DiagnosisNewborn ScreeningIn 2010 the US Department of Health and Human Services recommended adding severe combined immunodeficiency (SCID) to the nationally reviewed uniform panel of conditions subject to newborn screening. Universal newborn screening for SCID is now available in many states: at least 34 states have already implemented or agreed to move forward with screening. Screening is performed by assaying for T-cell receptor excision circles (TRECs), a byproduct of thymocyte antigen receptor gene rearrangement [Puck 2012]. Low TREC detection from DNA extracted from the Guthrie blood spot indicates possible lymphopenia [Chan & Puck 2005, Baker et al 2009, Chase et al 2010]. High false positive rates for low TRECs have been observed in premature infants (<37 weeks adjusted gestational age); not all states are retesting in this setting.In Wisconsin a five-year study screening more than 200,000 newborns found a false positive rate of 0.018%; specificity was 99.98%. Seventy-two infants had low TREC values (T-cell lymphopenia) from non-SCID conditions; five infants with autosomal recessive SCID were diagnosed [Verbsky et al 2012]. In the first year of screening in California, six infants were diagnosed with SCID, including two males with X-SCID [Puck 2012]. Newborn screening laboratories contact primary care physicians with positive (low) TREC results prompting further flow cytometric testing to assay for T cell lymphopenia and confirmatory molecular genetic testing as indicated. Educational materials from the Immune Deficiency Foundation Web site are available for families receiving an abnormal screen.Clinical DiagnosisThe term severe combined immunodeficiency (SCID) refers to a clinical syndrome that involves combined cellular and humoral immunodeficiency resulting from lack of or significant dysfunction of T lymphocytes and B lymphocytes. SCID typically presents clinically as recurrent or persistent infections that are severe, that do not respond to ordinary treatment, that are caused by opportunistic pathogens, and/or that cause failure to thrive [Puck 1999, Belmont & Puck 2001, Griffith et al 2009]. X-linked SCID (X-SCID) is the most common form of SCID affecting male infants. Concern for non-X-linked forms of SCID should be raised for female infants who manifest SCID-type symptoms, and for any infant who has physical features of a syndrome associated with SCID-type immunodeficiencies including DiGeorge syndrome, CHARGE syndrome, or microcephaly (see Differential Diagnosis). The primary care physician’s role in the diagnosis of SCID is early identification and rapid referral to an immune deficiency expert.TestingThe definitive diagnosis of X-SCID is now made by molecular genetic testing (see Table 2). Other supportive criteria for diagnosis of X-SCID include negative HIV viral load testing (RNA/DNA assay) and any criteria below: Marked lymphocytopenia (<3400 cells/mm³ for 0-3 months) and/or T cell (CD3+) lymphopenia (<1500 cells/mm³)Severe defect in T cell proliferation to the mitogen PHA (<10% of the lower limit of the reference/normal response)Marked decrease in thymic function: decreased or absent CD4+CD45RA+ naïve T cells or TRECsLymphocyte count. The absolute lymphocyte count compared to age-matched normal infants is usually low (see Table 1) [Buckley et al 1997, Myers et al 2002, Shearer et al 2003].The number of T cells is usually very low.B cells are generally present, but dysfunctional.NK cells are low in number or absent.Typical X-SCID is designated T^–B⁺NK^–.Table 1. Lymphocyte Counts in Infants with X-linked Severe Combined ImmunodeficiencyView in own windowCell TypeLymphocyte CountsControl ValuesAverageRange% of Affected IndividualsAverageRangeTotal lymphocytes<2,00070%5,400 ^{13,400-7,600 1 5,500 2>2,000 2 T cells2000-80090%-95%3,680 12,500-5,500 1B cells1,30044 - >3,000 395%730 1300-2,000 1NK cells<10088%420 1170-1,100 1Adapted from Conley et al [1990], Stephan et al [1993], Buckley et al [1997], Buckley et al [1999], Puck [1999], and unpublished data. See also Conley & Stiehm [1996]. 1. 0-3 months [Buckley 2012] 2. Cord blood [Altman 1961]3. Two individuals with low B cells (44 and 50 cells/μL) were considered to have X-SCID based on family history [Stephan et al 1993].Lymphocyte functional testsAntibody responses to vaccines and infectious agents are absent.T-cell responses to mitogens and/or anti-CD3 are lacking.Immunoglobulin concentrationsSerum concentrations of IgA and IgM are low.Serum concentration of IgG is generally normal at birth, but declines as maternally transferred IgG disappears by age three months.Thymus. The thymic shadow is absent on chest radiogram.Molecular Genetic TestingGene. IL2RG is the only gene in which mutations are known to cause X-SCID. Clinical testingTable 2. Summary of Molecular Genetic Testing Used in X-Linked Severe Combined ImmunodeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test Availability Affected Males 2Carrier FemalesIL2RGSequence analysisSequence variants 3~99%UnknownClinical Exonic and whole-gene deletions0% 4Deletion / duplication testing 5Exonic and whole-gene deletionsSee footnote 6Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Proportion of affected individuals with a mutation(s) as classified by test method [Noguchi et al 1993, Puck et al 1993, Puck 1996, Puck et al 1997a, Puck et al 1997b] 3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. Sequence analysis cannot detect exonic or whole-gene deletions on the X chromosome in carrier (heterozygous) females.