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| {{Cleanup|reason=Errors in data and uncited information|date=March 2015}} | | {{Short description|A genetic disorder affecting the immune system}} |
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| {{Infobox medical condition (new) | | {{Infobox medical condition (new) |
| | name = X-linked severe combined immunodeficiency | | | name = X-linked severe combined immunodeficiency |
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| | synonyms = X-SCID | | | synonyms = X-SCID |
| | image = X-linked recessive (2).svg | | | image = X-linked recessive (2).svg |
| | caption = X-linked recessive is the inheritance pattern of this disorder | | | caption = X-linked recessive is the inheritance pattern of this disorder |
| | pronounce = | | | pronounce = |
| | field = | | | field = [[Immunology]], [[Medical genetics]], [[Pediatrics]] |
| | symptoms = | | | symptoms = Severe recurrent infections, failure to thrive, chronic diarrhea, absence of lymphoid tissue |
| | complications = | | | complications = Life-threatening infections, growth delay, death without treatment |
| | onset = | | | onset = Within the first few months of life |
| | duration = | | | duration = Lifelong without treatment |
| | types = | | | types = X-linked (most common SCID type) |
| | causes = | | | causes = Mutation in the ''[[IL2RG]]'' gene (interleukin-2 receptor gamma chain) |
| | risks = | | | risks = Family history of SCID, male infants |
| | diagnosis = | | | diagnosis = [[T-cell receptor excision circles]] (TREC) screening, genetic testing, flow cytometry |
| | differential = | | | differential = Other forms of SCID, HIV/AIDS, congenital neutropenia |
| | prevention = | | | prevention = Prenatal genetic testing, newborn screening |
| | treatment = | | | treatment = [[Hematopoietic stem cell transplantation]], [[gene therapy]] |
| | medication = | | | medication = [[Antibiotics]], [[antifungals]], [[immunoglobulin replacement therapy]] |
| | prognosis = | | | prognosis = Good with early treatment; fatal if untreated |
| | frequency = | | | frequency = Rare; ~1 in 50,000 to 100,000 live births |
| | deaths = | | | deaths = High without prompt treatment |
| }} | | }} |
| '''X-linked severe combined immunodeficiency''' ('''X-SCID''') is an [[immunodeficiency]] disorder in which the body produces very few [[T cell]]s and [[NK cell]]s. | | '''X-linked severe combined immunodeficiency''' (X-linked SCID) is a genetic disorder that severely affects the immune system, leading to a lack of functional [[T cells]] and [[natural killer cells]]. This condition is part of a group of disorders known as [[severe combined immunodeficiency]] (SCID), which are characterized by a severely compromised immune system. |
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| In the absence of [[T helper cell|T cell help]], [[B cell]]s become defective.<ref name=Fisher>{{cite journal |last=Fisher |first=A. |author2=Hacein-Bey, S. |author3=Cavazzana-Calvo, M. |title=Gene therapy of severe combined immunodeficiencies|journal=Nature Reviews Immunology |doi=10.1038/nri859 |pmid=12154380 |date=August 2002 |volume=2 |issue=8 |pages=615–621}}</ref> It is an [[X-linked recessive inheritance]] trait, stemming from a [[mutation|mutated]] (abnormal) version of the ''IL2RG'' gene located on the [[X-chromosome]]. This [[gene]] encodes the [[IL-2RG|interleukin receptor common gamma chain]] [[protein]], which is a [[cytokine receptor]] sub-unit that is part of the [[receptor (biochemistry)|receptor]]s for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.<ref>{{cite journal |last=Buckley |first=R.H. |title=Advances in the Understanding and Treatment of Human Severe Combined Immunodeficiency |journal= Immunologic Research|year=2000 |volume=22 |issue=2–3 |pages=237–251 |doi=10.1385/ir:22:2-3:237 |pmid=11339359}}</ref><ref>{{cite journal |last=Puck |first=J.M. |first2=G. |last2=de Saint Basil |first3=K. |last3=Schwarz |first4=S. |last4=Fugmann |first5=R.E. |last5=Fischer |title=IL2RGbase: a database of γc-chain defects causing human X-SCID |journal=Immunology Today |date=November 1996 |volume=17 |issue=11 |pages=507–511 |doi=10.1016/0167-5699(96)30062-5 |pmid=8961626}}</ref>
| | ==Genetics== |
