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| ==Overview== | | ==Overview== |
| '''Severe combined immunodeficiency''', or '''Boy in the Bubble Syndrome''', is a genetic disorder in which both "arms" ([[B cell]]s and [[T cell]]s) of the [[adaptive immune system]] are crippled, due to a defect in one of several possible genes. SCID is a severe form of heritable [[immunodeficiency]]. It is also known as the "bubble boy" disease because its victims are extremely vulnerable to infectious diseases. The most famous case is the boy [[David Vetter]].
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| Chronic diarrhea, ear infections, recurrent [[Pneumocystis carinii pneumonia|''Pneumocystis jirovecii'']] pneumonia, and profuse oral [[candidiasis]] commonly occur. These babies, if untreated, usually die within 1 year due to severe, recurrent infections. However, treatment options are much improved since David Vetter.
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| ==Historical Perspective== | | ==Historical Perspective== |
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| | '''Type''' || '''Description''' | | | '''Type''' || '''Description''' |
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| | [[X-SCID|X-linked severe combined immunodeficiency]] || Most cases of SCID are due to [[mutation]]s in the gene encoding the [[common gamma chain]] (γ<sub>c</sub>), a protein that is shared by the receptors for [[interleukin]]s [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 7|IL-7]], [[Interleukin 9|IL-9]], [[Interleukin 15|IL-15]] and [[Interleukin 21|IL-21]]. These interleukins and their receptors are involved in the development and differentiation of T and B cells. Because the common gamma chain is shared by many interleukin receptors, mutations that result in a non-functional common gamma chain cause widespread defects in interleukin signalling. The result is a near complete failure of the immune system to develop and function, with low or absent [[T cells]] and [[NK cells]] and non-functional [[B cells]].<BR>The common gamma chain is encoded by the gene [[IL-2 receptor]] gamma, or IL-2Rγ, which is located on the X-chromosome. Therefore, immunodeficiency caused by mutations in IL-2Rγ is known as X-linked severe combined immunodeficiency. The condition is inherited in an [[X-linked recessive]] pattern. | | | [[X-SCID|X-linked severe combined immunodeficiency]] || |
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| | [[Adenosine deaminase deficiency]] || The second most common form of SCID after X-SCID is caused by a defective enzyme, [[adenosine deaminase]] (ADA), necessary for the breakdown of [[purine]]s. Lack of ADA causes accumulation of dATP. This metabolite will inhibit the activity of ribonucleotide diphosphate reductase, the enzyme that reduces ribonucleotides to generate deoxyribonucleotides. The effectiveness of the immune system depends upon lymphocyte proliferation and hence dNTP synthesis. Without functional ribonucleotide reductase, lymphocyte proliferation is inhibited and the immune system is compromised. | | | [[Adenosine deaminase deficiency]] || |
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| | [[Omenn syndrome]] || The manufacture of [[immunoglobulin]]s requires recombinase enzymes derived from the recombination activating genes [[RAG-1]] and [[RAG-2]]. These enzymes are involved in the first stage of [[V(D)J recombination]], the process by which segments of a [[B cell]] or [[T cell]]'s DNA are rearranged to create a new T cell receptor or B cell receptor (and, in the B cell's case, the template for antibodies).<BR>Certain mutations of the RAG-1 or RAG-2 genes prevent [[V(D)J recombination]], causing SCID.<ref name="pmid17572155">{{cite journal |author=Haq IJ, Steinberg LJ, Hoenig M, ''et al'' |title=GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes |journal=Clin. Immunol. |volume=124 |issue=2 |pages=165–9 |year=2007 |pmid=17572155 |doi=10.1016/j.clim.2007.04.013 |url=http://linkinghub.elsevier.com/retrieve/pii/S1521-6616(07)01181-3}}</ref> | | | [[Omenn syndrome]] || |
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| | JAK3 || [[Janus kinase-3]] (JAK3) is an enzyme that mediates transduction downstream of the γ<sub>c</sub> signal. Mutation of its gene also causes SCID.<ref name="pmid15661026">{{cite journal |author=Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O'Shea JJ |title=Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs |journal=Immunol. Rev. |volume=203 |issue= |pages=127–42 |year=2005 |pmid=15661026 |doi=10.1111/j.0105-2896.2005.00220.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0105-2896&date=2005&volume=203&spage=127}}</ref> | | | JAK3 || |
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| | Artemis/DCLRE1C || Mortan Cowan, MD, director of the Pediatric Bone Marrow Transplant Program at the University of California-San Francisco, noted that although researchers have identified about a dozen genes that cause SCID, the Navajo and Apache population has the most severe form of the disorder. This is due to the lack of a gene designated [[DCLRE1C|Artemis]]. Without the gene, children's bodies are unable to repair [[DNA]] or develop disease-fighting cells. <ref name="titleNews From Indian Country - A rare and once-baffling disease forces Navajo parents to cope" /><ref name="pmid12055248">{{cite journal |author=Li L, Moshous D, Zhou Y, ''et al'' |title=A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans |journal=J. Immunol. |volume=168 |issue=12 |pages=6323–9 |year=2002 |pmid=12055248 |doi= |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=12055248}}</ref> | | | Artemis/DCLRE1C || |