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Deletion/duplication analysis can be used to confirm a putative exonic/whole-gene deletion in males after failure to amplify by PCR in the sequence analysis.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. In a male with supportive criteria for X-SCID (negative HIV viral load testing and any of the following: marked lymphocytopenia, severe defect in T cell proliferation, and/or marked decrease in thymic function), molecular genetic testing of IL2RG is warranted.Molecular genetic testing can be performed as either of the following:Single gene testing in which sequence analysis of IL2RG is performed; if no mutation is identified, deletion/duplication analysis of IL2RG is performed next;Multi-gene panel testing, using a panel that includes IL2RG and a range of other genes in which mutation causes a similar phenotype. See Differential Diagnosis. Carrier testing for at-risk female relatives. Carriers are heterozygotes for this X-linked disorder and are asymptomatic. For at-risk females:Testing for known family-specific IL2RG mutations is the optimal approach for carrier testing.If testing for a known family-specific mutation is not possible: Sequence analysis of the IL2RG coding region and splice regions may be used to identify carriers of IL2RG mutations. Note: Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.If sequence analysis is uninformative, deletion testing may be used to detect exonic or whole-gene deletions and complex rearrangements.If sequence analysis and/or deletion testing are not an option for carrier testing or are not informative, X-chromosome inactivation studies performed on lymphocytes may help to assess carrier risk.
Note: Skewed X-chromosome inactivation secondary to presence of an IL2RG mutation occurs only in lymphocytes; X-chromosome inactivation, even in the presence of an IL2RG mutation, is random in neutrophils and other tissue types [Puck et al 1987, Conley et al 1988, Wengler et al 1993]. Moreover, some females have skewed X-chromosome inactivation by chance. Thus, in order to be valid, X-chromosome inactivation testing to identify carriers of X-SCID must reveal both skewed X-chromosome inactivation in lymphocytes and non-skewed X-chromosome inactivation in another blood lineage (e.g., granulocytes).Prenatal diagnosis/preimplantation genetic diagnosis (PGD) for at-risk pregnancies using molecular genetic testing requires prior identification of the disease-causing mutation in the family. When the family-specific mutation is not known, some centers consider analyzing a fetal blood sample for lymphoctyopenia, low numbers of T cells, and poor T-cell blastogenic responses to mitogens. Genetically Related (Allelic) DisordersThe only phenotypes associated with mutations in IL2RG are X-SCID and atypical X-SCID.}

Natural HistoryTypical X-linked SCID (X-SCID). Affected males appear normal at birth. As transplacentally transferred maternal serum antibody concentrations decline, infants with X-SCID are increasingly prone to infection. Most infants come to medical attention between age three and six months; however, presentation with life-threatening infection prior to three months is not uncommon. Infections that initially appear ordinary such as oral thrush, otitis media, respiratory viral infections (e.g., RSV, parainfluenza 3, adenovirus, influenza), and gastrointestinal diseases resulting in diarrhea may only cause concern when they do not respond to usual medical management.Nearly universal features during the first year of life are failure to thrive, oral/diaper candidiasis, absent tonsils and lymph nodes, recurrent infections, infections with opportunistic organisms such as Pneumocystis, and persistence of infections. Additional common features include rashes, diarrhea, cough and congestion, fevers, pneumonia, sepsis, and other severe bacterial infections.Less common features include the following:Disseminated infections (salmonella, varicella, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, BCG, and vaccine strain [live] polio virus)Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition that causes graft-vs-host disease (GVHD) characterized by erythematous skin rashes, hepatomegaly, and lymphadenopathy [Denianke et al 2001]Recurrent bacterial meningitisAtypical X-SCID. Individuals with mutations that result in production of a small amount of gene product or a protein with residual activity are less frequently seen. These individuals may have an atypical disease characterized as T⁺B⁺NK^– (in contrast to typical X-SCID, which is designated T^–B⁺NK^–).These individuals may have immune dysregulation and autoimmunity associated with rashes, splenomegaly, gastrointestinal malabsorption and/or short stature [DiSanto et al 1994, Schmalstieg et al 1995, Morelon et al 1996, Stephan et al 1996].

