X-linked severe combined immunodeficiency

X-linked severe combined immunodeficiency
Synonyms	X-SCID
Pronounce
Field
Symptoms
Complications
Onset
Duration
Types
Causes
Risks
Diagnosis
Differential diagnosis
Prevention
Treatment
Medication
Prognosis
Frequency
Deaths

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

In the absence of T cell help, B cells become defective.<ref name=Fisher>Fisher, A.,

 Gene therapy of severe combined immunodeficiencies, 
 Nature Reviews Immunology, 
 
 Vol. 2(Issue: 8),
 pp. 615–621,
 DOI: 10.1038/nri859,
 PMID: 12154380,</ref> It is an X-linked recessive inheritance trait, stemming from a mutated (abnormal) version of the IL2RG gene located on the X-chromosome. This gene encodes the interleukin receptor common gamma chain protein, which is a cytokine receptor sub-unit that is part of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.<ref>Buckley, R.H., 
 Advances in the Understanding and Treatment of Human Severe Combined Immunodeficiency, 
 Immunologic Research, 
 2000,
 Vol. 22(Issue: 2–3),
 pp. 237–251,
 DOI: 10.1385/ir:22:2-3:237,
 PMID: 11339359,</ref><ref>Puck, J.M., 
 IL2RGbase: a database of γc-chain defects causing human X-SCID, 
 Immunology Today, 
 
 Vol. 17(Issue: 11),
 pp. 507–511,
 DOI: 10.1016/0167-5699(96)30062-5,
 PMID: 8961626,</ref>

Symptoms and signs

Persons afflicted with X-SCID often have infections very early in life, before three months of age. This occurs due to the decreased amount of immunoglobulin G (IgG) levels in the infant during the three-month stage.<ref name="Vickers 2009 29–47">Peter,

 Severe Combined Immune Deficiency: Early Hospitalisation and Isolation, 
  
 Wiley, 
 2009, 
  
  
 ISBN 978-0-470-31986-4, 
  
  
  
 Pages: 29–47,</ref> This is followed by viral infections such as pneumonitis, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath.<ref name="molecular basis to clinical management">Sponzilli, Ivonne, 
 Severe Combined Immunodeficiency (SCID): from molecular basis to clinical management, 
 Acta Bio-medica: Atenei Parmensis, 
 2011,
 Vol. 82(Issue: 1),
 pp. 5–13,
 
 PMID: 22069950,</ref>  A telltale sign of X-SCID is candidiasis, a type of fungal infection caused by Candida albicans.<ref name=Diagnosis>Gennery, A.R., 
 Diagnosis of severe combined immunodeficiency, 
 Journal of Clinical Pathology, 
 2001,
 Vol. 54(Issue: 3),
 pp. 191–5,
 DOI: 10.1136/jcp.54.3.191,
 PMID: 11253129,
 PMC: 1731376,</ref> Candidiasis involves moist areas of the body such as skin, the mouth, respiratory tract, and vagina;  symptoms of oral candidiasis include difficulty in swallowing, pain on swallowing and oral lesions.  Recurrent eczema-like rashes are also a common symptom. Other common infections experienced by individuals with X-SCID include diarrhea, sepsis, and otitis media.<ref name="Vickers 2009 29–47"/> Some other common symptoms that are experienced by X-SCID patients include failure to thrive, gut problems, skin problems, and muscle hypotonia.<ref name="Vickers 2009 29–47"/>

In some patients symptoms may not appear for the first six months after birth.<ref name="Diagnosis"/> This is likely due to passive immunity received from the mother in order to protect the baby from infections until the newborn is able to make its own antibodies.<ref name="Diagnosis"/> As a result, there can be a silent period where the baby displays no symptoms of X-SCID followed by the development of frequent infections.

