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X-Linked Severe Combined Immunodeficiency

Synonyms: SCIDX1, X-Linked SCID, 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: April 14, 2016.

Summary

Clinical characteristics.

X-linked severe combined immunodeficiency (X-SCID) is a combined cellular and humoral immunodeficiency caused by a hemizygous pathogenic variant 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 with 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 testing of IL2RG, the only gene in which pathogenic variants 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; NK cells are low or absent. Sequence analysis of the IL2RG coding region detects a pathogenic variant 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 difficult-to-treat infections that may compromise vital organs. In the interval between diagnosis and immune reconstitution, management includes treatment of infections, immunoglobulin infusions and prophylactic antibiotics (particularly against Pneumocystis jirovecii), and isolation from cytomegalovirus (CMV) exposures.

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 or matched, unrelated bone marrow or cord blood stem cells can be used for transplantation as well, but each has particular conditioning and graft-versus-host disease risks to consider along with infection status. 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 retroviral transduction of autologous bone marrow stem/progenitor cells with a therapeutic gene has been successful for T-cell 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: Pneumocystis jirovecii, viral and encapsulated organism prophylaxis should be applied per transplantation protocols; IVIG prophylaxis should be considered to maintain serum IgG levels above 400mg/dL; prompt evaluation of illness should occur until the individual is immunologically competent; avoid immunizations until after restoration of immunocompetence; only use CMV-negative, irradiated blood products; avoid breast feeding and exposure to young children to prevent CMV transmission to babies with X-SCID.

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

Agents/circumstances to avoid: Live vaccines; transfusion of non-irradiated blood products; breast-feeding and breast milk; exposure to young children, sick contacts, or individuals with cold sores.

Evaluation of relatives at risk: When the pathogenic variant 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 that have removed the likely cancer-causing elements from the vectors.

Genetic counseling.

X-SCID is inherited in an X-linked manner. More than half of affected males have no family history of early deaths in maternal male relatives. If the mother of a proband is a heterozygote (carrier), the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and will not be affected. Males with X-SCID will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing of at-risk female relatives is most informative if the IL2RG pathogenic variant has been identified in an affected family member. Prenatal testing is possible for pregnancies at increased risk if the familial pathogenic variant is known.

Diagnosis

Suggestive Findings

X-linked severe combined immunodeficiency (X-SCID) should be suspected in male infants with recurrent or persistent infections that are severe, unresponsive to ordinary treatment, caused by opportunistic pathogens, or associated with failure to thrive or chronic diarrhea. Asymptomatic children with abnormal newborn screening or family history of X-SCID should be fully evaluated.

Supportive laboratory and radiographic findings

  • Low T-cell receptor excision circles (TRECs) on newborn screening
  • 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
  • Absent thymic shadow on chest radiogram
  • Decreased IL-21-induced STAT3 phosphorylation on functional testing compared to healthy controls, which indicates defective common-gamma chain function in B cells
  • Negative HIV viral load testing (RNA/DNA assay)

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 most states: thirty-four states, the District of Columbia, and the Navajo Nation have implemented screening, and seven additional states (Alabama, Georgia, Louisiana, Maryland, North Carolina, Kentucky, and Tennessee) are expected to start screening in 2016. (See SCID Newborn Screening: Current Status of Implementation Map.)

Educational materials from the Immune Deficiency Foundation website are available for families receiving an abnormal screen.

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 Counts% of Affected IndividualsControl Values
AverageRangeAverageRange
Total lymphocytes<2,00070%5,400 13,400-7,600 1
5,500 2>2,000 2
T cells2000-80090%-95% 33,680 12,500-5,500 1
B cells1,30044 - >3,000 495%730 1300-2,000 1
NK cells<10088%420 1170-1,100 1
1.

0-3 months [Buckley 2012]

2.

Cord blood [Altman 1961]

3.

Individuals with atypical X-SCID caused by Arg222Cys or rare splice site variants may have detectable T cells [Fuchs et al 2014, Okuno et al 2015].

4.

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.

Establishing the Diagnosis

The diagnosis of X-SCID is established in a proband with identification of a hemizygous pathogenic variant in IL2RG by molecular testing (see Table 2).

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of IL2RG is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes IL2RG and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • More comprehensive genomic testing (if available) including whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq) may be considered if serial single-gene testing (and/or use of a multi-gene panel that contains IL2RG) fails to confirm a diagnosis in an individual with features of X-SCID. For issues to consider in interpretation of genomic test results, click here.

Table 2.

Molecular Genetic Testing Used in X-Linked Severe Combined Immunodeficiency

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
IL2RGSequence analysis 3, 4~99% 5, 6
Gene-targeted deletion/duplication analysis 7~1% 8
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

5.

