X-linked severe combined immunodeficiency (X-SCID)

X-SCID comprises a phenotypic spectrum ranging from typical early-onset disease (fatal in infancy without treatment) to atypical, later-onset presentations with variable immunodeficiency, immune dysregulation, or autoimmunity. Affected males appear normal at birth. As transplacentally transferred maternal antibodies decline, infants become increasingly prone to infection; prior to universal newborn screening, most affected infants presented between three and six months of age, with life-threatening infection occasionally manifesting earlier. Universal newborn screening now identifies the majority of infants while still asymptomatic. Undiagnosed disease typically manifests with failure to thrive, oral and diaper candidiasis, persistent and recurrent infections, opportunistic infections (notably Pneumocystis jirovecii pneumonia), chronic diarrhoea, rashes, sepsis, and severe bacterial infections.

The estimated incidence is 1/58,000. This figure refers to SCID of all genetic causes, with X-SCID being the most prevalent form (9 of 42 typical SCID cases in US newborn screening).

X-SCID is caused by germline pathogenic variants in IL2RG (Xq13.1), which encodes the common gamma chain (γc). This subunit is shared by the receptors for interleukins 2, 4, 7, 9, 15, and 21; loss of γc disrupts IL-7 and IL-15 signalling and arrests the development of T and NK lymphocytes, producing the characteristic combined immunodeficiency.

X-SCID is inherited in an X-linked recessive manner. Affected males inherit the pathogenic IL2RG variant from a heterozygous mother; female carriers are typically asymptomatic. Each son of a carrier has a 50% risk of being affected, and each daughter has a 50% risk of being a carrier. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis is established when the criteria for SCID, leaky SCID, and Omenn syndrome are met. Newborn screening quantifies T-cell receptor excision circles (TRECs) from dried blood spots to detect T-cell lymphopenia; flow cytometric immunophenotyping then demonstrates absent or markedly reduced T and NK cells with preserved B cells, and lymphocyte proliferation to phytohaemagglutinin is below 10% of control values.

Main differential diagnoses include:

• JAK3-deficient SCID: identical T-B+NK- immunophenotype to X-SCID but autosomal recessive, affecting both males and females; JAK3
• IL7R-deficient SCID: T-B+NK+ immunophenotype with NK cells preserved (in contrast to X-SCID); autosomal recessive; IL7R
• Adenosine deaminase (ADA) deficiency: T-B-NK- immunophenotype with absence of all major lymphocyte lineages; autosomal recessive metabolic SCID with elevated deoxyadenosine metabolites; ADA

• Establishing the diagnosis confirms the clinical suspicion at the molecular level, providing a precise basis for clinical and family-related decisions.
• Identification of the underlying pathogenic variant enables condition-specific surveillance and is a prerequisite for targeted medical care; the choice and timing of interventions are determined by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, at-risk relatives can undergo predictive testing, allowing personalised genetic counselling and informed reproductive decisions.

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• Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014;133(4):1092-8. doi:10.1016/j.jaci.2013.09.044. PMID:; PMCID: PMC3972266.
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