INTRODUCTION — Genetic pathogenic variants 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 that 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 [4,5] (see "Newborn screening for inborn errors of immunity"). However, in the past and in countries 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 [1-3,6-8]. Patients may develop infections from opportunistic pathogens and 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".)
Germline heterozygous gain-of-function mutations of the JAK3 gene have been identified in patients with familial chronic lymphoproliferative disorder associated with immune dysregulation . This rare condition is not discussed here.
EPIDEMIOLOGY — SCID due to JAK3 deficiency is rare, accounting for only approximately 5 percent of all cases of SCID [3,10,11] and approximately 1 percent of all cases of immunodeficiency of known genetic origin .
PATHOGENESIS — 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 [13,14]. Cellular receptors for all these cytokines share the common gamma chain (gamma-c) transmembrane receptor [15-23] 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 [20,24].
Similar to pathogenic variants of gamma-c [25,26], JAK3 defects also cause a T-B+NK- SCID that is indistinguishable except for its autosomal recessive mode of inheritance (MIM #600802) (figure 1) [1,2], with females and males equally affected. Genetic pathogenic variants that impair the integrity of the gamma-c/JAK3 signaling pathway are characterized by a near total lack of circulating T lymphocytes and normal or increased number of B cells. Natural killer (NK) cells are usually severely reduced in numbers. In addition, JAK3 deficiency blocks development of innate lymphoid cells (ILCs) both in humans  and mice . The negative effects of JAK3 deficiency on lymphoid development are recapitulated in JAK3-knockout zebrafish models .
SCID with JAK3 deficiency can be regarded as a failure of multiple cytokine-mediated signaling pathways, similar to X-linked severe combined immunodeficiency (X-SCID). In particular, impaired IL-7 signaling appears to be responsible for the pronounced defect in T cell development, while impaired IL-15 signaling  is most likely responsible for the characteristic lack of NK cells in patients with JAK3 deficiency. This was demonstrated in a patient with atypical JAK3 deficiency who had NK cells and functionally impaired CD4+ T cells that transduced IL-2, IL-4, IL-15, and IL-21 signals but failed to respond to IL-7 . It is also corroborated by findings in IL-7 and IL-7 receptor alpha chain (IL-7R-alpha) knockout mice [32,33] and in humans affected with T-B+NK+ SCID due to IL-7R-alpha pathogenic variants . (See "Severe combined immunodeficiency (SCID): Specific defects", section on 'Interleukin 7 receptor alpha chain (CD127) deficiency'.)
In vitro studies of T cell differentiation with patient-derived induced pluripotent stem cells have shown that T cell development of JAK3-deficient cells is blocked at an early CD4- CD8- double-negative (DN) stage .
By comparison, B cell development is preserved up to the mature B cell stage, suggesting redundancy of the cytokines using the gamma-c/JAK3 axis for B cell lymphopoiesis in humans. However, intrinsic functions of B cells, including ability to undergo activation, proliferation, differentiation, and isotype switching, are impaired, resulting in the profound hypogammaglobulinemia and specific antibody deficiency characteristic of JAK3 deficiency [1,2,6,36].
In vitro studies with Epstein-Barr virus (EBV) immortalized lymphoblastoid B cell lines have shown impaired responses of JAK3-deficient B cells to IL-2 and IL-4 [37,38]. Response to IL-21 is critical for B germinal center formation and B cell differentiation and proliferation [39,40], and defective differentiation of B cells to plasmablasts has been reported in patients with JAK3 deficiency as a result of impaired IL-21-mediated signaling [41,42]. However, experience from bone marrow transplantation has indicated that JAK3-deficient B cells can in some cases mediate normal humoral immune responses after engraftment of human leukocyte antigen (HLA) identical allogeneic T cells , pointing to the lack of adequate T cell helper function as an important contributor to B cell dysfunction in JAK3 deficiency.