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| ==Epidemiology and Demographics== | | ==Epidemiology and Demographics== |
| Classical SCID has a reported incidence of about 1 in 65,000 live births in Australia.<ref name="pmid18221464">{{cite journal |author=Yee A, De Ravin SS, Elliott E, Ziegler JB |title=Severe combined immunodeficiency: A national surveillance study |journal=Pediatr Allergy Immunol |volume= 19|issue= |pages=080130211941085|year=2008 |pmid=18221464 |doi=10.1111/j.1399-3038.2007.00646.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0905-6157&date=2008&volume=&issue=&spage=}}</ref>
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| Recent studies indicate that one in every 2,500 children in the Navajo population inherit severe combined immunodeficiency. This condition is a significant cause of illness and death among Navajo children.<ref name="titleNews From Indian Country - A rare and once-baffling disease forces Navajo parents to cope">{{cite web |url=http://indiancountrynews.net/index.php?option=com_content&task=view&id=2109&Itemid=1 |title=News From Indian Country - A rare and once-baffling disease forces Navajo parents to cope |accessdate=2008-03-01 |format= |work=}}</ref> Ongoing research reveals a similar genetic pattern among the related Apache people.<ref name="pmid12055248">{{cite journal |author=Li L, Moshous D, Zhou Y, ''et al'' |title=A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans |journal=J. Immunol. |volume=168 |issue=12 |pages=6323–9 |year=2002 |pmid=12055248 |doi= |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=12055248}}</ref>
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| ==Risk Factors== | | ==Risk Factors== |
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| ==Screening== | | ==Screening== |
| Standard testing of SCID is not currently available for newborns due to the diversity of the genetic defect. Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not detected until about six months of age, usually indicated by recurrent infections. The delay in detection is because newborns carry their mother's [[antibody|antibodies]] for the first few weeks of life and SCID babies look normal.
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| ==Natural History, Complications, and Prognosis== | | ==Natural History, Complications, and Prognosis== |
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| ==Treatment== | | ==Treatment== |
| ===Medical Therapy=== | | ===Medical Therapy=== |
| The most common treatment for SCID is [[bone marrow transplant]]ation, which has been successful using either a matched donor (a sibling is generally best)or a half-matched donor, who would be either parent. The half-matched type of transplant is called haplo-identical and was perfected by Memorial Sloan Kettering Cancer Center in New York and also Duke University Medical Center which currently does the highest number of these transplants of any center in the world.<ref name="titleSevere Combined Immunodeficiency (SCID): Immunodeficiency Disorders: Merck Manual Professional">{{cite web |url=http://www.merck.com/mmpe/sec13/ch164/ch164l.html |title=Severe Combined Immunodeficiency (SCID): Immunodeficiency Disorders: Merck Manual Professional |accessdate=2008-03-01 |format= |work=}}</ref> [[David Vetter]], the original "bubble boy", had one of the first transplantations but eventually died because of an unscreened virus, [[Epstein-Barr]] (tests were not available at the time), in his newly transplanted bone marrow from his sister. Today, transplants done in the first three months of life have a high success rate. Physicians have also had some success with in utero transplants done before the child is born and also by using cord blood which is rich in stem cells.
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| More recently [[gene therapy]] has been attempted as an alternative to the bone marrow transplant. [[transduction_(genetics)|Transduction]] of the missing gene to hematopoietic stem cells using [[virus|viral]] [[vector (biology)|vector]]s is being tested in ADA SCID and X-linked SCID. The first gene therapy trials were performed in 1990, with peripheral T cells. In 2000, the first gene therapy "success" resulted in SCID patients with a functional immune system. These trials were stopped when it was discovered that two of ten patients in one trial had developed [[leukemia]] resulting from the insertion of the gene-carrying retrovirus near an [[oncogene]]. In 2007, four of the ten patients have developed leukemias <ref>[http://www.esgct.org/downloads/ESGTStatement.pdf Press release] from the [[European Society of Gene Therapy]]</ref>. Work is now focusing on correcting the gene without triggering an oncogene. No leukemia cases have yet been seen in trials of ADA-SCID, which does not involve the ''gamma c'' gene that may be oncogenic when expressed by a [[retrovirus]].
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| Trial treatments of SCID have been gene therapy's only success; since 1999, gene therapy has restored the immune systems of at least 17 children with two forms (ADA-SCID and X-SCID) of the disorder.
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| ===Surgery=== | | ===Surgery=== |
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