Combined T- and B-cell immunodeficiencies

The phenotypic spectrum extends from typical severe combined immunodeficiency (SCID) to delayed or late-onset forms. Approximately 80% of affected individuals present with typical SCID; the remaining 15-20% carry the delayed or late-onset combined immunodeficiency (CID) phenotype, sometimes termed ‘leaky’ SCID. Infants with typical SCID present in the first weeks to months of life with poor growth, persistent diarrhoea, extensive dermatitis, recurrent pneumonia, and other opportunistic infections. Laboratory investigation reveals marked lymphocytopenia, while physical examination shows absence of palpable lymphoid tissue (tonsils, lymph nodes) and an absent thymic shadow on chest radiograph.

CID is diagnosed between ages 1 and 10 years and, less commonly, in adulthood; recurrent otitis media, sinusitis, and upper respiratory infections predominate at presentation, while chronic pulmonary insufficiency and autoimmune phenomena including cytopenias and autoantibodies are often present by the time of diagnosis.

The estimated prevalence of typical SCID is approximately 1/58,000 live births in the United States, with European newborn-screening programmes reporting 1/45,000 to 1/63,000. Effectively, all cases have an identifiable monogenic basis.

More than 20 genes are associated with combined T- and B-cell immunodeficiencies. The genetic forms span cytokine-receptor and JAK-STAT signalling defects and other mechanisms (V(D)J-recombination and purine-metabolism). Examples include X-linked SCID (IL2RG; common γ-chain defect; affects males only), JAK3-deficient SCID (JAK3; downstream γ-chain signalling defect; phenocopies X-SCID), and adenosine deaminase deficiency (ADA; purine-metabolism defect; multisystem involvement).

The genetic conditions associated with combined T- and B-cell immunodeficiencies follow heterogeneous inheritance patterns. Most underlying conditions are inherited in an autosomal recessive manner; 18 of the 20 currently recognised SCID-associated genes show autosomal recessive inheritance, while X-linked SCID (caused by germline pathogenic variants in IL2RG) accounts for a substantial proportion of affected males.

• Where a genetic cause is suspected, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Hershfield M, Tarrant T. Adenosine deaminase deficiency. 2024 Mar 7. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301656.
• Haskologlu S, Kocak S, Tufan LS, Aksoy FE, Bastug D, Oner DA, et al. Newborn screening for SCID: the very first prospective pilot study from Türkiye. Front Immunol. 2024;15:1384195. doi:10.3389/fimmu.2024.1384195. PMID:; PMCID: PMC11526446
• Xiao N, Huang X, Zang W, Kiselev S, Bolkov MA, Tuzankina IA, et al. Health-related quality of life in patients with inborn errors of immunity: a bibliometric analysis. Front Immunol. 2024;15:1371124. doi:10.3389/fimmu.2024.1371124. PMID:; PMCID: PMC10954858
• Rana R, Afroz Keramat S, Ahmed M. Cost-effectiveness of newborn screening for severe combined immunodeficiency: a systematic review. Clin Exp Pediatr. 2025;68(9):628-40. doi:10.3345/cep.2025.00052. PMID:; PMCID: PMC12409193