Genetics

X-SCID is caused by a mutation occurring in the xq13.1 locus of the X-chromosome.<ref>Buckley, Rebecca H.,

 Molecular Defects in Human Severe Combined Immunodeficiency and Approaches to Immune Reconstitution, 
 Annual Review of Immunology, 
 
 Vol. 22(Issue: 1),
 pp. 625–655,
 DOI: 10.1146/annurev.immunol.22.012703.104614,
 PMID: 15032591,</ref>  Most often, this disease affects males whose mother is a carrier (heterozygous) for the disorder. Because females have two X-chromosomes, the mother will not be affected by carrying only one abnormal X-chromosome, but any male children will have a 50% chance of being affected with the disorder by inheriting the faulty gene. Likewise, her female children will have a 50% chance of being carriers for the immunodeficiency. X-SCID can also arise through de novo mutations and can be prevented in females by X-inactivation. In X-inactivation the preferential selection of the non-mutant X chromosome during development results in the outcome that none of the mature female cells actively express the X-SCID mutation, they are immunologically unaffected and have no carrier burden. A de novo mutation is an alteration in a gene caused by the result of a mutation in a germ cell (egg or sperm) or in the fertilized egg itself, rather than having been inherited from a carrier. Since only 1/3 of all X-SCID patients have a positive family history of SCID, it is hypothesized that de novo mutations account for a significant percentage of cases.<ref>

Shwartz, R.A.. Pediatric Severe Combined Immunodeficiency(link). {{{website}}}. MedScape.

</ref> X-inactivation occurs in a completely random manner, in females, very early in embryonic development. Once an X is inactivated, it remains inactivated throughout the life of that cell and any of its daughter cells. It is important to note that X-inactivation is reversed in female germline cells, so that all new oocytes receive an active X. Regardless of which X is inactivated in her somatic cells, a female will have a 50% chance of passing on the disease to any male children.<ref name=GeneReviews/>

Pathophysiology

Interleukins are produced by lymphocytes, among other cell types, and are released in response to antigenic and non-antigenic stimuli. The gene IL2RG codes for the common gamma chain protein, which is a common subunit of the individual receptors for Interleukin 2, Interleukin 4, Interleukin 7, Interleukin 9, Interleukin 15 and Interleukin 21.<ref>Cavazzana-Calvo, Marina,

 Gene therapy for severe combined immunodeficiency: are we there yet?, 
 The Journal of Clinical Investigation, 
 
 Vol. 117(Issue: 6),
 pp. 1456–65,
 DOI: 10.1172/jci30953,
 PMID: 17549248,
 PMC: 1878528,</ref> Signalling from these receptors normally promotes growth and differentiation of T-cells, B cells, natural killer cells, glial cells, and cells of the monocyte lineage, depending on the cell type and receptor activated.<ref name="Spolski 57–79">Spolski, Rosanne, 
 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity*, 
 Annual Review of Immunology, 
 
 Vol. 26(Issue: 1),
 pp. 57–79,
 DOI: 10.1146/annurev.immunol.26.021607.090316,
 PMID: 17953510,
 
 
 Full text,</ref> The most important receptors for X-SCID are those for Interleukin 2, Interleukin 4, Interleukin 7, and Interleukin 15. Specifically, Interleukin 2 and Interleukin 7 are responsible for T-cell proliferation and survival.<ref name="Leonard Cytokines">Leonard, Warren J., 
 Cytokines and immunodeficiency diseases, 
 Nature Reviews Immunology, 
 
 Vol. 1(Issue: 3),
 pp. 200–8,
 DOI: 10.1038/35105066,
 PMID: 11905829,
 
 
 Full text,</ref> Likewise, the action of Interleukin 4 and Interleukin 15 will lead to proliferation and differentiation of B-cells into antibody secreting plasma cells.<ref name="Leonard Cytokines"/> Lastly, Interleukin 15 helps generate developed and matured natural killer cells.<ref name="molecular basis to clinical management" />

The gene that encodes the common gamma chain in these interleukin receptors is mutated in X-SCID. The mutation leads to an absent or abnormally functioning common gamma chain. The mutation can occur through large, or even single nucleotide, deletions in the IL2RG gene, that disable the common gamma chain so that it is unable to bind with other receptor subunits and signal cytokine activation.<ref name="Spolski 57–79"/> Normally, when the interleukin binds to the trimeric receptor protein containing the alpha, beta, and gamma subunits, the common gamma subunit activates Janus Kinase 3 (JAK3), which leads to the phosphorylation of Signal Transducer and Activator of Transcription 5, STAT5. The STAT5 proteins dimerize and translocate to the nucleus, controlling subsequent downstream signalling.<ref name=Fisher/> Due to the fact that the common gamma chain is absent or abnormal, this downstream pathway is inhibited. This change prevents the T-lymphocytes from signaling other cells, like B-lymphocytes and natural killer cells. Because these cells never receive these signals, they can never mature and differentiate into full grown immune cells.