| | | X-linked SCID is caused by mutations in the ''IL2RG'' gene, which is located on the X chromosome. The ''IL2RG'' gene encodes the common gamma chain (γc), a protein that is a component of several interleukin receptors, including those for [[interleukin-2]], [[interleukin-4]], [[interleukin-7]], [[interleukin-9]], [[interleukin-15]], and [[interleukin-21]]. These interleukins are crucial for the development and function of immune cells. |
| ==Symptoms and signs==
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| 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">{{cite book |last=Vickers |first=Peter |title=Severe Combined Immune Deficiency: Early Hospitalisation and Isolation |year=2009 |publisher=Wiley |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">{{cite journal |last=Sponzilli |first=Ivonne |first2=Luigi D. |last2=Notarangelo |title=Severe Combined Immunodeficiency (SCID): from molecular basis to clinical management |journal=Acta Bio-medica: Atenei Parmensis |year=2011 |volume=82 |issue=1 |pages=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>{{cite journal |last=Gennery |first=A.R. |author2=Cant, A.J. |title=Diagnosis of severe combined immunodeficiency |journal=Journal of Clinical Pathology |year=2001 |volume=54 |issue=3 |pages=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"/>
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| 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.
| | Since the disorder is X-linked, it primarily affects males, who have only one X chromosome. Females, with two X chromosomes, are typically carriers and usually do not exhibit symptoms, although they can pass the mutated gene to their offspring. |
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| ==Genetics==
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| X-SCID is caused by a mutation occurring in the xq13.1 locus of the X-chromosome.<ref>{{cite journal |last=Buckley |first=Rebecca H. |title=Molecular Defects in Human Severe Combined Immunodeficiency and Approaches to Immune Reconstitution|journal=Annual Review of Immunology |date=1 April 2004 |volume=22 |issue=1 |pages=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 mutation]]s 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>{{cite web |last=Shwartz |first=R.A. |title=Pediatric Severe Combined Immunodeficiency |url=http://emedicine.medscape.com/article/888072-overview#a0156 |publisher=MedScape |accessdate=January 18, 2012}}</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/>
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| ==Pathophysiology== | | ==Pathophysiology== |
| [[Interleukins]] are produced by lymphocytes, among other cell types, and are released in response to [[antigenic]] and non-antigenic [[Stimulus (physiology)|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>{{cite journal |last=Cavazzana-Calvo |first=Marina |author2=Fischer, A. |title=Gene therapy for severe combined immunodeficiency: are we there yet? |journal=The Journal of Clinical Investigation |date=June 2007 |volume=117 |issue=6 |pages=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">{{cite journal |last=Spolski |first=Rosanne |last2=Leonard |first2=Warren J. |title=Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity* |journal=Annual Review of Immunology |date=1 April 2008 |volume=26 |issue=1 |pages=57–79 |doi=10.1146/annurev.immunol.26.021607.090316 |pmid=17953510 |url=https://zenodo.org/record/1234999 }}</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">{{cite journal |last=Leonard |first=Warren J. |title=Cytokines and immunodeficiency diseases |journal=Nature Reviews Immunology |date=December 2001 |volume=1 |issue=3 |pages=200–8 |doi=10.1038/35105066 |pmid=11905829|url=https://zenodo.org/record/1233113 }}</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 absence of a functional common gamma chain in X-linked SCID leads to a failure in the signaling pathways necessary for the development and maturation of T cells and natural killer cells. As a result, affected individuals have a severely compromised immune system, making them highly susceptible to infections. |
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| 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.
