X-linked severe combined immunodeficiency (X-SCID)

INTRODUCTION — 

X-linked severe combined immunodeficiency (X-SCID; also designated SCID-X1) is due to defects in the common gamma (gamma-c) chain (interleukin 2 receptor gamma [IL2RG]). The disorder is typically fatal in the first two years of life if not treated definitively.

X-SCID is discussed here. An overview of specific forms of SCID and a general overview of SCID are presented separately. Additional topics cover other specific SCID disorders. (See "Severe combined immunodeficiency (SCID): Specific defects" and "Severe combined immunodeficiency (SCID): An overview".)

EPIDEMIOLOGY — 

X-SCID (MIM #300400) is the most common SCID genotype, except in areas where there is a founder effect or a high level of consanguinity [1]. Assessments from a newborn screening (NBS) study in 11 NBS programs in the United States involving three million live births found that approximately 22 percent of infants with typical SCID have the X-linked form [1]. This number was supported by a study of NBS in California, which found in 2.5 million infants screened that 29 percent of babies identified with SCID had the X-linked form [2]. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

PATHOGENESIS — 

X-SCID is the result of defects in a gene on the X chromosome encoding the cytokine receptor subunit gamma-c (the interleukin receptor common gamma chain [IL2RG]) [3,4]. This receptor subunit is shared by at least six different cytokine receptor complexes: the receptors for interleukins (IL) 2, 4, 7, 9, 15, and 21 [5]. Pathogenic variants in this gene lead to profound derangement of the immune system via the blockade of multiple cytokine pathways important for lymphocyte development and function, resulting in absent T and natural killer (NK) cells with nonfunctional B cells (T-B+NK- SCID) [6].

The gamma-c subunit is also involved in growth hormone receptor signaling [7]. Thus, growth failure seen in some children with X-SCID may be due to both the underlying genetic defect and/or late effects from conditioning, recurrent infections, or nutritional deficiencies [8]. This could explain why some patients continue to have growth failure with short stature after partial correction of the defect with hematopoietic cell transplantation (HCT). (See 'Treatment' below.)

CLINICAL PRESENTATION — 

Most patients with SCID born in regions with newborn screening (NBS) are asymptomatic at diagnosis unless they have maternal-fetal graft-versus-host disease (GVHD) mediated by maternal T cells that have crossed the placenta or cytomegalovirus (CMV) infection acquired from the mother prenatally, during birth, or while breastfeeding. Those that are not diagnosed by NBS generally present during the first year of life with recurrent opportunistic infections, chronic diarrhea, thrush, otitis media, and failure to thrive. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical features'.)

Some patients with hypomorphic gene variants and leaky SCID present either later in life (if not diagnosed by NBS) with a clinical picture of combined immunodeficiency with chronic lung disease, warts, and other chronic infections or have an atypical presentation in the neonatal period, such as Omenn syndrome, which is due to an uncontrolled expansion of a few T cell clones. There are also reported cases of X-SCID in which subpopulations of T cells have somatic reversion of the interleukin 2 receptor gamma (IL2RG) pathogenic variant resulting in variable phenotypic expression, including attenuated disease in some patients [9]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T-B-NK+ SCID without radiation sensitivity due to RAG defects (includes most cases of Omenn syndrome)' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype'.)

LABORATORY ABNORMALITIES — 

In patients with X-SCID detected by newborn screening (NBS), low/absent T cell receptor excision circles (TRECs) reflect absent thymopoiesis, with severe lymphopenia seen with this disorder [10]. TRECs are very low, even with transplacentally transferred maternal T cells that are found in a majority of patients with X-SCID since the maternal cells are predominantly memory T cells. A large majority of patients with X-SCID have a T-B+NK- phenotype. T cells are absent or very low (less than 50 cells/microL [11,12]), with <20 percent naïve CD4+ T cells (CD4/CD45RA); B cells are present, often in normal numbers; and natural killer (NK) cells typically are absent or low (table 1). (See "Flow cytometry for the diagnosis of inborn errors of immunity" and "Laboratory evaluation of the immune system".)