Genotype-Phenotype CorrelationsMost mutations causing typical X-SCID are functionally null. Individuals with rare missense or regulatory mutations may have atypical X-SCID.

Differential DiagnosisSevere combined immunodeficiency (SCID) can be classified by the nature of T, B, and NK lymphocyte numbers and function (Table 3) [Puck 2012]. Presence of each subclass of lymphocytes in most individuals of each genotype is indicated by (+); absence by (–). X-SCID is the most common form of SCID. The clinical presentation of X-SCID, JAK3-SCID, and IL7RA-SCID is identical. In X-SCID, only males are affected; in JAK3- and IL7R1-SCID, both males and females are affected.Severe combined immune deficiency multi-gene panels may include testing for a number of the genes associated with disorders discussed below. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.Table 3. Types of Severe Combined Immunodeficiency (SCID)View in own windowDisease NameGene SymbolLymphocyte PhenotypeInheritanceCommentsT B NK X-SCIDIL2RG –+–XLRMajority of individuals with SCIDJAK3-SCIDJAK3 AR IL7R-SCIDIL7R–++AR CD45 deficiencyPTPRC (previously CD45) –+–AR ADA deficiencyADA –––ARDelayed SCID if ADA deficiency is partialRAG-deficient SCIDRAG1 ––+AR“Leaky SCID” ¹ when alleles are hypomorphicRAG2 ––+SCID AthabascanDCLRE1C (previously ARTEMIS) ––+ARAthabascan-speaking Native Americans (Navajo, Apache, and others) (10% carrier rate); also other ethnicitiesTCR deficiencyTRD, CD3E, CD247-/Low++ARRareLck deficiencyLCK-/Low++ARRarePNP deficiencyPNPLowLow+/LowARRareLIG4 deficiencyLIG4-++ARRareDNAPKCS deficiencyPRKDC--+ARRareNHEJ deficiencyNHEJ1 --+ARRareAK2 deficiencyAK2---ARRareFOXN1 deficiencyFOXN1-/Low++ARRareSTAT5a deficiencySTAT5A-/Low++ARRareCORO1a deficiencyCORO1A-/Low+/-+/-ARRareZAP-70 deficiencyZAP70+++/lowARRareOrai1 deficiencyORAI1+++ARRareStim1 deficiencySTIM1+++ARRareXLR = X-linked recessive AR = autosomal recessive1. See following: Newborn screening, Leaky SCID.Newborn screening results can show low or absent TRECs and clinically significant T lymphocytopenia (<1500 T cells/μL) in numerous conditions (adapted from criteria from Puck 2012):Typical SCID. <300 autologous T cells/μL and <10% of normal proliferation to the mitogen PHALeaky SCID. 300 to 1500 autologous T cells/μL and impaired but not absent (10%-30% of normal) proliferation to the mitogen PHA caused by incomplete (hypomorphic) mutation(s) in a typical SCID-related geneVariant SCID. No defect in a known SCID-related gene and 300 to 1500 autologous T cells/μL with impaired functionSyndromes with variably affected cellular immunity that may be severe, including complete DiGeorge syndrome, CHARGE syndrome, Jacobsen syndrome, RAC2-dominant interfering mutation, DOCK8-deficient hyper IgE syndrome, or cartilage-hair hypoplasiaOther X-linked immunodeficiencies include X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome, X-linked lymphoproliferative disease, NEMO (X-linked ectodermal dysplasia with varying immunodeficiency) (see Incontinentia Pigmenti), IPEX (autoimmunity, polyendocrinopathy, enteropathy), chronic granulomatous disease (CGD), and properdin deficiency.Whole-exome or genome sequencing. When no mutation is identified in an individual with a SCID phenotype after molecular genetic testing of a range of likely genes (either by tiered testing or use of a multi-gene panel), a genome-based approach (e.g., whole-exome sequencing) may be appropriate. These tests should not delay bone marrow transplantation in the presence of diagnostic clinical findings. Human immunodeficiency virus (HIV). Infants with HIV may also have recurrent and opportunistic infections and failure to thrive. They have evidence of HIV virus by p24 antigen testing or PCR testing. In contrast to T cells in SCID, T cells in HIV are generally present although absolute T cell numbers can be markedly reduced in some patients.