severe combined immunodeficiency originally called "Swiss-type agammaglobulinemia" (to distinguish it from agammaglobulinemia congenital type Bruton) was first described by Hitzig and Willi (1961) in Switzerland. These cases showed an autosomal recessive mode of inheritance (see 601457).

X-SCID, also known as Agammaglobulinemia, Swiss type, or Severe Combined Immunodeficiency, X-Linked, is a rare, autosomal recessive, severe, combined immunodeficiency(see Primary Immunodeficiency Classification below) with complete absence of gamma globulins, lymphoid tissue, and B and T lymphocytes; high susceptibility to infections, especially viral and opportunistic infections. Signs and symptoms, which often appear in early infancy, include failure to thrive, oral candidiasis, absent tonsils and lymph nodes, recurrent persistent infections, exanthema, diarrhea, fever, and pneumonia.

In a study of 108 SCID patients, Buckley et al (1997) found that IL2RG deficiency was responsible for approximately 42% of feces with agammaglobulinemia.

X-SCID is caused by mutations in the IL2RG gene, which encodes the gamma subunit of the interleukin-2 receptor (IL2RG; 308380). The disease affects only the male sex and is usually fatal in the first two years of life unless treated with bone marrow transplantation or gene therapy.

Severe combined immunodeficiency differs from agammaglobulinemia congeital type Bruton (300755) in the additional presence of lymphocytopenia, earlier age at death, susceptibility to viral, fungal, and bacterial infections, lack of type IV reactivity, atrophy of the thymus, and lack of benefit from gamma globulin administration.

The less severe X-linked combined immunodeficiency (312863) is also caused by a mutation in the IL2RG gene.

An autosomal recessive form of T-, B+, NK- SCID (600802) is caused by a mutation in the JAK3 gene (600173) on chromosome 19p13.

Rosen et al (1966) reported three families with SCID inherited in an X-linked recessive manner: all patients were male, and in one relationship there were nine affected males in five sibling pairs over three generations linked by females.

Gitlin and Craig (1963) reported on 15 boys with hypogammaglobulinemia and found that they could be divided into two almost equal groups on the basis of their clinical course. In the first group, infections began early in life, often before 3 months of age, followed by lymphopenia and persistent pneumonitis, candidiasis, and frequent exanthema. The disease was usually fatal in infancy, even in children treated with gamma globulin. Autopsy revealed an abnormally small thymus with thymic lymphoplasia.

In the second group of patients, infections occurred somewhat later, usually between 6 and 18 months of age. The infection was intermittent rather than persistent, and gamma globulin was clinically useful. These patients did not have lymphopenia, and in those who died, the thymus was not small, although germinal follicles and plasma cells were absent in the lymph nodes. About half of the patients in each group had a family history of severe infection in male relatives. The second group is classified as Bruton's X-linked agammaglobulinemia.

(Nezelof, 1992) reported a form of "thymic dysplasia" that is X-linked. Thymic dysplasia occurs in SCID (Nezelof, 1992).

Yount et al (1978) studied a child with X-linked SCID. Adenosine deaminase (ADA; 608958) and nucleoside phosphorylase (PNP; 164050) levels were normal. The patient had virtually no reactive lymphocytes. Despite an abundance of B lymphocytes, he exhibited profound humoral immunodeficiency. The authors suggested that the B cells were unable to differentiate into plasma cells that can synthesize and secrete immunoglobulins. A brother of the patient they studied died at 10 months of age from Pneumocystis carinii pneumonia complicated by disseminated influenza infection (Hong Kong strain). Autopsy revealed a hypoplastic thymus without epithelial corpuscles and absence of germinal centers in the lymph nodes and lamina propria of the intestine.

Conley et al (1984) noted that in two unrelated men with SCID and thymic lymphoplasia, the T cells had a typical female XX karyotype and were probably of maternal origin, whereas the B cells had a male XY karyotype. The authors suggested that SCID in these patients was the result of graft-versus-host disease (GVHD; see 614395).

Kellermayer et al (2006) reported a boy with X-linked SCID confirmed by genetic analysis. The patient had mild to moderate recurrent dermatitis consistent with spontaneous graft-versus-host disease.

Speckmann et al (2008) reported a boy with a relatively mild form of X-linked SCID diagnosed by molecular analysis at the age of 5 years (308380.0013). The main clinical symptom was recurrent bronchitis. Immunologic studies revealed a decreased number of circulating T and NK cells and a normal number of B cells. His unaffected mother was a carrier of the mutation.

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