Some patients with typical X-SCID can present with varying numbers of T cells due to transfer of maternal lymphocytes in utero [13]. Evaluation of T cell receptor variable region beta (TCR-V-beta) diversity shows skewing with oligo- or monoclonality in newly diagnosed patients with SCID who have detectable T cells. This is also true for patients with hypomorphic variants and a leaky X-SCID phenotype with some autologous T cells present [13]. There have also been reports of patients with a leaky X-SCID phenotype and features of Omenn syndrome [14].

Most patients with X-SCID have very low to absent lymphocyte proliferative responses to phytohemagglutinin (PHA; <10 percent of the lower limit of normal for the laboratory), although this test has lost its utility since molecular diagnosis is available relatively rapidly [11,12,15]. (See "Laboratory evaluation of the immune system", section on 'Response to mitogens'.)

With respect to B cell immunity in X-SCID, immunoglobulin levels are low, except for transplacental immunoglobulin G (IgG) in the first months of life, despite the presence of normal numbers of B cells. This is due to the fact that, in addition to absent T cell immunity, which is essential for B cells to function, autologous B cells are intrinsically abnormal in patients with X-SCID. Patients with X-SCID remain B cell immunodeficient even after a successful hematopoietic cell transplantation (HCT) in which T cell immunity is reconstituted but donor B cells fail to engraft [16].

DIAGNOSIS — 

Only tests specific for X-SCID are discussed here. The diagnosis of SCID in general is reviewed in detail separately. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects' and "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis' and "Laboratory evaluation of the immune system" and "Flow cytometry for the diagnosis of inborn errors of immunity".)

The diagnosis of X-SCID should be suspected in males with the T-B+NK- SCID phenotype , although not all of these patients will have absent NK cells. The diagnosis is confirmed by identifying a heterozygous pathogenic variant in the IL2RG gene by next-generation sequencing, which is available at commercial and research laboratories. T-B+NK- SCID in males must be differentiated from autosomal recessive Janus kinase 3 (JAK3) deficiency, which is clinically and immunologically indistinguishable except that both males and females are affected. Most centers are using a SCID gene panel that includes both IL2RG and JAK3. If the panel or whole exome sequencing is not available, males are screened for IL2RG defects first and then JAK3 if the IL2RG screening is negative (females are screened for JAK3 defects only). (See "Severe combined immunodeficiency (SCID) with JAK3 deficiency".)

While most patients with X-SCID present with the T-B+NK- phenotype, a small number may have T and/or natural killer (NK) cells present, depending upon the location of the pathogenic variant and/or reversions that may have occurred and/or the presence of maternal T cells [17]. Thus, male patients with SCID presenting with some T cells and/or NK cells should be evaluated for X-SCID (or JAK3-SCID) if other, more likely causes of this phenotype have been ruled out.

The diagnosis of X-SCID also may be established by demonstrating the absence of the gamma-c chain (CD132) on lymphocyte surfaces by flow cytometry, which has a relatively quick turnaround time compared with genetic testing. However, in many cases, a nonfunctional gamma-c may be expressed. The diagnosis of X-SCID may also be established by a skewed pattern of X-chromosome inactivation in maternal T cells, but this pattern cannot detect the 30 percent of cases resulting from spontaneous pathogenic variants. Genetic testing should still be performed to confirm the diagnosis.

The functional signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation assay also can be used to evaluate possible known and unknown SCID variants in this pathway including IL2RG and JAK3 [18]. The presence of tyrosine-phosphorylated STAT5, detected by flow cytometry after interleukin (IL) 2 stimulation, indicates a functional IL-2/JAK-3 signal transduction pathway; its absence indicates a defect in this pathway. While no longer routinely used for diagnosing IL2RG- or JAK3-SCID, this research assay can be used to further explore this critical lymphocyte signaling pathway in relatively rare situations in which a gene variant in IL2RG or JAK3 has been ruled out in a patient with the T-B+NK- SCID phenotype.