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with X-linked severe combined immunodeficiency (X-SCID), the following evaluations are recommended: History, including family history, growth and development, localized and generalized infectious processes, such as diarrhea, failure to thrive, pneumonia, sepsis, viral and fungal infectionsCBC and differential count to document absolute lymphocyte count, if not performed in the diagnostic work up Flow cytometric determination of T-cell, B-cell, NK-cell numbers, if not performed in the diagnostic work up In vitro mitogenesis assay of mononuclear cells stimulated with mitogens (PHA, ConA, PWM) and soluble antigens (Candida antigen, tetanus toxoid). Rarely mutations in the TCR pathway can alter the ability to proliferate after stimulation, despite normal numbers of T lymphocytes.Consultation with an specialist in immunodeficiencies Medical genetics consultationTreatment of ManifestationsThe current goals of treatment include prophylaxis for infections and preemptive bone marrow transplant (BMT) prior to the development of symptoms (see Prevention of Primary Manifestations).Diagnosis of X-SCID demands emergent treatment to provide a functional immune system.Interim management includes treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii) and, in most cases, fungal infections.Prevention of Primary ManifestationsBone marrow transplantation (BMT). Prompt immune reconstitution is required for survival of children with X-SCID [Myers et al 2002]. BMT was first successful in 1968 and remains the standard means of immune reconstitution. The general experience is that genotypically HLA-identical marrow transplantation restores T cell immunity in more than 90% of unconditioned patients with SCID, although B cell reconstitution occurs in only a limited subset of these patients [O’Reilly et al 1989, Buckley et al 1999].Although many centers have expertise in performing bone marrow transplantation in individuals with malignancy, the special issues arising in bone marrow transplantation for X-SCID require involvement of immunodeficiency specialists for an optimal outcome. Conditioning regimens that do not employ agents at doses resulting in long-lasting marrow aplasia are referred to as reduced-intensity conditioning (RIC) regimens. Patients with SCID have no immune system capable of rejecting the graft and, therefore, do not typically require fully ablative conditioning.HLA-matched bone marrow transplantation from a relative is preferred; however, most individuals lack a matched, related donor.For infants who do not have a matched, related donor, haploidentical parental bone marrow that has been depleted of mature T cells can be used [Buckley et al 1999]. In this technique, the bone marrow is depleted of T cells in order to remove mismatched T cells, which would react against the baby's tissues and cause graft versus host disease (GVHD).Matched, unrelated donor transplantation of bone marrow, peripherally harvested, or cord blood hematopoietic stem cells in association with RIC regimens is now being used at specialized transplantation centers, although GVHD can be a significant problem in some patients.Mismatched T cells can react against the baby's tissues and cause GVHD. Cord blood from normal infants is now being banked; frozen cells can be thawed and used as in other unrelated donor transplants.The best timing for BMT is immediately after birth because young infants are less likely than older infants to have had serious infections or failure to thrive. Younger infants also have more rapid engraftment, fewer post-transplantation infections, less GVHD, and shorter hospitalizations than those in whom BMT is delayed [Kane et al 2001, Myers et al 2002]. The optimal age and RIC regimen in young infants, however, remain to be determined. Complications following BMT in some individuals include GVHD, failure to make adequate antibodies requiring long-term immunoglobulin replacement, late loss of T cells presumably due to failure to engraft hematopoietic stem cells, chronic warts, and lymphocyte dysregulation.Administration of immunoglobulin. Long-term periodic administration of immunoglobulin may be required in those who fail to develop allogeneic, functional B lymphocytes.Gene therapy. Gene therapy performed using autologous bone marrow stem/progenitor cells transduced with gamma-retroviral vectors expressing a therapeutic gene has been successful in partially reconstituting the immune systems of young infants