Diagnosis

Diagnosis of X-SCID is possible through lymphocyte cell counts, lymphocyte function tests, and genetic testing. A healthy immune system should contain large amounts of lymphocytes, but individuals with X-SCID will contain unusually small amounts of T-cells, non-functional B-cells, and some natural killer cells.<ref name=GeneReviews> </ref>

Cell type	Normal lymphocyte count average (range)	X-SCID count average (range)
T-cells	3,680 (2,500–5,500)	200 (0-800)
B-cells	730 (300–2,000)	1,300 (44 - >3,000)
NK cells	420 (170–1,100)	<100
Total	0–3 months: 5,400 (3,400–7,300)	<2,000

<ref name=GeneReviews/>

Individuals with X-SCID often have decreased lymphocyte function. This can be tested through the introduction of agents to the immune system; the reaction of the lymphocytes is then observed. In X-SCID, Antibody responses to introduced vaccines and infections are absent, and T-cell responses to mitogens, substances that stimulate lymphocyte transformation, are deficient. IgA and IgM immunoglobulins, substances that aid in fighting off infections, are very low. ^{(March 2015)}

The absence of a thymic shadow on chest X-rays is also indicative of X-SCID.<ref name=GeneReviews/> In a normal child, a distinctive sailboat shaped shadow near the heart can be seen.<ref name="Diagnosis"/> The thymus gland in normal patients will gradually decrease in size because the need for the thymus gland diminishes. The decrease in the size of the thymus gland occurs because the body already has a sufficient number of developed T-cells.<ref name=EndocrineWeb> Rehan, Kelly M.. An Overview of the Thymus: The Gland that Protects You Long after It's Gone(link). {{{website}}}.

</ref> However, a patient with X-SCID will be born with an abnormally small thymus gland at birth.<ref name=GeneReviews/> This indicates that the function of thymus gland, of forming developed T-cells, has been impaired.

Since the mutation in X-SCID is X-linked, there are genetic tests for detecting carriers in X-SCID pedigrees. One method is to look for family-specific IL2RG mutations. Finally, if none of those options are available, there is an unusual pattern of nonrandom X-chromosome inactivation on lymphocytes in carriers, thus looking for such inactivation would prove useful.

If a mother is pregnant and the family has a known history of immunodeficiency, then doctors may perform diagnostic assessment in-utero. Chorionic Villus Sampling, which involves sampling of the placental tissue using a catheter inserted through the cervix, can be performed 8 to 10 weeks into gestation.<ref name=Fischer>Fischer, A.,

 Severe combined immunodeficiencies, 
 Clinical & Experimental Immunology, 
 2000,
 Vol. 122(Issue: 2),
 pp. 143–9,
 DOI: 10.1046/j.1365-2249.2000.01359.x,
 PMID: 11091267,
 PMC: 1905779,</ref>  Alternatively, Amniocentesis, which entails extracting a sample of the fluid which surrounds the fetus, can be performed 15 to 20 weeks into gestation.<ref name="Fischer"/>

Early detection of X-SCID (and other types of SCID) is also made possible through detection of T-cell recombination excision circles, or TRECs. TRECs are composed of excised DNA fragments which are generated during normal splicing of T-cell surface antigen receptors and T-cell maturation.<ref name="Trec Puck">Puck, Jennifer M.,

 Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: The winner is T-cell receptor excision circles, 
 Journal of Allergy and Clinical Immunology, 
 
 Vol. 129(Issue: 3),
 pp. 607–616,
 DOI: 10.1016/j.jaci.2012.01.032,
 PMID: 22285280,
 PMC: 3294074,</ref> This maturation process is absent across all SCID variants, as evidenced by the low counts of T-lymphocytes. The assay is performed using dried blood from a Guthrie card, from which DNA is extracted.<ref>Shearer, William T., 
 Screening for severe combined immunodeficiency in newborns, 
 Journal of Allergy and Clinical Immunology, 
 
 Vol. 129(Issue: 3),
 pp. 619–621,
 DOI: 10.1016/j.jaci.2011.12.992,
 PMID: 22277197,</ref> Quantitative PCR is then performed and the number of TRECs determined.<ref name="Verbsky 82–88">Verbsky, James W., 
 Newborn Screening for Severe Combined Immunodeficiency; The Wisconsin Experience (2008–2011), 
 Journal of Clinical Immunology, 
 