| | ==Clinical Presentation== |
| | Infants with X-linked SCID typically present within the first few months of life with recurrent infections, failure to thrive, and chronic diarrhea. Common infections include those caused by opportunistic organisms such as [[Pneumocystis jirovecii]], [[Candida albicans]], and various [[viruses]]. Without treatment, these infections can be life-threatening. |
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| ==Diagnosis== | | ==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>{{harvnb|GeneReviews|2016}}</ref> | | Diagnosis of X-linked SCID is often made through newborn screening programs that detect low levels of T-cell receptor excision circles (TRECs), which are byproducts of T-cell development. Confirmatory testing includes genetic testing to identify mutations in the ''IL2RG'' gene. |
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| {| class="wikitable"
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| ! Cell type !! Normal lymphocyte count average (range) !! X-SCID count average (range)
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| | T-cells || style="text-align:center;" | 3,680 (2,500–5,500) || style="text-align:center;" | 200 (0-800)
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| | B-cells || style="text-align:center;" | 730 (300–2,000) || style="text-align:center;" | 1,300 (44 - >3,000)
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| | NK cells || style="text-align:center;" | 420 (170–1,100) || style="text-align:center;" | <100
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| | Total || style="text-align:center;" | 0–3 months: 5,400 (3,400–7,300) || style="text-align:center;" | <2,000
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| |}<ref name=GeneReviews/>
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| 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. {{citation needed|reason=Source is unclear.|date=March 2015}}
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| 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>{{cite web |last=Rehan |first=Kelly M. |title=An Overview of the Thymus: The Gland that Protects You Long after It's Gone |url=http://www.endocrineweb.com/endocrinology/overview-thymus |work=EndocrineWeb}}</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.
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| Since the mutation in X-SCID is X-linked, there are [[genetic tests]] for detecting carriers in X-SCID [[Pedigree (animal)|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.
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| 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>{{cite journal |last=Fischer |first=A. |title=Severe combined immunodeficiencies |journal=Clinical & Experimental Immunology |year=2000 |volume=122 |issue=2 |pages=143–9 |doi=10.1046/j.1365-2249.2000.01359.x |pmc=1905779 |pmid=11091267 }}</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"/>
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| 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">{{cite journal |last=Puck |first=Jennifer M. |title=Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: The winner is T-cell receptor excision circles |journal=Journal of Allergy and Clinical Immunology |date=1 March 2012 |volume=129 |issue=3 |pages=607–616 |doi=10.1016/j.jaci.2012.01.032 |pmc=3294074 |pmid=22285280}}</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 [[dried blood spot|Guthrie card]], from which DNA is extracted.<ref>{{cite journal |last=Shearer |first=William T. |title=Screening for severe combined immunodeficiency in newborns |journal=Journal of Allergy and Clinical Immunology |date=1 March 2012 |volume=129 |issue=3 |pages=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">{{cite journal |last=Verbsky |first=James W. |last2=Baker |first2=Mei W. |last3=Grossman |first3=William J. |last4=Hintermeyer |first4=Mary |last5=Dasu |first5=Trivikram |last6=Bonacci |first6=Benedetta |last7=Reddy |first7=Sreelatha |last8=Margolis |first8=David |last9=Casper |first9=James |last10=Gries |first10=Miranda |last11=DeSantes |first11=Ken |last12=Hoffman |first12=Gary L. |last13=Brokopp |first13=Charles D. |last14=Seroogy |first14=Christine M. |last15=Routes |first15=John M. |title=Newborn Screening for Severe Combined Immunodeficiency; The Wisconsin Experience (2008–2011) |journal=Journal of Clinical Immunology |date=10 November 2011 |volume=32 |issue=1 |pages=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>{{Cite journal |last1=Chan |first1=K. |last2=Puck |first2=J. M. |doi=10.1016/j.jaci.2004.10.012 |title=Development of population-based newborn screening for severe combined immunodeficiency |journal=Journal of Allergy and Clinical Immunology |volume=115 |issue=2 |pages=391–8 |year=2005 |pmid=15696101 |pmc=|url=https://zenodo.org/record/1259083 }}</ref> A low TREC count indicates that there is insufficient development of T-cells in the thymus gland.