DIFFERENTIAL DIAGNOSIS — 

The only other T-B+NK- SCID is autosomal recessive Janus kinase 3 (JAK3) deficiency. As noted above, this can only be differentiated from X-SCID by genetic testing since the disorders are otherwise identical, other than JAK3-SCID being found in both males and females. The differential diagnosis of SCID is discussed in detail separately. (See 'Diagnosis' above and "Severe combined immunodeficiency (SCID): An overview", section on 'Differential diagnosis'.)

TREATMENT — 

Definitive therapy for X-SCID is allogeneic hematopoietic cell transplantation (HCT). Gene therapy is also an option for patients without a human leukocyte antigen (HLA) matched sibling donor, but is only available through clinical trials. HCT and gene therapy for X-SCID are discussed briefly here and in greater detail separately. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies", section on 'IL2RG and JAK3'.)

Hematopoietic cell transplantation — For full immune function to be restored with HCT, T, B, and natural killer (NK) cell engraftment must occur. If only donor T cells engraft, abnormal host B cells are still unable to make antibody, and patients will need lifelong immune globulin replacement therapy. Without any conditioning prior to HCT for X-SCID, only patients who receive HLA-matched sibling donors have a high likelihood of achieving full immunity [19,20].

In a retrospective collaborative study from US, Canadian, and European centers, patients with X-SCID who received an HLA-matched sibling were compared with those receiving a closely matched, unrelated donor without conditioning [21]. There was no significant difference in CD3 or CD4 counts at last follow-up between either cohort. However, 80 percent of the 20 evaluable patients with interleukin 2 receptor gamma (IL2RG) or Janus kinase 3 (JAK3) who received an HLA-matched sibling graft at last follow-up were off immune globulin replacement therapy. However, of 16 recipients of an unrelated donor transplant, only 25 percent were off immune globulin replacement therapy. In addition, graft-versus-host disease (GVHD) was significantly higher in the unrelated donor recipient cohort. Thus, when alternative donors such as haplocompatible (half-matched) related or unrelated donors (including cord blood) are used, some degree of myeloablative conditioning is needed to increase the chances of reconstituting B and NK cell immunity. (See "Immune globulin therapy in inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies", section on 'IL2RG and JAK3'.)

In a retrospective analysis by the Primary Immune Deficiency Treatment Consortium (PIDTC) of 662 patients with SCID who received an allogeneic HCT between 1982 and 2012 in the United States and Canada, the overall survival for the entire cohort was 71 percent, with recipients of HLA-matched sibling grafts having the best outcome of >95 percent survival at 10 years posttreatment. No significant differences in survival were found among the different types of alternative donors. Genotype was a significant factor in outcome when alternative donors were used. Patients who had either IL2RG or JAK3 pathogenic variants had the best overall survival of approximately 80 percent at 10 years. In terms of immune reconstitution, post-alternative donor allogeneic HCT X-SCID and JAK3-SCID recipients had the highest rate of T cell reconstitution at two to five years posttransplant, but these patients had the lowest rate of B cell reconstitution (becoming able to stop immune globulin replacement therapy) compared with some other genotypes (eg, IL7R, CD3 receptors, CD45, or adenosine deaminase [ADA] SCID) [20].

Gene therapy — Experimental autologous gene replacement therapy for X-SCID has been investigated since the late 1990s. Gene therapy represents an approach that avoids having to settle for an imperfect (alternative) donor and risking GVHD or rejection. The strategy consists of removing hematopoietic stem cells (HSCs) from the affected individual, correcting them by inserting a normal copy of complementary DNA (cDNA) or the defective gene of interest, and transplanting back into the patient the autologous corrected cells. When delivered into HSCs using a retroviral vector (either a gamma-retrovirus or a lentivirus), the correct gene sequence becomes permanently integrated into the chromosomal deoxyribonucleic acid (DNA), preserved in the genome of future cells as they divide. (See "Overview of gene therapy for inborn errors of immunity" and "Overview of gene therapy, gene editing, and gene silencing".)

