View source for Severe combined immunodeficiency

{{Infobox_Disease |
  Name           = {{PAGENAME}} |
  Image          = |
  Caption        = |
  DiseasesDB     = 11978 |
  ICD10          = {{ICD10|D|81|0|d|80}}-{{ICD10|D|81|2|d|80}} |
  ICD9           = {{ICD9|279.2}} |
  ICDO           = |
  OMIM           = |
  MedlinePlus    = |
  eMedicineSubj  = med |
  eMedicineTopic = 2214 |
  MeshID         = D016511 |
}}
__NOTOC__
{{Search infobox}}
{{CMG}}; '''Associate Editor-In-Chief:''' {{M.B}} {{HK}}

'''''Synonyms and Keywords:''''' ''Combined Immunodeficiencies; SCID; Immunodeficiency Syndrome, Severe Combined; Alymphocytosis; Severe Mixed Immunodeficiency Syndrome''

==Overview==
Severe combined immunodeficiency syndromes (SCID) are a heterogeneous group of diseases owing to numerous molecular defects in the development and function of both [[T cell|T]] and [[B cell|B cells]]. SCID is a life-threatening condition of overwhelming infections, typically in the first year of life, unless the underlying defect is corrected. The accepted classification system for SCID is based upon particular [[Molecule|molecular]] [[defect]], which is detected. The most common [[Genetics|genetic]] condition responsible for SCID is a [[mutation]] of the common [[Gamma|γ chain]] of the [[interleukin]] ([[Interleukin|IL]]) [[Receptor (biochemistry)|receptors]], and accounts for approximately 50% of all patients with SCID. [[Adenosine deaminase deficiency|Adenosine deaminase (ADA) deficiency]] is an another significant [[mutation]] accounts for 20% of all SCID cases. [[Symptom|Symptoms]] of SCID are recurrent severe [[Infection|infections]], [[chronic diarrhea]], and [[failure to thrive]] ([[FTT]]). Without [[newborn screening]] for SCID, a [[diagnosis]] is often not made until the infant develops several episodes of severe [[Infection|infections]]. Early diagnosis through population-wide newborn screening and early [[hematopoietic cell]] [[Organ transplant|transplantation]] (HCT) improve outcomes. Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent. 

==Historical Perspective==
* Severe combined immunodeficiency was first reported by Glanzmann and Riniker in 1950. Swiss infants with the condition were profoundly [[Lymphocytopenia|lymphopenic]] and died of [[infection]] before their first or second birthdays.<ref>Glanzmann E, Riniker P: Essential lymphocytophthisis; new clinical aspect of infant pathology. Ann Paediatr Jul-Aug 175 (1-2), 1-32.5 (1950)</ref> 
* The first discovered molecular cause of  SCID, [[adenosine deaminase deficiency]], was reported in 1972.<ref>{{Cite journal
 | author = [[E. R. Giblett]], [[J. E. Anderson]], [[F. Cohen]], [[B. Pollara]] & [[H. J. Meuwissen]]
 | title = Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity
 | journal = [[Lancet (London, England)]]
 | volume = 2
 | issue = 7786
 | pages = 1067–1069
 | year = 1972
 | month = November
 | pmid = 4117384
}}</ref> 
* Severe Combined Immunodeficiency may be best known from news stories and a movie in the 1980s about David Vetter, the Boy in the Bubble, who was a prominent sufferer of severe combined immunodeficiency and became famous for living in a sterile environment.

* In 1993, the molecular basis of X-linked human SCID was discoverd.<ref>{{Cite journal
 | author = [[M. Noguchi]], [[H. Yi]], [[H. M. Rosenblatt]], [[A. H. Filipovich]], [[S. Adelstein]], [[W. S. Modi]], [[O. W. McBride]] & [[W. J. Leonard]]
 | title = Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans
 | journal = [[Cell]]
 | volume = 73
 | issue = 1
 | pages = 147–157
 | year = 1993
 | month = April
 | pmid = 8462096
}}</ref> Progress in molecular biology and the Human Genome Project, as well as increased knowledge of diverse components of the immune system through evaluations of mutant mice and humans with genetically diagnosed immunodeficiencies, have all contributed to this comprehension.

==Classification==
* Previous classification system for SCID was based upon the presence of molecular defects affecting T cell numbers and presence or absence of defects affecting B and/or NK cell numbers, and SCID syndromes were classified as T'''-'''B'''+'''NK'''+''', T'''-'''B'''+'''NK'''-''', T'''-'''B'''-'''NK'''+''', or T'''-'''B'''-'''NK'''-''' (cell type present: '''+''' and cell type abscent: '''-''').  