Genetics — The human JAK3 gene maps to chromosome 19p12-13.1 , is composed of 23 exons , and contains an open reading frame of 3372 bp . Many different types of pathogenic variants (deletions, insertions, missense, nonsense, and splice-site variants) affecting this locus have been described in patients with JAK3 deficiency, with no evidence for preferential hot spots, but reports of possible founder effects have been described [3,47,48]. Both "null" variants and defects compatible with residual expression of a mutated JAK3 protein have been observed. In all cases studied, however, these pathogenic variants interfere with normal cytokine signal transduction and result in severely reduced phosphorylation of the JAK3 molecule itself and of downstream proteins, such as the signal transducer and activator of transcription 5 (STAT5) [2,3,6,7,37,38,43,49-52].
CLINICAL MANIFESTATIONS — Patients with SCID due to JAK3 deficiency are readily identified by newborn screening with the T cell receptor excision circle (TREC) assay routinely conducted in the US and in a growing number of countries worldwide. When not identified by population-based screening, JAK3-SCID typically presents at a few months of age with infectious complications that classically defined SCID in the pre-newborn screening era. These infants typically have recurrent or severe respiratory infections, intractable diarrhea, thrush, and failure to thrive [1-3,6-8]. Failure to recover from infections and coexisting infections with multiple pathogens are characteristic. Infections are frequently caused by opportunistic pathogens and become life threatening, a true pediatric medical emergency [3,8,47]. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations'.)
Infectious diarrhea caused by the attenuated live rotavirus vaccine is often present if infants have inadvertently received this vaccine, which is contraindicated in infants known to have immune defects . Severe or fatal infection can be seen with other live-attenuated vaccines (oral polio, varicella, Bacillus Calmette-Guérin) as well. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations'.)
The immune system in infants with SCID is impaired in its capacity to reject foreign cells. Thus, these infants may present with graft-versus-host disease due to transplacentally acquired maternal T cells (or, if unirradiated transfusions have been given, unrelated-donor allogeneic T cells). The infiltrating foreign cells cause rashes, abdominal organomegaly, and tissue damage. In rare cases of hypomorphic pathogenic variant of JAK3, in which residual protein function is preserved, the disease may present as Omenn syndrome, with erythroderma rash, adenopathy, eosinophilia, elevated immunoglobulin E (IgE), and oligoclonal expansion of autologous T cells with poor diversity. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations' and "Severe combined immunodeficiency (SCID): An overview", section on 'Detection of maternal T cell engraftment' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype'.)
Certain pathogenic variants of the JAK3 gene can lead to a broad spectrum of clinical presentations, including milder immunodeficiency of later clinical onset or uncontrolled lymphocyte proliferation . It is hypothesized that "leaky" JAK3 variants compatible with the expression of low and variable levels of functional JAK3 protein are responsible for the differences in disease severity and the unique and almost paradoxical clinical features observed in some patients .
In one affected family, for example, compound heterozygote variants in the JAK3 gene resulted in a severe lymphoproliferative disorder in an 8-year-old child, but his 18-year-old sibling with identical defects was nearly asymptomatic . The genetic defects of these siblings were associated with low amounts of functional protein. In addition, somatic chimerism with presence of JAK3 revertant T cells was reported in two affected siblings and appeared to modulate their clinical and immunologic phenotype, which evolved from combined immunodeficiency to predominant CD4+ lymphopenia .
Skin granulomas have been reported in some patients with hypomorphic JAK3 pathogenic variants [55,56]. Although no pathogens have been identified within these lesions, presence of the rubella virus vaccine strain has been demonstrated in granulomas of patients with other forms of combined immunodeficiency . Chronic active Epstein-Barr virus (CAEBV) infection was reported as the presenting sign in an adolescent with hypomorphic JAK3 deficiency .
Thus, partial JAK3 defects may be the basis for the immunologic problems in patients with increased, but not overwhelming, susceptibility to infection and/or disorders of immune regulation who do not meet the typical phenotypic characteristics of SCID patients. Although most such patients are expected to have low numbers of TRECs that are identified in the neonatal period by TREC screening, further experience with these rare patients is required to define the disease presentation in the newborn screening era . Indeed, immunologic investigations of patients with JAK3 deficiency identified by newborn screening may detect atypical findings that would only result in clinical manifestations in the posttransplant period .
