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X-Linked Severe Combined Immunodeficiency

Synonyms: SCID, X-Linked; SCIDX1; X-SCID

, MD, PhD, , MD, and , MD.

Author Information
, MD, PhD
University of Washington
Seattle, Washington
, MD
University of Washington
Seattle, Washington
, MD
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: January 24, 2013.

Summary

Disease characteristics. X-linked severe combined immunodeficiency (X-SCID) is a combined cellular and humoral immunodeficiency caused by mutations in IL2RG. In typical X-SCID lack of IL2RG function results in near complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes. X-SCID is almost universally fatal in the first two years of life unless reconstitution of the immune system is achieved through bone marrow transplant or gene therapy. In the absence of family history of X-SCID and prior to newborn screening for X-SCID, most males with typical X-SCID come to medical attention between ages three and six months. During the first year of life nearly all untreated males with X-SCID exhibit failure to thrive, oral/diaper candidiasis, absent tonsils and lymph nodes, recurrent infections, infections with opportunistic organisms such as Pneumocystis, and persistence of infections despite conventional treatment. Additional common features include rashes, diarrhea, cough and congestion, fevers, pneumonia, sepsis, and other severe bacterial infections. Males with atypical X-SCID may have immune dysregulation and autoimmunity associated with rashes, gastrointestinal malabsorption, and short stature.

Diagnosis/testing. In many states, testing for X-SCID is now frequently part of newborn screening. Follow-up confirmatory testing includes lymphocyte counts, lymphocyte subset enumeration by flow cytometry, and molecular genetic testing of IL2RG, the only gene in which mutations are known to cause X-SCID. Absolute lymphocyte count compared to age-matched normal infants is usually low. The number of T cells is usually very low; B cells are generally present but nonfunctional; the number of NK cells is low or absent. Sequence analysis of the IL2RG coding region detects a mutation in more than 99% of affected males.

Management. Treatment of manifestations: Immune reconstitution by bone marrow transplantation (BMT) or gene replacement therapy is required for survival; thus, diagnosis at as young an age as possible enables early immune reconstitution, and prevents complications such as the occurrence of difficult to treat infections that may compromise vital organs. In the interval between diagnosis and immune reconstitution management includes treatment of infections and use of immunoglobulin infusions and prophylactic antibiotics, particularly against Pneumocystis.

Prevention of primary manifestations: BMT using HLA-matched bone marrow from a relative is presently the preferred option; haploidentical parental bone marrow depleted of mature T cells may also be used. Matched, unrelated donor transplantation of bone marrow or cord blood stem cells can be used, but graft-versus-host disease is a significant problem. The best timing for BMT is immediately after birth. Infants undergoing transplantation in the first 3.5 months of life have a much higher rate of survival than those undergoing transplantation later. Long-term periodic administration of immunoglobulin may be required in those who fail to develop allogeneic, functional B lymphocytes. Gene therapy using autologous bone marrow stem/progenitor cells transduced retrovirally with a therapeutic gene has been successful for immune reconstitution for some individuals, but is presently only considered for those who are not candidates for BMT or have failed BMT.

Prevention of secondary complications: Defer immunizations until after restoration of immunocompetence; only use CMV-negative, irradiated blood products; avoid breast feeding to prevent CMV transmission to babies with X-SCID. Prophylaxis for PCP and bacterial infections should be started as soon as possible, and other fungal and viral prophylaxis can be considered.

Surveillance: Monitor growth, immune and lung function, and gastrointestinal and dermatologic findings every 6 to 12 months after successful BMT.

Agents/circumstances to avoid: Live vaccines; transfusion of non-irradiated blood products; breast-feeding.

Evaluation of relatives at risk: When the disease-causing mutation in the family is known, prenatal diagnosis of at-risk males allows preparation for bone marrow transplantation to be initiated before birth.

Therapies under investigation: A variety of second-generation therapeutic gene transfer vectors for X-SCID are presently under evaluation in clinical trials.

Genetic counseling. X-SCID is inherited in an X-linked manner. More than one-half of affected males have no family history of early deaths in maternal male relatives. If the mother of a proband is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will not be affected. Males with X-SCID will pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing IL2RG mutation has been identified in the family.

Diagnosis

Newborn Screening

In 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 Diagnosis

The 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.

Testing

The 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 TRECs

Lymphocyte 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 TB+NK.