 Vol. 32(Issue: 1),
 pp. 82–88,
 DOI: 10.1007/s10875-011-9609-4,
 PMID: 22068910,</ref> Individuals who have the SCID phenotype will have TREC counts as low as <30, compared to approximately 1020 for a healthy infant.<ref>, 
 Development of population-based newborn screening for severe combined immunodeficiency, 
 Journal of Allergy and Clinical Immunology, 
 2005,
 Vol. 115(Issue: 2),
 pp. 391–8,
 DOI: 10.1016/j.jaci.2004.10.012,
 PMID: 15696101,
 
 
 Full text,</ref> A low TREC count indicates that there is insufficient development of T-cells in the thymus gland.<ref>Puck, Jennifer M., 
 Expert Commentary: Practical Issues in Newborn Screening for Severe Combined Immune Deficiency (SCID), 
 Journal of Clinical Immunology, 
 
 Vol. 32(Issue: 1),
 pp. 36–38,
 DOI: 10.1007/s10875-011-9598-3,
 PMID: 22012274,
 PMC: 4380147,</ref> This technique can predict SCID even when lymphocyte counts are within the normal range. Newborn screening of X-SCID based on TREC count in dried blood samples has recently been introduced in several states in the United States including California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin.<ref>

IDF SCID Newborn Screening Campaign(link). {{{website}}}.

</ref> In addition, pilot trials are being performed in several other states beginning in 2013.<ref> Wilkerson, Sarah. Updates from Washington – Day 2(link). {{{website}}}.

</ref>

Treatments

Treatment for X-linked SCID can be divided into two main groups, the prophylactic treatment (i.e. preventative) and curative treatment.<ref name="Fischer 2000 143–149">Fischer, A.,

 Severe Combined Immunodeficiencies (SCID), 
 Clinical & Experimental Immunology, 
 2000,
 Vol. 122(Issue: 2),
 pp. 143–9,
 DOI: 10.1046/j.1365-2249.2000.01359.x,
 PMID: 11091267,
 PMC: 1905779,</ref> The former attempts to manage the opportunistic infections common to SCID patients<ref name="Fischer 2000 143–149"/> and the latter aims at reconstituting healthy T-lymphocyte function.<ref name="Rans"/>

From the late 60s to early 70s, physicians began using "bubbles", which were plastic enclosures used to house newborns suspected to have SCIDS, immediately after birth.<ref name=Johnston>Johnston Jr., R.B.,

 The Boy in the Bubble, 
 JAMA: The Journal of the American Medical Association, 
 2006,
 Vol. 296(Issue: 4),
 pp. 453–4,
 DOI: 10.1001/jama.296.4.453,</ref>  The bubble, a form of isolation, was a sterile environment which meant the infant would avoid infections caused by common and lethal pathogens.<ref name="Johnston"/> On the other hand, prophylactic treatments used today for X-linked SCID are similar to those used to treat other primary immunodeficiencies.<ref name=Rans>Rans, T.S., 
 The evolution of gene therapy in X-linked severe combined immunodeficiency, 
 Annals of Allergy, Asthma & Immunology, 
 2009,
 Vol. 102(Issue: 5),
 pp. 357–363,
 DOI: 10.1016/S1081-1206(10)60504-2,
 PMID: 19492655,</ref>  There are three types of prophylactic treatments, namely, the use of medication, sterile environments, and intravenous immunoglobulin therapy (IVIG).<ref name="Rans"/> First, antibiotics or antivirals are administered to control opportunistic infections, such as fluconazole for candidiasis, and acyclovir to prevent herpes virus infection.<ref>, 
 Antimicrobial prophylaxis for primary immunodeficiencies, 
 Current Opinion in Allergy and Clinical Immunology, 
 2009,
 Vol. 9(Issue: 6),
 pp. 525–530,
 DOI: 10.1097/ACI.0b013e328332be33,
 PMID: 19812481,
 
 
 Full text,</ref> In addition, the patient can also undergo intravenous immunoglobulin (IVIG) supplementation.<ref name=Nolte>Nolte, M. T., 
 Intravenous immunoglobulin therapy for antibody deficiency, 
 Clinical and Experimental Immunology, 
 1979,
 Vol. 36(Issue: 2),
 pp. 237–43,
 