LABORATORY FINDINGS — Lymphopenia is a common, although not universal, laboratory finding in patients with T-B+NK- SCID due to JAK3 deficiency since B cells may be elevated in numbers, masking the lack of T and natural killer (NK) cells. However, CD3 T cells and, in particular, numbers of CD3/CD4- and CD3/CD8-positive T cells that express the CD45RA naïve marker are profoundly low. Flow cytometry analysis of lymphocyte subsets shows low to undetectable numbers of CD3 T cells and NK cells (<50 NK cells/microL and <1 percent of total lymphocytes), while B cell numbers are normal or increased [6,8,47]. Development of other types of innate lymphoid cells (ILCs), with the possible exception of ILC type 1 (ILC1), is also compromised in patients with SCID due to JAK3 or interleukin 2 receptor gamma (IL2RG; common gamma [gamma-c] chain) pathogenic variants, although this deficiency may not contribute to increase susceptibility to infections . Studies in Jak3-mutated mice have shown that JAK3 deficiency results in a differentiation block of bone marrow ILC precursors . (See "Severe combined immunodeficiency (SCID): An overview", section on 'Laboratory abnormalities'.)
Immunoglobulin M (IgM) and immunoglobulin A (IgA) levels are markedly decreased despite the presence of B cells. Immunoglobulin G (IgG) acquired transplacentally during the last seven weeks of pregnancy is usually present initially and declines postnatally, and antibody responses are not elicited following immunization. The severe reduction in the number of T and NK cells is associated with a lack of in vitro proliferation to mitogens such as phytohemagglutinin (PHA) and of NK in vitro cytotoxic activity, respectively [3,8,36,47].
DIAGNOSIS — Only tests specific for JAK3 deficiency will be discussed here. The diagnosis of SCID, including newborn screening for SCID based on enumeration of T cell receptor excision circles (TRECs), is discussed in detail separately (table 2 and algorithm 1). Neonatal screening identifies JAK3 deficiency in the first weeks of life, before appearance of clinical symptoms . (See "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis' and "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)
The genes that should be considered for sequencing in a patient with T-B+NK- SCID are IL2RG, encoding for the common gamma chain of the interleukin (IL) 2 receptor (gamma-c), in males and JAK3 in both males and females (table 1). X-linked severe combined immunodeficiency (X-SCID), caused by pathogenic variants of the IL2RG gene, encoding for gamma-c, is discussed separately. (See "X-linked severe combined immunodeficiency (X-SCID)".)
A definitive diagnosis of JAK3 deficiency requires demonstration of pathogenic variants of the JAK3 gene and/or biochemical analysis revealing defective JAK3 expression and/or function in patient lymphocytes. Biochemical studies (Western blot analysis of JAK3 expression, assessment of JAK3 and/or signal transducer and activator of transcription 5 [STAT5] phosphorylation in response to cytokine stimulation) are usually performed on lymphoblastoid B cell lines obtained from affected patients after Epstein-Barr virus (EBV) mediated immortalization because only severely reduced numbers of T cells are available from lymphopenic infants, and they may be of maternal origin [3,6,7,43,49-51].
Preparing B cell lines for performing biochemical assays generally requires several weeks, during which diagnosis by gene sequencing can be performed. Screening assays based upon single-strand conformation polymorphisms (SSCP) techniques were formerly performed  but are rarely done now that rapid gene sequencing is available in most settings. In rare cases, deep intronic variants that create novel cryptic splice sites may also cause the disease, indicating the need for careful analysis of noncoding regions in patients with a T-B+NK- SCID phenotype in which no IL2RG or JAK3 exonic or canonical splice-site pathogenic variants have been identified . Moreover, synonymous exonic pathogenic variants that create novel cryptic splice sites may also cause JAK3 deficiency . In such cases, sequencing of the complementary deoxyribonucleic acid (cDNA) product may facilitate the diagnosis. Identification of the specific gene pathogenic variants in the patient and confirmation of asymptomatic JAK3 variant carrier status in the parents by sequencing allows for definitive diagnosis, as well as genetic counseling and prenatal diagnosis for management of future pregnancies .