Table 1. Lymphocyte Counts in Infants with X-Linked Severe Combined Immunodeficiency

Cell TypeLymphocyte CountsControl Values
AverageRange% of Affected IndividualsAverageRange
Total 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 1
B cells1,30044 - >3,000 395%730 1300-2,000 1
NK cells<10088%420 1170-1,100 1

Adapted 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 tests

  • Antibody responses to vaccines and infectious agents are absent.
  • T-cell responses to mitogens and/or anti-CD3 are lacking.

Immunoglobulin concentrations

  • Serum 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 Testing

Gene. IL2RG is the only gene in which mutations are known to cause X-SCID.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in X-Linked Severe Combined Immunodeficiency

Gene Symbol 1Test Method 2Mutations DetectedMutation Detection Frequency by Test Method 3
Affected Males 4Carrier Females
IL2RGSequence analysisSequence variants 5~99%Unknown
Exonic and whole-gene deletions0% 6
Deletion / duplication testing 7Exonic and whole-gene deletionsSee footnote 8Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. 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]

5. 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. For issues to consider in interpretation of sequence analysis results, click here.

6. Sequence analysis cannot detect exonic or whole-gene deletions on the X chromosome in carrier (heterozygous) females.

7. 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.

8. 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.

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:

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.

Clinical Description

Natural History

Typical 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 meningitis

Atypical 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 TB+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 Correlations

Most mutations causing typical X-SCID are functionally null.

Individuals with rare missense or regulatory mutations may have atypical X-SCID.

Nomenclature

Before the T-cell defect in X-SCID was recognized, X-SCID was included in the designation "Swiss-type agammaglobulinemia." This term is no longer used.

Prevalence

The incidence of X-SCID is unknown; it is estimated to be at least 1:50,000-100,000 births.

Individuals from all ethnic groups are affected in equal frequency. Because of population structure, X-SCID may account for a larger proportion of individuals with all types of SCID in the United States than in Europe.

Differential Diagnosis

Severe 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)

Disease NameGene SymbolLymphocyte PhenotypeInheritanceComments
T B NK
X-SCIDIL2RG +XLRMajority of individuals with SCID
JAK3-SCIDJAK3 AR
IL7R-SCIDIL7R++AR
CD45 deficiencyPTPRC (previously CD45) +AR
ADA deficiencyADA ARDelayed SCID if ADA deficiency is partial
RAG-deficient SCIDRAG1 +AR“Leaky SCID” 1 when alleles are hypomorphic
RAG2 +
SCID AthabascanDCLRE1C (previously ARTEMIS) +ARAthabascan-speaking Native Americans (Navajo, Apache, and others) (10% carrier rate); also other ethnicities
TCR deficiencyTRD, CD3E, CD247-/Low++ARRare
Lck deficiencyLCK-/Low++ARRare
PNP deficiencyPNPLowLow+/LowARRare
LIG4 deficiencyLIG4-++ARRare
DNAPKCS deficiencyPRKDC--+ARRare
NHEJ deficiencyNHEJ1 --+ARRare
AK2 deficiencyAK2---ARRare
FOXN1 deficiencyFOXN1-/Low++ARRare
STAT5a deficiencySTAT5A-/Low++ARRare
CORO1a deficiencyCORO1A-/Low+/-+/-ARRare
ZAP-70 deficiencyZAP70+++/lowARRare
Orai1 deficiencyORAI1+++ARRare
Stim1 deficiencySTIM1+++ARRare

XLR = X-linked recessive

AR = autosomal recessive

1. 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 PHA
  • Leaky 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 gene
  • Variant SCID. No defect in a known SCID-related gene and 300 to 1500 autologous T cells/μL with impaired function
  • Syndromes 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 hypoplasia

Other 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 infections
  • CBC 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 consultation

Treatment of Manifestations

The 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 Manifestations

Bone 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.

Surveillance

After 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 Avoid

The 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 Risk

In 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 Investigation

Second 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked severe combined immunodeficiency (X-SCID) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Molecular genetic testing can often determine the family member in whom the mutation initially arose. Determining the family member in whom a de novo mutation arose is important for determining which branches of the family are at risk for X-SCID.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will not be affected.
  • Germline mosaicism has been demonstrated in this condition [O'Marcaigh et al 1997]. Thus, even if the disease-causing mutation has not been identified in the mother's leukocytes, the sibs are still at increased risk.