Proportion of affected individuals with a pathogenic variant(s) as classified by test method [Noguchi et al 1993, Puck et al 1993, Puck 1996, Puck et al 1997a, Puck et al 1997b]

6.

Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

8.

Deletion/duplication analysis can be used to confirm a putative exon/whole-gene deletion in males after failure to amplify by PCR in the sequence analysis. To date, five large deletions in IL2RG have been reported [Clark et al 1995, Hacein-Bey et al 1996, Niemela et al 2000, Lee et al 2011, Zhang et al 2013].

Clinical Characteristics

Clinical Description

Typical X-linked severe combined immunodeficiency (X-SCID). Affected males appear normal at birth. As transplacental transfer of 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. With more than 75% of states participating in newborn screening for SCID, a common presentation now is an asymptomatic, healthy appearing child.

Delayed diagnosis can lead to features such as 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.

Infections that initially appear ordinary such as oral thrush, otitis media, respiratory viral infections (e.g., RSV, parainfluenza, adenovirus, influenza), and gastrointestinal diseases resulting in diarrhea may cause concern only when they persist or do not respond to usual medical management.

Less common features include the following:

  • Disseminated infections (salmonella, varicella, cytomegalovirus [CMV], 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
  • In rare cases, neurologic features such as opisthotonus, infantile spasms, and hypsarrhythmia

Atypical X-SCID. Individuals with pathogenic variants 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). It is critical to perform functional testing when atypical X-SCID is suspected.

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, Fuchs et al 2014].

Additionally, rare cases of somatic reversion events resulting in a later-onset combined immunodeficiency in males inheriting a pathogenic IL2RG allele have been reported [Okuno et al 2015].

Genotype-Phenotype Correlations

Most pathogenic variants causing typical X-SCID are functionally null.

Individuals with a missense or other potentially non-loss-of-function variant may have atypical X-SCID.

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). Presence of each subclass of lymphocytes in most individuals of each genotype is indicated by (+); absence by (–). Since the implementation of newborn screening the incidence of each SCID type has become clearer; however, X-SCID remains one of the most common forms of SCID [Kwan et al 2014]. The clinical presentation of X-SCID, JAK3-SCID, and IL7R-SCID is identical. In X-SCID, only males are affected; in JAK3- and IL7R-SCID, both males and females are affected.

Table 3.

Types of Classic Severe Combined Immunodeficiency (SCID)

DisorderGene(s)Lymphocyte PhenotypeMOIComments
TBNK
X-SCIDIL2RG+XLR
JAK3-SCID (OMIM)JAK3AR
IL7R-SCID (OMIM)IL7R++AR
CD45 deficiency (OMIM)PTPRC (previously CD45)++/–AR
Adenosine deaminase deficiencyADAARDelayed SCID if ADA deficiency is partial
RAG-deficient SCID (OMIM)RAG1+AR"Leaky SCID" due to hypomorphic alleles 1, increasingly detected w/newborn screening 2
RAG2+
SCID Athabaskan (OMIM)DCLRE1C+AR10% carrier rate among Athabaskan-speaking Native Americans (e.g., Navajo, Apache)
TCR deficiencyCD3D, CD3E, CD247–/Low++ARRare
DNAPKCS deficiency (OMIM)PRKDC+ARRare
Reticular dysgenesis (OMIM)AK2ARRare
CORO1a deficiency (OMIM)CORO1A–/Low+/–+/–ARRare

Molecular causes of SCID based on the International Union of Immunological Societies expert committee for primary immunodeficiency

1.

See following: Newborn screeningLeaky SCID.

2.

Note: A growing list of rare causes of SCID-like phenotypes include pathogenic variants in the following additional genes: CD3G, CD8A, CHD7, CIITA, DOCK8, FOXN1, LCK, LIG4, MTHFD1, NBS1, NHEJ1, ORAI1, PCFT, PGM3, PNP, PRKDC, RFX-B, RFXANK, RFX5, RFXAP, RMRP, STIM1, TBX1, TTC7A, ZAP70.

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 a hypomorphic allele (partial loss of gene function) 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, such as DiGeorge syndrome, CHARGE syndrome, Jacobsen syndrome, RAC2-dominant interfering mutation, DOCK8-deficient hyper IgE syndrome, and cartilage-hair hypoplasia
  • Transient lymphopenia and abnormal TREC screening associated with prematurity (<37 weeks adjusted gestational age). Repeat testing is warranted.