 PMID: 477026,
 PMC: 1537711,</ref>  Here, a catheter is inserted into the vein and a fluid, containing antibodies normally made by B-cells, is injected into the patient's body.<ref>Farrington, E., 
 Intravenous immunoglobulin, 
 Pediatric Nursing, 
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 Vol. 22(Issue: 4),
 pp. 344–7,
 
 PMID: 8852117,</ref> Antibodies, Y-shaped proteins created by plasma cells, recognize and neutralize any pathogens in the body.<ref name=Shishido>Shishido, S.N., 
 Humoral innate immune response and disease, 
 Clinical Immunology, 
 2012,
 Vol. 144(Issue: 2),
 pp. 142–158,
 DOI: 10.1016/j.clim.2012.06.002,
 PMID: 22771788,
 PMC: 3576926,</ref>  However, the IVIG is expensive, in terms of time and finance.<ref>, 
 I.V. immunoglobulin therapy for infectious diseases, 
 Drug and Therapeutics Bulletin, 
 
 Vol. 48(Issue: 5),
 pp. 57–60,
 DOI: 10.1136/dtb.2009.07.0032,
 PMID: 20447982,</ref>  Therefore, the aforementioned treatments only prevent the infections, and are by no means a cure for X-linked SCID.<ref name="Rans"/>

Bone marrow transplantation (BMT) is a standard curative procedure and results in a full immune reconstitution, if the treatment is successful.<ref name="Burg 561–571">Burg, Mirjam,

 Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency, 
 European Journal of Pediatrics, 
 
 Vol. 170(Issue: 5),
 pp. 561–571,
 DOI: 10.1007/s00431-011-1452-3,
 PMID: 21479529,
 PMC: 3078321,</ref>  Firstly, a bone marrow transplant requires a human leukocyte antigen (HLA) match between the donor and the recipient.<ref name="Buckley 1409–1411">Buckley, Rebecca H., 
 The multiple causes of human SCID, 
 Journal of Clinical Investigation, 
 
 Vol. 114(Issue: 10),
 pp. 1409–11,
 DOI: 10.1172/JCI23571,
 PMID: 15545990,
 PMC: 525750,</ref>  The HLA is distinct from person to person, which means the immune system utilizes the HLA to distinguish self from foreign cells.<ref name="Martelli 48–56">Martelli, Massimo F, 
 Transplants across human leukocyte antigen barriers, 
 Seminars in Hematology, 
 
 Vol. 39(Issue: 1),
 pp. 48–56,
 DOI: 10.1053/shem.2002.29255,
 PMID: 11799529,</ref>  Furthermore, a BMT can be allogenic or autologous, which means the donor and recipient of bone marrow can be two different people or the same person, respectively.<ref name="Buckley 1409–1411"/>  The autologous BMT involves a full HLA match, whereas, the allogenic BMT involves a full or half (haploidentical) HLA match.<ref>, 
 Recipient T-cell immune reconstitution in X-linked SCID after haploidentical maternal bone marrow transplant, 
 Ann. N. Y. Acad. Sci., 
 
 Vol. 770(Issue: 1),
 pp. 376–7,
 DOI: 10.1111/j.1749-6632.1995.tb31074.x,
 PMID: 8597380,</ref>  Particularly, in the allogenic BMT the chances of graft-versus-host-disease occurring is high if the match of the donor and recipient is not close enough.<ref name="Martelli 48–56"/>  In this case, the T-cells in the donor bone marrow attack the patient's body because the body is foreign to this graft.<ref name="Kohn 477–488">Kohn, Donald B., 
 Occurrence of leukaemia following gene therapy of X-linked SCID, 
 Nature Reviews Cancer, 
 
 Vol. 3(Issue: 7),
 pp. 477–488,
 DOI: 10.1038/nrc1122,
 PMID: 12835668,</ref>  The depletion of T-cells in the donor tissue and a close HLA match will reduce the chances of graft-versus-host disease occurring.<ref name="Rans 357–363">Rans, Tonya S., 
 The evolution of gene therapy in X-linked severe combined immunodeficiency, 
 Annals of Allergy, Asthma & Immunology, 
 
 Vol. 102(Issue: 5),
 pp. 357–363,
 DOI: 10.1016/S1081-1206(10)60504-2,
 PMID: 19492655,</ref>  Moreover, patients who received an exact HLA match had normal functioning T-cells in fourteen days.<ref name="Buckley 508–516">Buckley, Rebecca H., 
 Hematopoietic Stem-Cell Transplantation for the Treatment of Severe Combined Immunodeficiency, 
 New England Journal of Medicine, 
 