JAK3 deficiency is compatible with the presence of significant numbers of circulating, although mostly poorly functioning, T cells [47,51,63]. Thus, screening for JAK3 expression and/or pathogenic variants should not be limited to T cell lymphopenic patients. Such screening should also be considered in all undefined cases of combined immunodeficiency, especially those presenting with high proportions of peripheral B cells.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of SCID is discussed in detail separately. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Differential diagnosis'.)
The clinical and immunologic phenotype of JAK3 deficiency has features similar to X-linked severe combined immunodeficiency (X-SCID) . If natural killer (NK) cells are present to some degree, it can be confused with interleukin 7 receptor alpha (IL-7R-alpha) deficiency, which is typically a T-B+NK+ SCID . Features that can help distinguish JAK3 deficiency from other forms of SCID include the following:
●Parental consanguinity and presentation in female subjects can distinguish JAK3 deficiency from X-SCID .
●Absence or very low numbers of NK cells in patients with JAK3 deficiency (with the exception of some patients with atypical JAK3 deficiency ) can aid the differential diagnosis with IL-7R-alpha deficiency, with the latter being compatible with NK cell development .
●Molecular diagnosis can be made by sequencing a panel of SCID genes or by whole exome sequencing using next-generation sequencing methodology. Gene panels may focus on genes encoding proteins that have been found defective in T-B+ SCID (including CD3 delta, epsilon, and zeta chains; CD45; IL2RG; IL-2R-alpha chain; IL-7R-alpha; JAK3; and coronin-1A) or a comprehensive panel of SCID T-B+ and T-B- SCID genes (with addition to the above of adenylate kinase 2 associated with reticular dysgenesis; adenosine deaminase [ADA]; DNA crosslinked repair enzyme 1C or Artemis; ligase 4, nonhomologous end-joining protein 1, or Cernunnos; DNA-dependent protein kinase; Ras-related C3 botulinum toxin substrate 2 [RAC2]; and recombinase-activating genes 1 and 2) (table 1). These methods are becoming more widely used as costs and turnaround time for whole exome sequencing decrease.
TREATMENT — A general overview of the management of SCID, including precautions that are undertaken prior to therapy while the definitive diagnosis is being determined, is discussed separately. The treatment of choice for SCID due to JAK3 deficiency is hematopoietic cell transplantation (HCT). Gene therapy is under investigation. HCT (including preferred donor source and complications after HCT) and gene therapy are reviewed in detail separately. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures' and "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Overview of gene therapy for inborn errors of immunity".)
While awaiting determination of the optimal donor for HCT, it is essential that patients are maintained free from infections that could compromise their health status and ultimately the outcome of transplantation. If possible, reverse isolation should be used to protect these patients from environmental pathogens. It is imperative to provide protective immune globulin infusions and prophylactic antimicrobials to minimize the chance of Pneumocystis jirovecii pneumonia and other infections by bacterial, viral, and other fungal pathogens. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures'.)
Hematopoietic cell transplantation — No extensive data series are available on the specific results of HCT in JAK3-deficient patients because of the rarity of the disease. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)
A small series of 10 patients with JAK3 deficiency received HCT at a single institution . Transplantation was from a human leukocyte antigen (HLA) identical family donor in two cases, from an unrelated cord blood in one case, and from a haploidentical parent in seven cases. Pre-HCT chemotherapy was used only in the patient who received cord blood transplantation. Nine of the 10 patients had attained robust T cell reconstitution and were reported to be alive and no longer prone to recurrent or opportunistic infections between 4 and 18 years after HCT. However, only three patients were able to discontinue treatment with intravenous immune globulin, and donor B cell engraftment was achieved only in the child who received pre-HCT conditioning. In addition, seven of the nine patients continued to have poor natural killer (NK) cell numbers and/or function.