Not all T-cell disorders are detected with the TREC test despite the presence of impaired immune function. For example, individuals with MHC class II deficiency still retain CD8+ T cells and ZAP70 deficiency presents with very a high CD4/CD8 ratio. These individuals can present with a SCID-like phenotype.

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 (OMIM).

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 individuals.

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, and localized and generalized infectious processes (e.g., 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, and NK-cell numbers, if not performed in the diagnostic work up
  • In vitro mitogen assay of mononuclear cells (using PHA, ConA, or PWM) and soluble antigens (Candida antigen, tetanus toxoid). Rarely, pathogenic variants in the TCR pathway can alter the ability to proliferate after stimulation in response to anti-CD3 stimulation, despite normal numbers of T lymphocytes.
  • Functional screening of STAT3 phosphorylation after IL-21 stimulation to test functionality of the common-gamma chain
  • Consultation with a specialist in immunodeficiency
  • Consultation with a clinical geneticist and/or genetic counselor

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).

  • An individual diagnosed with X-SCID requires 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.
  • Isolation from exposure to CMV (breast milk, young children, blood products) is indicated.

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 individuals with SCID, although B-cell reconstitution occurs in only a limited subset of these individuals [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. Individuals with SCID have no immune system capable of rejecting the graft and, therefore, do not typically require fully ablative conditioning; regimens that do not employ agents at doses resulting in long-lasting marrow aplasia are referred to as reduced-intensity conditioning (RIC) regimens. Additionally, protocols including alpha/beta T-cell depletion in graft preparations are now being used to improve unrelated donor graft outcomes.

  • 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, Pai et al 2014]. 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 peripherally harvested bone marrow (or less frequently cord blood hematopoietic stem cells) in association with partially myeloablative or RIC regimens is now being used at specialized transplantation centers, although GVHD can be a significant problem in some individuals.

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 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. The Primary Immune Deficiency Treatment Consortium (PIDTC) found in 25 centers over the last decade significantly better outcomes (>90% survival) in children receiving transplantation in early infancy (age <3.5 months) without prior infections even after alternative donor grafts were used [Pai et al 2014]. 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, remains to be determined. BMT after age 3.5 months and/or a history of infections resulted in a dramatic decrease in survival post transplantation.

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 after transplantation.

Gene therapy. Gene therapy has been evaluated in individuals not eligible for BMT, after failed BMT, and in individuals with only haploidentical donors. Gene therapy performed using autologous bone marrow stem/progenitor cells transduced with gamma-retroviral vectors expressing a therapeutic gene resulted in significant T-cell reconstitution in the majority of young infants with X-SCID, but only limited success in those with severe infections at the time of transplantation [reviewed in Fischer et al 2011, Hacein-Bey-Abina et al 2014].

  • B-cell reconstitution was less consistent with roughly half being able to discontinue gamma-globulin replacement therapy.
  • Unfortunately, between two early trials, five of 20 individuals developed leukemia-like disease requiring ALL-type therapy due to retroviral insertional activation of cellular growth regulatory genes [Howe et al 2008, Hacein-Bey-Abina et al 2010, Deichmann et al 2011]. Newer, second-generation vectors utilizing self-inactivating (SIN) gamma-retroviral vectors have shown similar efficacy in T-cell reconstitution with improved safety design, no adverse events reported in nine individuals over three years post transplantation, and significantly fewer insertions found in genes implicated in lymphoproliferation [Hacein-Bey-Abina et al 2014]. Clinical trials using an SIN-lentiviral vector in conjunction with busulfan-based partial myeloablative conditioning are underway for both infants and older individuals who have failed BMT. Initial results in a small number of older individuals have demonstrated sustained myeloid viral marking and restoration of T, B, and NK cell numbers and function [Author, personal communication].

See also Therapies Under Investigation.

Prevention of Secondary Complications

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, lymphocyte dysregulation, and rarely, malignancy. All individuals have some degree of immunodeficiency, especially during the first six to 12 months following transplantation. PJP, viral and encapsulated organism prophylaxis should be applied per transplantation protocols. IVIG prophylaxis should be considered to maintain serum IgG levels above 400mg/dL. Prompt evaluation of illness should occur until the individual is deemed immunologically competent. Individuals with primary immunodeficiency post transplantation will require bacteriophage testing off all immunosuppressive therapy to determine eligibility for re-vaccination. Only CMV-negative, irradiated blood products should be used. Avoid breast feeding and exposure to young children to prevent CMV transmission to babies with X-SCID.