<ref>{{cite journal |last=Puck |first=Jennifer M. |author2=Routes, Jack |author3=Filipovich, Alexandra H. |author4=Sullivan, Kate |title=Expert Commentary: Practical Issues in Newborn Screening for Severe Combined Immune Deficiency (SCID) |journal=Journal of Clinical Immunology |date=20 October 2011 |volume=32 |issue=1 |pages=36–38 |doi=10.1007/s10875-011-9598-3 |pmc=4380147 |pmid=22012274}}</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>{{cite web |title=IDF SCID Newborn Screening Campaign |url=http://primaryimmune.org/patients-and-families/idf-scid-initiative/idf-scid-newborn-screening-campaign |work=Immune Deficiency Foundation}}</ref> In addition, pilot trials are being performed in several other states beginning in 2013.<ref>{{cite web |last=Wilkerson |first=Sarah |title=Updates from Washington – Day 2 |url=http://www.savebabies.org/blog/2013/02/updates-from-washington-day-2/ |work=Save Babies Through Screening Foundation}}</ref>
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| ==Treatments==
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| 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">{{cite journal |last=Fischer |first=A. |title=Severe Combined Immunodeficiencies (SCID) |journal=Clinical & Experimental Immunology |year=2000 |volume=122 |issue=2 |pages=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"/>
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| 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>{{cite journal |last=Johnston Jr. |first=R.B. |title=The Boy in the Bubble |journal=JAMA: The Journal of the American Medical Association |year=2006 |volume=296 |issue=4 |pages=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 immunodeficiency|primary immunodeficiencies]].<ref name=Rans>{{cite journal |last=Rans |first=T.S. |author2=England, R. |title=The evolution of gene therapy in X-linked severe combined immunodeficiency |journal=Annals of Allergy, Asthma & Immunology |year=2009 |volume=102 |issue=5 |pages=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>{{Cite journal |last1=Freeman |first1=A. F. |last2=Holland |first2=S. M. |doi=10.1097/ACI.0b013e328332be33 |title=Antimicrobial prophylaxis for primary immunodeficiencies |journal=Current Opinion in Allergy and Clinical Immunology |volume=9 |issue=6 |pages=525–530 |year=2009 |pmid=19812481 |url=https://zenodo.org/record/1234915 }}</ref> In addition, the patient can also undergo [[intravenous immunoglobulin]] (IVIG) supplementation.<ref name=Nolte>{{cite journal |last=Nolte |first=M. T. |author2=Pirofsky, B. |author3=Gerritz, G. A. |author4=Golding, B. |title=Intravenous immunoglobulin therapy for antibody deficiency |journal=Clinical and Experimental Immunology |year=1979 |volume=36 |issue=2 |pages=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>{{cite journal |last=Farrington |first=E. |last2=Hochwald |first2=C. |title=Intravenous immunoglobulin |journal=Pediatric Nursing |year=1996 |volume=22 |issue=4 |pages=344–7 |pmid=8852117}}</ref> [[Antibodies]], Y-shaped proteins created by plasma cells, recognize and neutralize any pathogens in the body.<ref name=Shishido>{{cite journal |last=Shishido |first=S.N. |author2=Varahan, S. |author3=Yuan, K. |author4=Li, X. |author5=Fleming, S. D. |title=Humoral innate immune response and disease |journal=Clinical Immunology |volume=144 |issue=2 |pages=142–158 |year=2012 |doi=10.1016/j.clim.2012.06.002 |pmid=22771788 |pmc=3576926 |hdl=2097/16670 }}</ref> However, the IVIG is expensive, in terms of time and finance.<ref>{{cite journal |title=I.V. immunoglobulin therapy for infectious diseases |journal=Drug and Therapeutics Bulletin |date=6 May 2010 |volume=48 |issue=5 |pages=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"/>