Approximately 70 patients with X-SCID have been treated with gene therapy in the US and Europe since the late 1990s [22]. The initial studies in England and France treated 21 patients using a gamma-retroviral vector (first generation) containing the complementary DNA (cDNA) sequence of the IL2RG gene. Of the 20 patients who were reconstituted by this treatment, five developed leukemia from insertional mutagenesis of the vector that activated a neighboring oncogene (LMO2). One patient died of the leukemia, but the other four were cured of their leukemia following an allogeneic HCT [22]. A sixth patient developed insertional mutagenesis subsequent to this publication, increasing the incidence to 30 percent [23]. The results since then, using a second-generation self-inactivating gamma-retroviral vector, have shown stably corrected T cell immunity without any leukemia thus far, with approximately 10 years of follow-up [24]. In these early studies, the large majority of patients failed to reconstitute B cell immunity and have remained on immune globulin replacement therapy. (See "Immune globulin therapy in inborn errors of immunity".)

A third-generation lentiviral vector containing the IL2RG cDNA was first studied for the treatment of older patients with X-SCID who had failed a prior allogeneic haplocompatible transplant [25]. This vector has subsequently been used to treat newly diagnosed infants with X-SCID [26]. The trial in older patients incorporated nonmyeloablative conditioning with low-dose busulfan that was 40 to 50 percent of the myeloablative dose used in allogeneic transplantation. In the initial report, five patients were treated, and all showed multilineage (T, B, NK, and myeloid cell) gene transduction and T cell immune reconstitution [27]. Seven of the eight patients treated thus far survived with gene-transduced T, B, NK, and myeloid cells. Those furthest from treatment were able to stop immune globulin replacement therapy. The patient who died had severe chronic lung disease pre-gene therapy that progressed despite immune reconstitution. There are ongoing studies of gene therapy for patients with newly diagnosed X-SCID using targeted low-dose exposure busulfan comparable with that being used for ADA-SCID gene therapy. In one of these studies, T and NK cell numbers normalized within three to four months of infusion in seven of eight patients, and T cell numbers normalized in the final patient after a boost of gene-corrected cells; preexisting infections cleared; and growth was normal during a median follow-up of 16.4 months [26]. Four patients were able to discontinue immune globulin replacement, and three of these four had responded to vaccines at the time of publication. The primary side effects noted were transient neutropenia and thrombocytopenia due to busulfan. Two patients developed mild mucositis. There has been no evidence of insertional mutagenesis. Longer-term follow-up is still necessary to determine the extent to which T, B, and NK cell immunity is restored and to monitor patients for the risk of insertional mutagenesis.

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

●Newborn screening and presentation – X-linked severe combined immunodeficiency (X-SCID, or SCID-X1; MIM #300400) is the most common form of SCID. Patients not diagnosed by newborn screening (NBS) usually present in the first few months of life with recurrent severe infections, chronic diarrhea, and failure to thrive. With NBS for SCID, the large majority of patients are two to three weeks of age at diagnosis and are asymptomatic. (See 'Introduction' above and 'Epidemiology' above and 'Clinical presentation' above.)

●Pathogenesis – X-SCID is due to defects in the common gamma chain (gamma-c; interleukin 2 receptor gamma [IL2RG]). (See 'Pathogenesis' above.)

●Laboratory findings – Peripheral T and natural killer (NK) cells are very low to absent, and immunoglobulins are also very low to absent despite normal B cell numbers (table 1). (See 'Laboratory abnormalities' above.)

●Confirmation of diagnosis – The diagnosis is confirmed by identifying a heterozygous pathogenic variant in the IL2RG gene. (See 'Diagnosis' above.)

●Treatment – Allogeneic hematopoietic cell transplantation (HCT) is curative in the majority of patients receiving a human leukocyte antigen (HLA) matched sibling donor. Patients who receive HCT from alternative donors have T cell immune reconstitution with less frequent B cell reconstitution but good survival rates. Results of experimental autologous gene therapy with low-dose chemotherapy are promising, but long-term results are lacking in the published literature. (See "Overview of gene therapy for inborn errors of immunity" and 'Treatment' above and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD and Ewelina Mamcarz, MD, who contributed to earlier versions of this topic review.