Severe combined immunodeficiency, X-linked (X-SCID)

With a proportion of 40-50%, X-linked severe combined immunodeficiency (X-SCID) is by far the most common entity of all SCID diseases. X-SCID is caused by mutations in the IL2RG gene, which codes for the IL2 receptor y-chain, which is a component of the IL2 receptor and various other interleukin receptors. Both the cellular and the humoral immune system are affected. X-SCID patients usually show an almost complete absence of T lymphocytes and NK cells and a normal number of B lymphocytes, although their function is impaired.

Without appropriate therapy, X-SCID is almost always fatal within the first few years of life. Untreated boys suffer from recurrent infections that are difficult to treat and show failure to thrive, candidiasis, missing tonsils and lymph nodes. Skin rashes, diarrhea, fever, pneumonia, sepsis and other severe bacterial infections are common.

The treatment of choice is an early blood stem cell transplant, which should ideally take place within the first three months after birth. Long-term substitution with immunoglobulins may be necessary if no functional donor B lymphocytes develop. Patients with IL2RG gene mutations that allow residual protein function may develop atypical X-SCID, characterized by the presence of T lymphocytes, immune dysregulation and autoimmunity.

The IL2RG gene is located on the X chromosome and comprises 8 exons. To date, a total of 200 mutations have been identified, which can occur across all exons, with a "hot spot" in exon 5. In only around a third of cases is there a positive family history of affected male relatives in previous generations. The majority of mutations therefore occur sporadically. Female carriers are usually healthy and show "non-random" inactivation of the affected X chromosome in all lymphocytic populations.

References

Shearer et al. 2014, J Allergy Clin Immunol 133:1092 / Buckley et al. 1997, J Pediatr 130:378 / Puck et al. 1997, Blood 89:1968 / Puck et al. 1993, Hum Mol Genet 2:1099