with X-SCID [Hacein-Bey-Abina et al 2002 (reviewed in Fischer et al 2011)].Two older adolescents did not experience immune reconstitution following attempted gene transfer therapy with a gammaretroviral vector [Thrasher et al 2005]. Five of 20 infants who received retroviral gene therapy developed leukemia due to insertional activation of cellular growth regulatory genes [Howe et al 2008, Hacein-Bey-Abina et al 2010, Deichmann et al 2011]. Although the leukemias were successfully treated with chemotherapy in all but one of the children, gammaretroviral gene therapy is currently only considered for patients who are not candidates for BMT or have failed BMT. See also Therapies Under Investigation.SurveillanceAfter successful bone marrow transplantation, routine evaluation of affected boys every six to 12 months is appropriate to monitor donor cell engraftment, growth, immune and lung function, and gastrointestinal and dermatologic issues.Agents/Circumstances to AvoidThe following should be avoided:Live vaccines. All immunizations should be deferred until after restoration of immunocompetence.Transfusion of non-irradiated blood products. Only CMV-negative, irradiated (1500 to 5000 RADS) blood products should be used.Breast-feeding and breast milk, until maternal CMV status is established by CMV DNA PCR testing of a blood sample. If such testing is negative, breast milk is safe for feeding. If such testing is positive, breast milk can be tested for the presence of the virus. Evaluation of Relatives at RiskIn one study, most couples at risk of having an affected male desired prenatal testing to help prepare for optimal treatment of an affected newborn: bone marrow transplantation centers were chosen, HLA testing of family members and the prenatal sample was carried out, and a search for a marrow donor could be initiated [Puck et al 1997a].See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSecond generation gene replacement strategies based on self-inactivating gamma-retroviral and lentiviral vectors are in early clinical development (see ClinicalTrials.gov), and similar strategies based on self-inactivating foamy viral vectors are in pre-clinical development. Thus, it is anticipated that over the next several years, gene transfer therapies with improved safety and efficacy profiles will become increasingly available. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. X-Linked Severe Combined Immunodeficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDIL2RGXq13​.1Cytokine receptor common subunit gammaIL2RG @ LOVD
CCHMC - Human Genetics Mutation Database
IL2RG @ LOVD at NCBIIL2RGData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for X-Linked Severe Combined Immunodeficiency (View All in OMIM) View in own window 300400SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED; SCIDX1 308380INTERLEUKIN 2 RECEPTOR, GAMMA; IL2RGMolecular Genetic PathogenesisIL2RG encodes the common gamma chain (γc), an essential component of the receptors for interleukins 2, 4, 7, 9, 15, and 21.Normal allelic variants. IL2RG spans 4.5 kb of genomic DNA. The coding sequence of 1,124 nucleotides is divided into eight exons (NM_000206.2). There are no common normal allelic variants.Pathologic allelic variants. More than 300 mutations have been identified spanning all eight exons of the gene. They are primarily single-nucleotide changes or changes of a few nucleotides, small insertions, deletions, and splice defects. Mutation hot spots in the IL2RG are reported [Puck 1996, Puck 1997, Puck et al 1997b]. (For more information, see Table A.)Normal gene product. The normal gene product is the common gamma chain, or gamma-c, which is a transmembrane protein in the cytokine receptor gene superfamily. It is a component of multiple cytokine receptors on the surface of lymphocytes and other hematopoietic cells, including the receptors for IL-2, -4, -7, -9, -15, and 21. Gamma-c has 389 amino acid residues (NP_000197.1).Abnormal gene product. More than two thirds of mutations result in lack of protein expression; however, nonfunctional truncated gamma-c proteins or gamma-c proteins bearing amino acid substitutions, insertions, or deletions have been described.