Severe Combined Immunodeficiency (SCID) Group of rare primary immunodeficiencies characterized by a profound block in T-cell development as a consequence of an intrinsic deficiency. Clinical consequences occur within 3-6 months following birth. The most frequent clinical manifestations are recurrent oral candidiasis, failure to thrive, protracted diarrhea, Pneumocystis jirovecii infections. Six distinct causative mechanisms have been identified:

• Cytokine signaling deficiency: Most frequent SCID accounting for 40-50% of cases with the absence of T and NK cells. These pts have a deficiency in the gamma chain receptor shared by several cytokine receptors (interleukins 2, 4, 7, 9, 15, 21). The same phenotype seen in X-linked SCID can be inherited as an autosomal recessive disease due to mutations in the JAK3 protein kinase gene.
• Purine metabolism deficiency: About 20% of SCID pts are deficient in adenosine deaminase (ADA) due to mutations in the ADA gene.
• Defective rearrangements of T- and B-cell receptors: Account for ~20-30% of SCID cases. Main deficiencies involve recombinase activating genes (RAG-1, RAG-2) DNA-dependent protein kinase, DNA ligase 4, and Cernunnos deficiencies.
• Defective (pre-) T-cell receptor signaling in the thymus: Rare deficiencies in CD3 subunits associated with the (pre) TCR and CD45.
• Reticular dysgenesis: Extremely rare. Results from adenylate kinase 2 deficiency.
• Defective egress of lymphocytes: Defective egress of T cells from the thymus resulting from deficiency in coronin-1A.