Severe combined immunodeficiency (SCID) with JAK3 deficiency
- Fabio Candotti, MD
Fabio Candotti, MD
- Associate Professor
- University Hospital of Lausanne (CHUV)
- Luigi D Notarangelo, MD
Luigi D Notarangelo, MD
- Section Editor — Immunology and Immunodeficiency
- Bethesda, MD
Genetic mutations affecting the common gamma (gamma-c) chain of the interleukin (IL)-2 receptor and the associated downstream signaling enzyme Janus kinase 3 (JAK3) both result in a clinical presentation of T cell-negative, B cell-positive, natural killer (NK) cell-negative severe combined immunodeficiency (T-B+NK- SCID) (table 1 and figure 1). In contrast to the X chromosome-linked gamma-c form of SCID, which affects only males, SCID due to defects of the JAK3 gene results in T-B+NK- SCID that is transmitted via an autosomal recessive mode of inheritance (MIM #600802) and affects males and females equally [1-3].
SCID due to JAK3 deficiency is increasingly identified in otherwise healthy infants by newborn screening with the T cell receptor excision circle (TREC) test  (see "Newborn screening for primary immunodeficiencies"). However, in the past and in states where SCID is not included in population-wide newborn screening panels, affected infants come to medical attention at a few months of age with infectious complications of SCID, including persistent, recurrent and increasingly severe bacterial, viral, and fungal infections; intractable diarrhea; thrush; and failure to thrive [1-3,5-7]. Patients may develop infections from live-attenuated vaccines. Graft-versus-host reaction from transplacentally acquired maternal T cells or donor allogeneic T cells from transfusions often increases the severity of the clinical phenotype. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations'.)
The pathogenesis, clinical features, diagnosis, and treatment of T-B+NK- SCID with JAK3 deficiency are presented in this topic review. An overview of the different forms of SCID can be found separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)
SCID due to JAK3 deficiency is rare, accounting for only approximately 6 percent of all cases of SCID [3,8,9] and approximately 1 percent of all cases of immunodeficiency of known genetic origin .
Signal transduction by the hematopoietic cytokines, interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, is of critical importance for the development and function of the cells of the immune system [11,12]. Cellular receptors for all these cytokines share the common gamma chain (gamma-c) transmembrane receptor [13-21] that lacks intrinsic catalytic activity but mediates signal transduction via its physical association with other transmembrane cytokine receptor chains and an intracellular member of the Janus family of protein kinases, JAK3 [18,22].
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