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| 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">{{cite journal |last=Burg |first=Mirjam |author2=Gennery, Andy R. |title=Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency |journal=European Journal of Pediatrics |date=9 April 2011 |volume=170 |issue=5 |pages=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">{{cite journal |last=Buckley |first=Rebecca H. |title=The multiple causes of human SCID |journal=Journal of Clinical Investigation |date=15 November 2004 |volume=114 |issue=10 |pages=1409–11 |pmid=15545990 |pmc=525750 |doi=10.1172/JCI23571 }}</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">{{cite journal |last=Martelli |first=Massimo F |author2=Aversa, Franco |author3=Bachar-Lustig, Ester |author4=Velardi, Andrea |author5=Reich-Zelicher, Shlomit |author6=Tabilio, Antonio |author7=Gur, Hilit |author8=Reisner, Yair |title=Transplants across human leukocyte antigen barriers |journal=Seminars in Hematology |date=1 January 2002 |volume=39 |issue=1 |pages=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>{{cite journal |vauthors=de la Morena MT, Wayne AS, Day NK, Haag MM, Hinds-Frey KR, Nelson RP, Sutcliffe MJ, Good RA |title=Recipient T-cell immune reconstitution in X-linked SCID after haploidentical maternal bone marrow transplant |journal=Ann. N. Y. Acad. Sci. |volume=770 |issue= 1|pages=376–7 |date=December 1995 |pmid=8597380 |doi=10.1111/j.1749-6632.1995.tb31074.x |bibcode=1995NYASA.770..376M }}</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">{{cite journal |last=Kohn |first=Donald B. |author2=Sadelain, Michel |author3=Glorioso, Joseph C. |title=Occurrence of leukaemia following gene therapy of X-linked SCID |journal=Nature Reviews Cancer |date=1 July 2003 |volume=3 |issue=7 |pages=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">{{cite journal |last=Rans |first=Tonya S. |author2=England, Ronald |title=The evolution of gene therapy in X-linked severe combined immunodeficiency |journal=Annals of Allergy, Asthma & Immunology |date=1 May 2009 |volume=102 |issue=5 |pages=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">{{cite journal |last=Buckley |first=Rebecca H. |author2=Schiff, Sherrie E. |author3=Schiff, Richard I. |author4=Markert, M. Louise |author5=Williams, Larry W. |author6=Roberts, Joseph L. |author7=Myers, Laurie A. |author8=Ward, Frances E. |title=Hematopoietic Stem-Cell Transplantation for the Treatment of Severe Combined Immunodeficiency |journal=New England Journal of Medicine |date=18 February 1999 |volume=340 |issue=7 |pages=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>{{cite journal |last=Kondo |first=Motonari |author2=Wagers, Amy J. |author3=Manz, Markus G. |author4=Prohaska, Susan S. |author5=Scherer, David C. |author6=Beilhack, Georg F. |author7=Shizuru, Judith A. |author8=Weissman, Irving L. |title=Biology of Hemaptopoietic Stem Cells and Progenitors: Implications for Clinical Application |journal=Annual Review of Immunology |date=1 April 2003 |volume=21 |issue=1 |pages=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">{{cite journal |last=Fischer |first=A. |title=Severe combined immunodeficiencies (SCID) |journal=Clinical and Experimental Immunology |date=1 November 2000 |volume=122 |issue=2 |pages=143–9 |doi=10.1046/j.1365-2249.2000.01359.x |pmid=11091267 |pmc=1905779}}</ref>
| | ==Treatment== |
| | | The primary treatment for X-linked SCID is [[hematopoietic stem cell transplantation]] (HSCT), which can restore immune function if performed early in life. Gene therapy is an emerging treatment option that involves correcting the genetic defect in the patient's own hematopoietic stem cells. |
| [[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>{{cite journal |last=Buckley |first=Rebecca H. |title=The multiple causes of human SCID |journal=Journal of Clinical Investigation |date=15 November 2004 |volume=114 |issue=10 |pages=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>{{cite journal |vauthors=((Woods N-B)), Bottero V, Schmidt M, von Kalle C, Verma IM |title=Gene therapy: Is IL2RG oncogenic in T-cell development?: X-SCID transgene leukaemogenicity (reply) |journal=Nature |volume=443 |pages=E6–E7 |date=21 September 2006 |pmid=16988660 |doi=10.1038/nature05220 |issue=7109|bibcode=2006Natur.443E...6W }}</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">{{cite journal |last=Cavazzana-Calvo |first=M. |title=Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 Disease |journal=Science |date=28 April 2000 |volume=288 |issue=5466 |pages=669–672 |doi=10.1126/science.288.5466.669 |pmid=10784449|bibcode=2000Sci...288..669C }}</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>{{cite web |url=http://angt.austrianova.com/angt/Brevia.pdf |title=Gene Therapy Insertional Mutagenesis Insights |work=Science |date=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>{{cite web |url=http://www.medicalnewstoday.com/articles/42339.php |title=X-SCID Gene Therapy Poses Substantial Cancer Risk |work=Medical News Today |date=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 (genetics)|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"/>
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| ==Prognosis== | | ==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.
