X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

In the absence of T cell help, B cells become defective. It is an X-linked recessive inheritance trait, stemming from a mutated (abnormal) version of the IL2RG gene located on the X-chromosome. This gene encodes the interleukin receptor common gamma chain protein, which is a cytokine receptor sub-unit that is part of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

People with X-SCID often have infections very early in life, before three months of age. This occurs due to the decreased amount of immunoglobulin G (IgG) levels in the infant during the three-month stage. This is followed by viral infections such as pneumonitis, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath. A telltale sign of X-SCID is candidiasis, a type of fungal infection caused by Candida albicans. Candidiasis involves moist areas of the body such as skin, the mouth, respiratory tract, and vagina; symptoms of oral candidiasis include difficulty in swallowing, pain on swallowing and oral lesions. Recurrent eczema-like rashes are also a common symptom. Other common infections experienced by individuals with X-SCID include diarrhea, sepsis, and otitis media. Some other common symptoms that are experienced by X-SCID patients include failure to thrive, gut problems, skin problems, and muscle hypotonia.

In some patients symptoms may not appear for the first six months after birth. This is likely due to passive immunity received from the mother in order to protect the baby from infections until the newborn is able to make their own antibodies. As a result, there can be a silent period where the baby displays no symptoms of X-SCID followed by the development of frequent infections.^{[citation needed]}

X-SCID is caused by a mutation occurring in the xq13.1 locus of the X-chromosome. Most often, this disease affects males whose mother is a carrier (heterozygous) for the disorder. Because females have two X-chromosomes, the mother will not be affected by carrying only one abnormal X-chromosome, but any male children will have a 50% chance of being affected with the disorder by inheriting the faulty gene. Likewise, her female children will have a 50% chance of being carriers for the immunodeficiency. X-SCID can also arise through de novo mutations and can be prevented in females by X-inactivation. In X-inactivation the preferential selection of the non-mutant X chromosome during development results in the outcome that none of the mature female cells actively express the X-SCID mutation, they are immunologically unaffected and have no carrier burden. A de novo mutation is an alteration in a gene caused by the result of a mutation in a germ cell (egg or sperm) or in the fertilized egg itself, rather than having been inherited from a carrier. Since only 1/3 of all X-SCID patients have a positive family history of SCID, it is hypothesized that de novo mutations account for a significant percentage of cases. X-inactivation occurs in a completely random manner, in females, very early in embryonic development. Once an X is inactivated, it remains inactivated throughout the life of that cell and any of its daughter cells.

X-inactivation is reversed in female germline cells, so that all new oocytes receive an active X. Regardless of which X is inactivated in her somatic cells, a female will have a 50% chance of passing on the disease to any male children.

Interleukins are produced by lymphocytes, among other cell types, and are released in response to antigenic and non-antigenic stimuli. The gene IL2RG codes for the common gamma chain protein, which is a common subunit of the individual receptors for Interleukin 2, Interleukin 4, Interleukin 7, Interleukin 9, Interleukin 15 and Interleukin 21. Signalling from these receptors normally promotes growth and differentiation of T-cells, B cells, natural killer cells, glial cells, and cells of the monocyte lineage, depending on the cell type and receptor activated. The most important receptors for X-SCID are those for Interleukin 2, Interleukin 4, Interleukin 7, and Interleukin 15. Specifically, Interleukin 2 and Interleukin 7 are responsible for T-cell proliferation and survival. Likewise, the action of Interleukin 4 and Interleukin 15 will lead to proliferation and differentiation of B-cells into antibody secreting plasma cells. Lastly, Interleukin 15 helps generate developed and matured natural killer cells.

The gene that encodes the common gamma chain in these interleukin receptors is mutated in X-SCID. The mutation leads to an absent or abnormally functioning common gamma chain. The mutation can occur through large, or even single nucleotide, deletions in the IL2RG gene, that disable the common gamma chain so that it is unable to bind with other receptor subunits and signal cytokine activation. Normally, when the interleukin binds to the trimeric receptor protein containing the alpha, beta, and gamma subunits, the common gamma subunit activates Janus Kinase 3 (JAK3), which leads to the phosphorylation of Signal Transducer and Activator of Transcription 5, STAT5. The STAT5 proteins dimerize and translocate to the nucleus, controlling subsequent downstream signalling. Due to the fact that the common gamma chain is absent or abnormal, this downstream pathway is inhibited. This change prevents the T-lymphocytes from signaling other cells, like B-lymphocytes and natural killer cells. Because these cells never receive these signals, they can never mature and differentiate into full grown immune cells.^{[citation needed]}