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. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If such testing is negative and the mother is CMV serology negative, breast milk may rarely be considered safe for feeding. Frequent retesting of breast milk is required given the risk of primary infection in the mother. Pasteurization of breast milk remains controversial in preparation for BMT given the severe negative consequences in BMT outcomes.
  • Exposure to young children, sick contacts, or individuals with cold sores

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk male relatives of an affected individual by molecular genetic testing of the IL2RG pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

When the pathogenic variant in the family is known, prenatal diagnosis of at-risk males allows preparation for bone marrow transplantation to be initiated before birth. Most couples at risk of having an affected male have 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

The following investigations are underway:

  • Second-generation gene replacement strategies based on self-inactivating (SIN) gamma-retroviral (RV) and lentiviral (LV) vectors lacking the LTR enhancers with high insertional genotoxicity are in early clinical development (see ClinicalTrials.gov), and similar strategies based on self-inactivating foamy viral vectors are in pre-clinical development.
  • Multi-institutional Phase I/II trials using an SIN RV vector carrying the IL2Rgamma cDNA have recently completed enrollment for infants with X-SCID performed without conditioning. Using the same SIN RV vector, the NIH has enrolled older males with X-SCID who had prior transplantation but did not achieve satisfactory immune reconstitution for a clinical trial using reduced-intensity conditioning.
  • St. Jude Children's Research Hospital and Seattle Children's Hospital are enrolling infants with X-SCID and the NIH is enrolling older males who had prior transplantation in SIN LV clinical trials using low dose busulfan conditioning.
  • The PIDTC is developing a clinical trial assessing the impact of busulfan dose escalation in infants receiving marrow transplantation in classic SCID. This work may provide new information regarding optimal conditioning regimens for transplant and/or gene therapy.

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

  • The father of an affected male will not have the disorder nor will he be hemizygous for the IL2RG pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected son and the pathogenic variant cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism. Female germline mosaicism has been documented in X-SCID [O'Marcaigh et al 1997].
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo IL2RG pathogenic variant, in which case the mother is not a carrier. More than half of affected males have no family history of early deaths in maternally related affected males [Puck et al 1997b].

Sibs of a proband. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband has an IL2RG pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and will not be affected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the IL2RG pathogenic variant cannot be detected in the leukocyte DNA of the mother, the sibs are still at increased risk because of the possibility of maternal germline mosaicism. Germline mosaicism has been demonstrated in this condition [O'Marcaigh et al 1997].

Offspring of a proband. Males with X-SCID will pass the pathogenic variant to all of their daughters, who will be (heterozygotes) carriers, and to none of their sons.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the pathogenic variant, and the aunts' offspring, depending on their gender, may be at risk of being heterozygotes (carriers) for the pathogenic variant or of being affected.

Note: Molecular genetic testing can often determine the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous (carriers) for this X-linked disorder are asymptomatic. (2) Identification of female heterozygotes requires either (a) prior identification of the IL2RG pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Related Genetic Counseling Issues

See Evaluation of Relatives at Risk for information on prenatal diagnosis of at-risk males to allow preparation for bone marrow transplantation.

Family planning

  • The optimal time for determination of genetic risk, clarification of genetic status of at-risk females, 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 heterozygotes (carriers), or are at increased risk of being heterozygotes (carriers) or affected.

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, allelic variants, 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 younger than 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.

For more information, see the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Prenatal Testing

If the IL2RG pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Percutaneous umbilical blood sampling (PUBS). If the IL2RG pathogenic variant has not been identified, fetal blood sampling is considered in some centers. Fetal blood is analyzed for lymphocytopenia, 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.

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the IL2RG pathogenic variant 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
  • 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
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • 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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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

Gene structure. IL2RG spans 4.5 kb of genomic DNA. The coding sequence of 1,124 nucleotides is divided into eight exons (NM_000206.2). IL2RG encodes the common gamma chain (γc), an essential component of the receptors for interleukins 2, 4, 7, 9, 15, and 21. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 200 pathogenic variants spanning all eight exons of the gene have been identified. They are primarily single-nucleotide changes or changes of a few nucleotides, small insertions, deletions, and splice defects. Mutation hot spots in IL2RG are reported at codons p.Arg224, p.Arg226, p.Arg285, and p.Arg289 [Puck 1996, Puck 1997, Puck et al 1997b]. (For more information, see Table A.)

Table 4.

IL2RG Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.670C>Tp.Arg224TrpNM_000206​.2
c.676C>Tp.Arg226Cys
c.677G>Ap.Arg226His
c.854G>Ap.Arg285Gln
c.865C>Tp.Arg289Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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 pathogenic variants 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

Published Guidelines/Consensus Statements

  1. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 4-5-16.

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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 vaccine 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

  • 14 April 2016 (sw) Comprehensive update posted live
  • 30 July 2015 (ea/ams) Revision: STAT5a removed from Differential Diagnosis
  • 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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