Generally, JAK3 deficiency has been grouped with other forms of T-B+ SCID (ie, X-linked severe combined immunodeficiency [X-SCID] and interleukin 7 receptor alpha [IL-7R-alpha] deficiency) in studies of HCT outcomes including larger series of patients. In a European series, for example, 10-year survival after HCT was 70 percent for 345 patients with T-B+ SCID . Results from a single-center study were similar, with a survival rate of 72 percent (43 patients) 15 years after HCT . In addition, a retrospective analysis of 662 patients with SCID who received HCT between 1982 and 2012 in North America found that overall survival was approximately 80 percent in the 211 followed with JAK3 deficiency or X-SCID, which was significantly better than that seen in patients affected with adenosine deaminase (ADA) or Artemis deficiency . Early age (<3.5 months of life) and lack of active infections at the time of transplantation are associated with improved outcome after haploidentical HCT in patients with X-SCID and JAK3 deficiency .
Successful reconstitution of T cell numbers and function can be obtained after transplantation of bone marrow-derived hematopoietic progenitors obtained from HLA-identical siblings; matched, unrelated volunteer donors; and haploidentical parents [36,47,68-70]. The lack of NK cells (and NK cell function) in JAK3-deficient patients makes graft rejection improbable, thereby facilitating the success of HCT. In addition, the early block in thymic T cell development that is characteristic of JAK3 deficiency probably favors thymic repopulation by the donor's normal lymphoid precursors and their differentiation into mature T cells.
The situation is quite different with regards to the reconstitution of the humoral immune response. Differentiation proceeds up to mature B cells in patients with JAK3 deficiency. The presence of these B cells, although functionally deficient, and that of their progenitors creates competition between autologous- and donor-derived B lymphopoiesis following HCT. Thus, the reconstitution of humoral immunity following haploidentical HCT is often incomplete, leading to the need of long-term administration of immune globulin infusions [3,36,69]. Development of effective B cell function is more common following HCT from HLA-identical sibling donors and in patients receiving reduced-intensity or myeloablative conditioning [66,67]; it also has been observed even in some patients who maintained autologous B cells following HCT [36,43,69]. Reconstitution of NK function also seems unpredictable in patients with JAK3 deficiency .
An important complication of HCT in patients with SCID due to JAK3 deficiency is the appearance of warts due to papillomavirus infection even several years after transplant . This long-term complication has been observed particularly in patients with X-SCID or JAK3 deficiency and less often in patients with SCID due to other genetic causes, suggesting that warts reflect an incomplete correction of defective gamma-c-mediated signaling defect in particular cell types, such as keratinocytes. However, the possible contribution of incomplete or vanishing immune reconstitution cannot be formally excluded.
Altogether, these results clearly indicate that HCT is a lifesaving procedure for SCID due to JAK3 deficiency . However, in the absence of an HLA-identical family donor, the procedure is imperfect and leaves room for improvement.
Gene therapy — Because of the phenotypic and biologic similarities between JAK3 deficiency and X-SCID and in light of the success of gene therapy in a series X-SCID patients, it is arguable that genetic correction of JAK3 deficiency may also result in clinical benefit [72,73]. On the other hand, one potential concern of using a "gene addition" approach is that the expression of the transferred gene is evicted from the cellular mechanisms of regulation and is constitutively expressed under the control of strong viral promoters. JAK3 has an important role in cell proliferation [24,37], and deregulated JAK3 expression could potentially result in uncontrolled cell division causing malignancy. (See "Overview of gene therapy for inborn errors of immunity".)
Preclinical experiments in vitro [37,38] and in vivo [74-76] have illustrated the potential of gene therapy for JAK3 deficiency. Retroviral-mediated JAK3 gene transfer was able to correct the biologic abnormalities of JAK3-deficient human B cell lines leading to reconstitution of IL-2 signaling (as assessed by IL-2-induced phosphorylation of JAK3 and signal transducer and activator of transcription 5 [STAT5]) and IL-2-mediated cell proliferation [37,38].