* Beyond this phenotypic classification and the functional status of these cells, since the mutated genes responsible for the majority of patients with SCID are now recognized,Then, it is more acceptable to classify SCID based upon the particular molecular defect once it is detected, in addition, the genotype identification can affect treatment methods and measurements for post treatment complications<ref name="BuckleySchiff1997">{{cite journal|last1=Buckley|first1=Rebecca H.|last2=Schiff|first2=Richard I.|last3=Schiff|first3=Sherrie E.|last4=Markert|first4=M.Louise|last5=Williams|first5=Larry W.|last6=Harville|first6=Terry O.|last7=Roberts|first7=Joseph L.|last8=Puck|first8=Jennifer M.|title=Human severe combined immunodeficiency: Genetic, phenotypic, and functional diversity in one hundred eight infants|journal=The Journal of Pediatrics|volume=130|issue=3|year=1997|pages=378–387|issn=00223476|doi=10.1016/S0022-3476(97)70199-9}}</ref>:
{| class="wikitable"
| style="background:#4479BA; color: #FFFFFF;" align="center" + |Type
| style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene defects
| style="background:#4479BA; color: #FFFFFF;" align="center" + |Description                                                                                                                                                                                                                                
|- 
| style="background:#DCDCDC;" align="center" + |[[X-SCID|X-linked severe combined immunodeficiency]] 
|''IL-2R common gamma chain''|| ''IL2RG is'' a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. These interleukins and their receptors are involved in the development and differentiation of T and B cells. Mutations 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. ''IL2RG'' is encoded on the X chromosome; therefore, this variant of SCID is X-linked, and account for approximately 50% of all patients with SCID.
|-
| style="background:#DCDCDC;" align="center" + |Janus-associated kinase 3  deficiency (T<sup>–</sup> B<sup>+</sup>NK<sup>–</sup>) 
|''Janus kinase 3''
|JAK3 is a protein tyrosine kinase (PTK) that associates with the common γ chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of XL-SCID. 
|- 
| style="background:#DCDCDC;" align="center" + |[[Adenosine deaminase deficiency]] 
|ADA|| ADA deficiency accounts for 20% of all SCID cases. Adenosine deaminase (ADA), is necessary for the breakdown of purines. Lack of ADA leads to the accumulation of intermediate dATP, which results in lymphocyte toxicity,particularly with immature thymic lymphocytes, then lymphocyte proliferation is inhibited and the immune system is compromised.
|-
| style="background:#DCDCDC;" align="center" + |Bare lymphocyte syndrome 
|gene regulating expression of MHC type II
|Bare lymphocyte syndrome is a deficiency of major histocompatibility complex (MHC). MHC type II is decreased on mononuclear cells. MHC type I levels may be decreased or absent entirely. The defect occurs in a gene regulating expression of MHC type II
|-
| style="background:#DCDCDC;" align="center" + |ζ chain–associated protein (ZAP)-70 deficiency
| Tyrosine kinase
|Due to the mutation in the gene coding for tyrosine kinase, which is important in T-cell signalling and it is critical in positive and negative selection of T cells in the thymus
|-
| style="background:#DCDCDC;" align="center" + |Reticular dysgenesis
| Adenylate kinase 2
|Reticular dysgenesis is a rare variant of SCID arising from the inability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase 2 malfunction.
|-
| style="background:#DCDCDC;" align="center" + |IL-7R α chain deficiency
|''IL-7RA''
|
|-
| style="background:#DCDCDC;" align="center" + |Ligase 4 deficiency (T<sup>–</sup> B<sup>–</sup> NK<sup>+</sup>)
|
|
|-
| style="background:#DCDCDC;" align="center" + |CD45 deficiency
|
|
|- 
| style="background:#DCDCDC;" align="center" + |[[Omenn syndrome]] 
|RAG-1 or

RAG-2
| Recombination activating genes (RAG) mutations result in recombinase enzymes disturbances. These enzymes are essential for 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. Certain mutations of the RAG-1 or RAG-2 genes prevent V(D)J recombination, causing SCID.<ref>{{Cite journal
 | author = [[Tim Niehues]], [[Ruy Perez-Becker]] & [[Catharina Schuetz]]
 | title = More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2
 | journal = [[Clinical immunology (Orlando, Fla.)]]
 | volume = 135
 | issue = 2
 | pages = 183–192
 | year = 2010
 | month = May
 | doi = 10.1016/j.clim.2010.01.013
 | pmid = 20172764
}}</ref>
 |- 
 | style="background:#DCDCDC;" align="center" + |Artemis/DCLRE1C 
|''DCLRE1C''|| An enzyme that opens DNA hairpin during variable diversity joining [VDJ] rearrangement and ''RAG1'' and ''RAG2'' deficiencies
|}