Offspring of a proband. Males with X-SCID will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of the proband. The proband's maternal female relatives may be at risk of being carriers, and their offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible. See Molecular Genetic Testing.

Related Genetic Counseling Issues

In 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].

The authors recommend that genetic counseling for X-SCID include children in age-appropriate discussions and that counselors help parents weigh benefits of early testing and disclosure versus the potential harm of loss of child autonomy given the risk of carrier status in females.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Carrier testing of minors. Carrier testing of at-risk female relatives under the age 18 years warrants consideration of specific issues, including the minor's experience (or lack of experience) with the disorder, the implications of the test results, the significance that she attributes to them, and the likelihood of her becoming a mother in the near future. The possible benefits of early testing and disclosure must be weighed against the potential harm of loss of autonomy [Fanos et al 2001, Fanos & Puck 2001]. It is important to assess the minor's ability to understand options and consequences. A minor who can project into the future and has a stable set of values with which to weigh options is the best candidate to participate in determining whether or not to undergo X-SCID carrier testing.

Prenatal Testing

Molecular genetic testing. Prenatal testing is possible for pregnancies of women who are carriers for X-SCID [Puck et al 1997a]. The usual procedure is to perform chromosome analysis for sex determination on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis at about 15 to18 weeks' gestation. If the karyotype is 46,XY and if the disease-causing IL2RG mutation has been identified in a family member, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Percutaneous umbilical blood sampling (PUBS). When the family-specific mutation is not known, fetal blood sampling is considered in some centers. Fetal blood is analyzed for lymphoctyopenia, low numbers of T cells, and poor T-cell blastogenic responses to mitogens, all of which can be definitively demonstrated in affected pregnancies by 17 weeks’ gestation; however, caution is necessary as maternal blood contamination can yield false normal results. Involvement of experienced high-risk perinatologists, genetics experts, and immunologists is advised.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Canadian Immunodeficiencies Patient Organization (CIPO)
    362 Concession Road 12
    RR #2
    Hastings Ontario K0L 1Y0
    Canada
    Phone: 877-262-2476 (toll-free)
    Fax: 866-942-7651 (toll-free)
    Email: info@cipo.ca
  • Immune Deficiency Foundation (IDF)
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204
    Phone: 800-296-4433 (toll-free)
    Email: idf@primaryimmune.org
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Firside
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
    Email: info@ipopi.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • National Human Genome Research Institute (NHGRI)
  • NCBI Genes and Disease
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org
  • Primary Immunodeficiency Diseases Registry at USIDNET
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204-4803
    Phone: 866-939-7568
    Fax: 410-321-0293
    Email: contact@usidnet.org
  • RDCRN Patient Contact Registry: Primary Immune Deficiency Treatment Consortium

Molecular Genetics

Information 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 Databases

Data 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)

300400SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED; SCIDX1
308380INTERLEUKIN 2 RECEPTOR, GAMMA; IL2RG

Molecular Genetic Pathogenesis

IL2RG 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.

References

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Suggested Reading

  1. Alter HJ, Klein HG. The hazards of blood transfusion in historical perspective. Blood. 2008;112:2617–26. [PMC free article: PMC2962447] [PubMed: 18809775]
  2. Rühl H, Bein G, Sachs UJ. Transfusion-associated graft-versus-host disease. Transfus Med Rev. 2009;23:62–71. [PubMed: 19056035]
  3. Werther RL, Crawford NW, Boniface K, Kirkwood CD, Smart JM. Rotavirus vac- cine induced diarrhea in a child with severe combined immunodeficiency. J Allergy Clin Immunol. 2009;124:600. [PubMed: 19660805]

Chapter Notes

Author History

Eric J Allenspach, MD, PhD (2013-present)
Joie Davis, APRN, BC, APNG; National Institutes of Health (2003-2013)
Jennifer M Puck, MD; National Institutes of Health (2003-2013)
David J Rawlings, MD (2013-present)
Andrew Scharenberg, MD (2013-present)

Revision History

  • 24 January 2013 (me) Comprehensive update posted live
  • 12 December 2005 (me) Comprehensive update posted to live Web site
  • 26 August 2003 (me) Review posted to live Web site
  • 23 April 2003 (jd) Original submission
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