| | With early diagnosis and treatment, individuals with X-linked SCID can have a significantly improved prognosis. However, without treatment, the condition is usually fatal within the first year of life due to overwhelming infections. |
| | |
| 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">{{cite journal |last=Cossu |first=Fausto |title=Genetics of SCID |journal=Italian Journal of Pediatrics |date=1 January 2010 |volume=36 |issue=1 |pages=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>{{cite book |editor1=Nima Rezaei |editor2=Asghar Aghamohammadi |editor2-link=Asghar Aghamohammadi |editor3=Luigi Notarangelo |title=Primary immunodeficiency diseases : definition, diagnosis, and management |year=2008 |publisher=Springer |location=Berlin |isbn=978-3-540-78537-8 |page=45}}</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>{{cite journal |last=Dvorak |first=C C |author2=Cowan, M J |title=Hematopoietic stem cell transplantation for primary immunodeficiency disease |journal=Bone Marrow Transplantation |date=29 October 2007 |volume=41 |issue=2 |pages=119–126 |doi=10.1038/sj.bmt.1705890 |pmid=17968328|doi-access=free }}</ref> The results of bone marrow transplant are most successful when the closest human leukocyte antigen match has been found.<ref>{{cite journal |last=Mikkers |first=Harald |author2=Pike-Overzet, Karin |author3=Staal, Frank J.T. |title=Induced pluripotent stem cells and severe combined immunodeficiency: merely disease modeling or potentially a novel cure? |journal=Pediatric Research |date=8 February 2012 |volume=71 |issue=4–2 |pages=427–432 |doi=10.1038/pr.2011.65 |pmid=22430378|doi-access=free }}</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.
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| ==Epidemiology==
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| 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>{{harvnb|Davis|Puck|1993}}</ref>
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| ==See also==
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| *[[Severe combined immunodeficiency]]
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| *[[List of genetic disorders]]
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| == Notes and references ==
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| {{Reflist}}
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| ==References==
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| {{More footnotes|date=April 2009}}
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| *https://web.archive.org/web/20081122091233/http://www.scid.net/about.htm
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| *{{cite book |first=Eric |last=Allenspach |first2=David J. |last2=Rawlings |first3=Andrew M. |last3=Scharenberg |chapter=X-Linked Severe Combined Immunodeficiency |chapterurl=https://www.ncbi.nlm.nih.gov/books/NBK1410/#x-scid.Prevention_of_Primar |veditors=Pagon RA, Bird TD, Dolan CR, Stephens K |title=GeneReviews® [Internet] |publisher=University of Washington |location=Seattle WA |year=2016 |origyear=1993 |id=NBK1410 |pmid=20301584 |ref={{harvid|GeneReviews|2016}}}}
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| *{{OMIM|308380|Interleukin 2 receptor, Gamma; IL2RG}}
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| *{{OMIM|300400|Severe Combined Immunodeficiency, X-Linked; SCIDX1}}
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| | ==Related pages== |
| | * [[Severe combined immunodeficiency]] |
| | * [[Immune system]] |
| | * [[Genetic disorder]] |
| | * [[Hematopoietic stem cell transplantation]] |
| == External links == | | == External links == |
| {{Medical resources | | {{Medical resources |
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| {{X-linked disorders}} | | {{X-linked disorders}} |
| {{Cell surface receptor deficiencies}} | | {{Cell surface receptor deficiencies}} |
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| {{DEFAULTSORT:X-Linked Severe Combined Immunodeficiency}} | | {{DEFAULTSORT:X-Linked Severe Combined Immunodeficiency}} |
| [[Category:Combined T and B–cell immunodeficiencies]] | | [[Category:Combined T and B–cell immunodeficiencies]] |
| [[Category:Cell surface receptor deficiencies]] | | [[Category:Cell surface receptor deficiencies]] |
| {{stb}}
| | [[Category:Genetic disorders]] |
| | [[Category:Immunodeficiency]] |
| | [[Category:X-linked recessive disorders]] |
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