==Pathophysiology==
* SCID is a syndrome caused by mutations in any of more than 15 known genes, whose products are pivotal for the development, function, differentiation and proliferation of both T and B cells and may also affect natural killer (NK) cells.  
* Antibody production is severely impaired even when mature B cells are present, since B cells require signals from T cells to produce antibody.  
* NK cells are present in approximately 50 percent of patients with SCID and may provide a degree of protection against bacterial and viral infections in these patients. Determining the presence or absence of NK cells is also helpful in classifying patients with SCID. 

==Causes==
* Combined immunodeficiency diseases are a heterogeneous group of disorders arising from mutations in any of more than 15 known gene, the most common genetic condition responsible for SCID is a mutation of the common γ chain of the interleukin (IL) receptors. A list of gene defects that cause SCID is presented in the below table:
{| class="wikitable"
|+'''Gene defects associated with severe combined immunodeficiency'''
| style="background:#DCDCDC;" align="center" + |''IL-2R common gamma chain''       
|ILR2                   
|-
| style="background:#DCDCDC;" align="center" + |''Janus kinase 3''
|JAK3    
|-
| style="background:#DCDCDC;" align="center" + |''IL-7Ra chain''
|     ''IL7RA''
|-
| style="background:#DCDCDC;" align="center" + |IL-2Ra chain (CD25) deficiency
|ILR2
|-
| style="background:#DCDCDC;" align="center" + |CD45
|PTPRC
|-
| style="background:#DCDCDC;" align="center" + |CD3 delta OR epsilon OR zeta
|CD3
|-
| style="background:#DCDCDC;" align="center" + |Coronin 1A
|CORO1A
|-
| style="background:#DCDCDC;" align="center" + |''Recombinase activating genes 1 and 2''
|RAG1/RAG2
|-
| style="background:#DCDCDC;" align="center" + |''DNA cross-link repair enzyme 1C'' 
| ''DCLRE1C(Artemis)''
|-
| style="background:#DCDCDC;" align="center" + |''Adenosine deaminase''
|ADA
|-
| style="background:#DCDCDC;" align="center" + |Adenylate kinase 2
|AK2
|-
| style="background:#DCDCDC;" align="center" + |DNA ligase IV
|LIG4
|-
| style="background:#DCDCDC;" align="center" + |Nonhomologous end-joining protein 1 
|    ''NHEJ1''
|}