 Vol. 340(Issue: 7),
 pp. 508–516,
 DOI: 10.1056/NEJM199902183400703,
 PMID: 10021471,</ref>  However, those who received a haploidentical HLA match, their T-cells started to function after four months.<ref name="Buckley 508–516"/>  In addition, the reason BMT is a permanent solution is because the bone marrow contains multipotent hematopoietic stem cells<ref name="Burg 561–571"/>  which become common lymphoid or common myeloid progenitors.<ref name=Kondo03>Kondo, Motonari, 
 Biology of Hemaptopoietic Stem Cells and Progenitors: Implications for Clinical Application, 
 Annual Review of Immunology, 
 
 Vol. 21(Issue: 1),
 pp. 759–806,
 DOI: 10.1146/annurev.immunol.21.120601.141007,
 PMID: 12615892,</ref>  In particular, the common lymphoid progenitor gives rise to the lymphocytes involved in the immune response (B-cell, T-cell, natural killer cell).<ref name=Kondo03/>  Therefore, a BMT will result in a full immune reconstitution but there are aspects of BMT that need to be improved (i.e. GvHD).<ref name="Fischer 143–149">Fischer, A., 
 Severe combined immunodeficiencies (SCID), 
 Clinical and Experimental Immunology, 
 
 Vol. 122(Issue: 2),
 pp. 143–9,
 DOI: 10.1046/j.1365-2249.2000.01359.x,
 PMID: 11091267,
 PMC: 1905779,</ref>

Gene therapy is another treatment option which is available only for clinical trials.<ref name="Kohn 477–488"/> X-linked SCID is a monogenic disorder, the IL2RG gene is mutated, so gene therapy will replace this mutated gene with a normal one.<ref>Buckley, Rebecca H.,

 The multiple causes of human SCID, 
 Journal of Clinical Investigation, 
 
 Vol. 114(Issue: 10),
 pp. 1409–11,
 DOI: 10.1172/JCI23571,
 PMID: 15545990,
 PMC: 525750,</ref>  This will result in a normal functioning gamma chain protein of the interleukin receptor.<ref name="Rans 357–363"/>  In order to transfer a functional gene into the target cell, viral or non-viral vectors can be employed.<ref name="Rans 357–363"/>  Viral vectors, such as the retrovirus, that incorporate the gene into the genome result in long-term effects.<ref name="Kohn 477–488"/>  This, coupled with the bone marrow stem cells, has been successful in treating individuals with X-SCID.<ref>, 
 Gene therapy: Is IL2RG oncogenic in T-cell development?: X-SCID transgene leukaemogenicity (reply), 
 Nature, 
 
 Vol. 443(Issue: 7109),
 pp. E6–E7,
 DOI: 10.1038/nature05220,
 PMID: 16988660,</ref> In one particular trial by Cavazzana-Calvo et al., ten children were treated with gene therapy at infancy for X-SCID.<ref name="Cavazzana-Calvo 669–672">Cavazzana-Calvo, M., 
 Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 Disease, 
 Science, 
 
 Vol. 288(Issue: 5466),
 pp. 669–672,
 DOI: 10.1126/science.288.5466.669,
 PMID: 10784449,</ref>  Nine of the ten were cured of X-SCID.<ref name="Cavazzana-Calvo 669–672"/>  However, about three years after treatment, two of the children developed T-cell leukemia due to insertion of the IL2RG gene near the LMO2 gene and thereby activating the LMO2 gene (a known oncogene).<ref>

Gene Therapy Insertional Mutagenesis Insights(link). {{{website}}}.

16 January 2004.

</ref> A third child developed leukemia within two years of that study being published, likely as a direct result of the therapy.<ref>

X-SCID Gene Therapy Poses Substantial Cancer Risk(link). {{{website}}}.