A series of in vivo experiments were performed and showed that ex-vivo retroviral-mediated JAK3 gene transfer into hematopoietic progenitors from JAK3 knockout mice was able to restore specific T and B cell functions in mice transplanted with gene-corrected cells. Treated mice developed T cells able to respond to mitogens and develop specific cytotoxic responses. In addition, good reconstitution of humoral immunity was achieved following the procedure, with increased numbers of B cells and antibody production. More importantly, the same mice showed generation of specific antibody responses upon immunization and improved survival after exposure to influenza virus infection [74,75].
Another crucial finding of these experiments was that myeloablation was not necessary for the achievement of these significant improvements . The strong selective advantage of JAK3-corrected lymphoid cells over unmodified autologous counterparts is probably responsible for these results that suggest that preparative conditioning is needed in the case of JAK3 gene therapy protocols in humans.
A single JAK3-deficient patient who had failed HCT was enrolled in a gene therapy trial. The results of that experience were only published in abstract form and showed no evidence of immune reconstitution at seven months posttreatment . This trial was placed on clinical hold, and no additional patients were enrolled because of the occurrence of leukemia in two children treated with gene therapy for X-SCID . It is reasonable to assume that expression of JAK3 could have similar consequences. For these reasons, the US Food and Drug Administration (FDA) Biological Response Modifiers Advisory Committee made the recommendation in 2003 that, until more information is acquired, gene therapy for X-SCID and JAK3-SCID should be performed only on patients for whom alternative therapies are not available or have already failed. More recent developments in gene therapy for SCID include the use of self-inactivating vectors or lentivirus vectors that have been shown to be safer than the original constructs used for X-SCID gene therapy.
In addition, the ultimate goal of gene therapy (ie, the correction of the genetic defect within its genomic contest) is becoming a close reality thanks to the technologies of gene editing. Among these, a CRISPR/Cas9-based approach has been used to achieve the homology-directed repair of a pathogenic C1837T nonsense pathogenic variant of the JAK3 gene in induced pluripotent stem cells (iPSCs) derived from a patient with JAK3 deficiency. In vitro differentiation experiments showed that, contrary to the original, mutated cells, the corrected iPSCs were able to generate T and NK cells. This demonstrates that lymphoid differentiation capability was restored, opening the way to the future development of this technology for gene therapy of patients affected with SCID due to JAK3 deficiency .
PROGNOSIS — Affected patients typically die within the first year or two of life unless the underlying defect is corrected (see 'Treatment' above and "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Overview of gene therapy for inborn errors of immunity"). More research is needed on very long-term outcomes to determine the best methods for hematopoietic cell transplantation (HCT) and/or gene therapy.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Genetics – Defects of the Janus kinase 3 (JAK3) gene result in a type of T cell-negative, B cell-positive, natural killer (NK) cell-negative severe combined immunodeficiency (T-B+NK- SCID) that is transmitted via an autosomal recessive mode of inheritance (MIM #600802). (See 'Introduction' above and 'Genetics' above.)
●Pathogenesis – JAK3 is expressed in hematopoietic cells and is required for signal transduction of several cytokines. It is essential for lymphoid cell development. (See 'Pathogenesis' above.)
●Newborn screening and clinical presentation – Patients with SCID due to JAK3 deficiency are readily identified by SCID newborn screening because of their failure to generate mature T cells in the thymus. In locales where SCID newborn screening is not performed, affected infants present at a few months of age with the infectious complications that comprise the classical clinical features of SCID, including recurrent or severe respiratory infections, intractable diarrhea, thrush, and failure to thrive. (See 'Clinical manifestations' above.)
●Diagnosis and differential – Definitive diagnosis requires demonstration of deleterious homozygous or compound heterozygous pathogenic variants of the JAK3 gene and/or biochemical evidence of impairment of JAK3 expression and/or function in patient lymphocytes. The clinical and immunologic phenotype of JAK3 deficiency has features distinct from X-linked SCID (X-SCID) and interleukin 7 receptor alpha (IL-7R-alpha) deficiency. (See 'Diagnosis' above and 'Differential diagnosis' above.)
●Treatment – The treatment of choice for SCID due to JAK3 deficiency is hematopoietic cell transplantation (HCT). Gene therapy is under investigation. (See 'Treatment' above and "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Overview of gene therapy for inborn errors of immunity".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
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