X-Linked Severe Combined Immunodeficiency
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.
- 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].
- 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 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 T–B+NK–.
Table 1.
Lymphocyte Counts in Infants with X-Linked Severe Combined Immunodeficiency
| Cell Type | Lymphocyte Counts | % of Affected Individuals | Control Values | ||
|---|---|---|---|---|---|
| Average | Range | Average | Range | ||
| Total lymphocytes | <2,000 | 70% | 5,400 1 | 3,400-7,600 1 | |
| 5,500 2 | >2,000 2 | ||||
| T cells | 200 | 0-800 | 90%-95% 3 | 3,680 1 | 2,500-5,500 1 |
| B cells | 1,300 | 44 - >3,000 4 | 95% | 730 1 | 300-2,000 1 |
| NK cells | <100 | 88% | 420 1 | 170-1,100 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.
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 multigene 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 multigene panel that includes IL2RG and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that contains IL2RG) fails to confirm a diagnosis in an individual with features of X-SCID. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2.
Molecular Genetic Testing Used in X-Linked Severe Combined Immunodeficiency
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|---|---|
| IL2RG | Sequence analysis 3, 4 | ~99% 5, 6 |
| Gene-targeted deletion/duplication analysis 7 | ~1% 8 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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 used may 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 T–B+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)
| Disorder | Gene(s) | Lymphocyte Phenotype | MOI | Comments | ||
|---|---|---|---|---|---|---|
| T | B | NK | ||||
| X-SCID | IL2RG | – | + | – | XLR | |
| JAK3-SCID (OMIM 600802) | JAK3 | AR | ||||
| IL7R-SCID (OMIM 608971) | IL7R | – | + | + | AR | |
| CD45 deficiency (OMIM 608971) | PTPRC (previously CD45) | – | + | +/– | AR | |
| Adenosine deaminase deficiency | ADA | – | – | – | AR | Delayed SCID if ADA deficiency is partial |
| RAG-deficient SCID (OMIM 601457) | RAG1 | – | – | + | AR | "Leaky SCID" due to hypomorphic alleles 1, increasingly detected w/newborn screening 2 |
| RAG2 | – | – | + | |||
| SCID Athabaskan (OMIM 602450) | DCLRE1C | – | – | + | AR | 10% carrier rate among Athabaskan-speaking Native Americans (e.g., Navajo, Apache) |
| TCR deficiency | CD3D, CD3E, CD247 | –/Low | + | + | AR | Rare |
| DNAPKCS deficiency (OMIM 615966) | PRKDC | – | – | + | AR | Rare |
| Reticular dysgenesis (OMIM 267500) | AK2 | – | – | – | AR | Rare |
| CORO1a deficiency (OMIM 615401) | CORO1A | –/Low | +/– | +/– | AR | Rare |
AR = autosomal recessive; MOI = mode of inheritance; XLR = X-linked recessive
Molecular causes of SCID based on the International Union of Immunological Societies expert committee for primary immunodeficiency
- 1.
See following: Newborn screening – Leaky SCID.
- 2.
Kwan et al [2014]
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 variant, 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 312060).
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 in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.