30 April 2006.

</ref> This condition is known as insertional mutagenesis, where the random insertion of a gene interferes with the tumor suppressor gene or stimulates an oncogene.<ref name="Kohn 477–488"/> There is currently no approved gene therapy on the market, but there are many clinical trials into which X-SCID patients may enroll. Therefore, research in the field of gene therapy today and in the future is needed to avoid the occurrence of leukemia.<ref name="Rans 357–363"/> In particular, research into the use of insulator and suicide genes is warranted as this may prevent cancer from developing.<ref name="Kohn 477–488"/> The insulator gene inhibits the activation of adjacent genes. On the other hand, the suicide gene is stimulated when a tumour begins to form, and this will result in the deactivation of the therapeutic gene.<ref name="Kohn 477–488"/> Moreover, the use of restriction enzymes such as the zinc-finger nuclease (ZFN) is being studied.<ref name="Kohn 477–488"/> The ZFN allows the researcher to choose the site of gene integration.<ref name="Kohn 477–488"/> Vector safety is important in the field of gene therapy, hence vectors that self-inactivate the promoter and enhancer (SIN) and adenoviruses that creates no immune response are prominent areas of research for vector biologists.<ref name="Kohn 477–488"/>

Prognosis

X-linked SCID is a known pediatric emergency which primarily affects males.<ref name="Buckley 1409–1411"/> If the appropriate treatment such as intravenous immunoglobulin supplements, medications for treating infections or a bone marrow transplant is not administered, then the prognosis is poor.<ref name="Verbsky 82–88"/> The patients with X-linked SCID usually die two years after they are born.<ref name="Fischer 143–149"/> For this reason, the diagnosis of X-linked SCID needs to be done early to prevent any pathogens from infecting the infant.

However, the patients have a higher chance of survival if the diagnosis of X-linked SCID is done as soon as the baby is born.<ref name="Verbsky 82–88"/> This involves taking preventative measures to avoid any infections that can cause death. For example, David Vetter had a high chance of having X-linked SCID because his elder sibling had died due to SCID.<ref name="Cossu 76">Cossu, Fausto,

 Genetics of SCID, 
 Italian Journal of Pediatrics, 
 
 Vol. 36(Issue: 1),
 pp. 76,
 DOI: 10.1186/1824-7288-36-76,
 PMID: 21078154,
 PMC: 2999594,</ref> This allowed the doctors to place David in the bubble and prevented infections.<ref name="Cossu 76"/> In addition, if X-linked SCID is known to affect a child, then live vaccines should not be administered and this can save the infant's life. Vaccines, which are pathogens inserted into the body to create an immune response, can lead to death in infants with X-linked SCID.<ref>, 
  
 Primary immunodeficiency diseases : definition, diagnosis, and management, 
  
 Berlin:Springer, 
 2008, 
  
  
 ISBN 978-3-540-78537-8,</ref> Moreover, with proper treatments, such as a bone marrow transplant, the prognosis is good. The bone marrow transplant has been successful in treating several patients and resulted in a full immune reconstitution and the patient can live a healthy life.<ref>Dvorak, C C, 
 Hematopoietic stem cell transplantation for primary immunodeficiency disease, 
 Bone Marrow Transplantation, 
 
 Vol. 41(Issue: 2),
 pp. 119–126,
 DOI: 10.1038/sj.bmt.1705890,
 PMID: 17968328,</ref> The results of bone marrow transplant are most successful when the closest human leukocyte antigen match has been found.<ref>Mikkers, Harald, 
 Induced pluripotent stem cells and severe combined immunodeficiency: merely disease modeling or potentially a novel cure?, 
 Pediatric Research, 
 
 Vol. 71(Issue: 4–2),
 pp. 427–432,
 DOI: 10.1038/pr.2011.65,
 PMID: 22430378,</ref> If a close match is not found, however, there is a chance of graft-versus-host-disease which means the donor bone marrow attacks the patient's body.<ref name="Rans 357–363"/> Hence, a close match is required to prevent any complications.

Epidemiology

There is no information on birth ratios/rates, but "X-Linked SCID is the most common form of SCID and it has been estimated to account for 46% to 70% of all SCID cases."<ref> </ref>

See also

• Severe combined immunodeficiency
• List of genetic disorders

References

• https://web.archive.org/web/20081122091233/http://www.scid.net/about.htm
• Eric,

 GeneReviews® [Internet], 
  
 Seattle WA:University of Washington, 
 2016, 
  
  
  
  
 ID: NBK1410,

• Online Mendelian Inheritance in Man (OMIM) Interleukin 2 receptor, Gamma; IL2RG -308380

• Online Mendelian Inheritance in Man (OMIM) Severe Combined Immunodeficiency, X-Linked; SCIDX1 -300400

External links

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