==Differentiating {{PAGENAME}} from Other Diseases==
* Severe combined immunodeficiency must be differentiated from other diseases that cause recurrent and/or opportunistic infection, chronic diarrhea, and failure to thrive (FTT), such as:<ref>{{Cite journal
 | author = [[Jessica C. Barry]], [[Terrence Blaine Crowley]], [[Soma Jyonouchi]], [[Jennifer Heimall]], [[Elaine H. Zackai]], [[Kathleen E. Sullivan]] & [[Donna M. McDonald-McGinn]]
 | title = Identification of 22q11.2 Deletion Syndrome via Newborn Screening for Severe Combined Immunodeficiency
 | journal = [[Journal of clinical immunology]]
 | volume = 37
 | issue = 5
 | pages = 476–485
 | year = 2017
 | month = July
 | doi = 10.1007/s10875-017-0403-9
 | pmid = 28540525
}}</ref><ref>{{Cite journal
 | author = [[I. Celine Hanson]] & [[William T. Shearer]]
 | title = Ruling out HIV infection when testing for severe combined immunodeficiency and other T-cell deficiencies
 | journal = [[The Journal of allergy and clinical immunology]]
 | volume = 129
 | issue = 3
 | pages = 875–876
 | year = 2012
 | month = March
 | doi = 10.1016/j.jaci.2012.01.065
 | pmid = 22386446
}}</ref><ref>{{Cite journal
 | author = [[Arturo Borzutzky]], [[Brian Crompton]], [[Anke K. Bergmann]], [[Silvia Giliani]], [[Sachin Baxi]], [[Madelena Martin]], [[Ellis J. Neufeld]] & [[Luigi D. Notarangelo]]
 | title = Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter
 | journal = [[Clinical immunology (Orlando, Fla.)]]
 | volume = 133
 | issue = 3
 | pages = 287–294
 | year = 2009
 | month = December
 | doi = 10.1016/j.clim.2009.08.006
 | pmid = 19740703
}}</ref>
:* [[X-linked agammaglobulinemia|Agammaglobulinemia]]
:* [[Human Immunodeficiency Virus (HIV)|HIV]]/[[HIV AIDS|AIDS]]
:* Syndromes like [[22q11.2 deletion syndrome|DiGeorge]], [[CHARGE syndrome|CHARGE]], [[Wiskott-Aldrich syndrome|Wiskott-Aldrich]], [[cartilage-hair hypoplasia]]
:* Extreme [[malnutrition]]
===Differentiating SCID from other causes of humoral immunodeficiency===
SCID should be differentiated from other disorders leading to [[hypogammaglobulinemia]] and defects of [[humoral immunity]]. The following conditions may be considered as differentials:<ref name="pmid17910333">{{cite journal |vauthors=Agarwal S, Cunningham-Rundles C |title=Assessment and clinical interpretation of reduced IgG values |journal=Ann. Allergy Asthma Immunol. |volume=99 |issue=3 |pages=281–3 |date=September 2007 |pmid=17910333 |pmc=3099256 |doi=10.1016/S1081-1206(10)60665-5 |url=}}</ref><ref name="pmid7679206">{{cite journal |vauthors=Korthäuer U, Graf D, Mages HW, Brière F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA |title=Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM |journal=Nature |volume=361 |issue=6412 |pages=539–41 |date=February 1993 |pmid=7679206 |doi=10.1038/361539a0 |url=}}</ref><ref name="pmid9255191">{{cite journal |vauthors=Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, Resnick I, Fasth A, Baer M, Gomez L, Sanders EA, Tabone MD, Plantaz D, Etzioni A, Monafo V, Abinun M, Hammarstrom L, Abrahamsen T, Jones A, Finn A, Klemola T, DeVries E, Sanal O, Peitsch MC, Notarangelo LD |title=Clinical spectrum of X-linked hyper-IgM syndrome |journal=J. Pediatr. |volume=131 |issue=1 Pt 1 |pages=47–54 |date=July 1997 |pmid=9255191 |doi= |url=}}</ref><ref name="pmid14663287">{{cite journal |vauthors=Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME |title=The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients |journal=Medicine (Baltimore) |volume=82 |issue=6 |pages=373–84 |date=November 2003 |pmid=14663287 |doi=10.1097/01.md.0000100046.06009.b0 |url=}}</ref><ref name="pmid10352287">{{cite journal |vauthors=Subauste CS, Wessendarp M, Sorensen RU, Leiva LE |title=CD40-CD40 ligand interaction is central to cell-mediated immunity against Toxoplasma gondii: patients with hyper IgM syndrome have a defective type 1 immune response that can be restored by soluble CD40 ligand trimer |journal=J. Immunol. |volume=162 |issue=11 |pages=6690–700 |date=June 1999 |pmid=10352287 |doi= |url=}}</ref><ref name="pmid8993019">{{cite journal |vauthors=Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, Bonnefoy JY, Cosyns M, Weinberg A |title=Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM |journal=J. Immunol. |volume=158 |issue=2 |pages=977–83 |date=January 1997 |pmid=8993019 |doi= |url=}}</ref><ref name="pmid20180797">{{cite journal |vauthors=Davies EG, Thrasher AJ |title=Update on the hyper immunoglobulin M syndromes |journal=Br. J. Haematol. |volume=149 |issue=2 |pages=167–80 |date=April 2010 |pmid=20180797 |pmc=2855828 |doi=10.1111/j.1365-2141.2010.08077.x |url=}}</ref><ref name="pmid20101521">{{cite journal |vauthors=Yel L |title=Selective IgA deficiency |journal=J. Clin. Immunol. |volume=30 |issue=1 |pages=10–6 |date=January 2010 |pmid=20101521 |pmc=2821513 |doi=10.1007/s10875-009-9357-x |url=}}</ref><ref name="pmid19153537">{{cite journal |vauthors=Suzuki H, Kaneko H, Fukao T, Jin R, Kawamoto N, Asano T, Matsui E, Kasahara K, Kondo N |title=Various expression patterns of alpha1 and alpha2 genes in IgA deficiency |journal=Allergol Int |volume=58 |issue=1 |pages=111–7 |date=March 2009 |pmid=19153537 |doi=10.2332/allergolint.O-08-549 |url=}}</ref><ref name="pmid11720003">{{cite journal |vauthors=Cunningham-Rundles C |title=Physiology of IgA and IgA deficiency |journal=J. Clin. Immunol. |volume=21 |issue=5 |pages=303–9 |date=September 2001 |pmid=11720003 |doi= |url=}}</ref><ref name="pmid15093556">{{cite journal |vauthors=Edwards E, Razvi S, Cunningham-Rundles C |title=IgA deficiency: clinical correlates and responses to pneumococcal vaccine |journal=Clin. Immunol. |volume=111 |issue=1 |pages=93–7 |date=April 2004 |pmid=15093556 |doi=10.1016/j.clim.2003.12.005 |url=}}</ref><ref name="pmid305332">{{cite journal |vauthors=Chipps BE, Talamo RC, Winkelstein JA |title=IgA deficiency, recurrent pneumonias, and bronchiectasis |journal=Chest |volume=73 |issue=4 |pages=519–26 |date=April 1978 |pmid=305332 |doi= |url=}}</ref><ref name="pmid5056860">{{cite journal |vauthors=Zinneman HH, Kaplan AP |title=The association of giardiasis with reduced intestinal secretory immunoglobulin A |journal=Am J Dig Dis |volume=17 |issue=9 |pages=793–7 |date=September 1972 |pmid=5056860 |doi= |url=}}</ref><ref name="pmid18683032">{{cite journal |vauthors=Aghamohammadi A, Cheraghi T, Gharagozlou M, Movahedi M, Rezaei N, Yeganeh M, Parvaneh N, Abolhassani H, Pourpak Z, Moin M |title=IgA deficiency: correlation between clinical and immunological phenotypes |journal=J. Clin. 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{| class="wikitable"
|+
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Disorder 
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Defect (Mechanism of Development)
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Characteristic Features
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Clinical Presentation
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Laboratory Findings
|-
|[[X-linked agammaglobulinemia|'''X-Linked (Bruton) Agammaglobulinemia''']]
|
* Defect in [[tyrosine kinase]] [[gene]] ([[Bruton's tyrosine kinase|BTK]])
* [[B cells]] fail to mature
|
* [[X-linked recessive]] pattern of inheritance
* Increased [[prevalence]] in [[males]]
|
* Recurrent [[bacterial]] and [[enteroviral]] [[infections]] after 6 months of age 
* Pre-disposition to development of [[infections]] by [[encapsulated organisms]]
* Pre-disposition to development of Giardia infections
* Absent lymph nodes and tonsils
|
* Normal [[CD19|CD19+ B cell]] count
* Decreased pro-[[B cells]] 
* Increased pre-[[B cells]]
* Decreased [[immunoglobulins]] of all classes 
|-
|[[IgA deficiency|'''Selective IgA Deficiency''']]
|
* [[Stem cell]] defect (Transferrable with [[Bone marrow transplant|marrow transplant]])
* Lack of [[Interleukin 4|IL-4]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 10|IL-10]], [[TGF beta|TGF-β]], and [[Interleukin 21|IL-21]]
* [[Mutations]] in [[transmembrane]] activator and calcium-modulator and [[cyclophilin]] ligand interactor ([[TACI]], [[TNFRSF13B]]) 
|
* Most common primary [[immune deficiency]]
|
* Majority of the cases are [[asymptomatic]]
* Respiratory and [[gastrointestinal]] infections ([[mucosal]] infections)
* Associated with [[autoimmune diseases]]
* [[Atopy]]
* [[Anaphylaxis]] to [[IgA]] containing products
|
* Serum [[IgA]] < 7 mg/dl
* Normal [[IgG]] and [[IgM]] levels
|-
|[[Common variable immunodeficiency|'''Common Variable Immunodeficiency''']]
|
* Defective [[B cell]] differentiation
|
* May be acquired in 20-30 years of age
|
* May present with other [[autoimmune diseases]]
* Associated with [[bronchiectasis]]
* Associated with [[lymphoma]]
* Associated with sinopulmonary infections ([[Bacterial]], [[enteroviral]] and [[parasitic]] such as [[Giardia]])
|
* Decreased [[plasma cells]]
* Decreased [[immunoglobulins]]
|-
|[[Job's syndrome|'''Autosomal dominant hype IgE syndrome (Job's Syndrome)''']]
|
* Defieciency of [[T helper 17 cell|Th17 cells]] due to [[STAT3]] [[mutation]]
* Impaired [[neutrophils]] to sites of [[infection]]
|
* Distinctive coarse facies
* Cold (non-inflammatory) Staphylococcal abscesses
* Retained primary teeth
* Eczema
|
|
* Increased levels of [[IgE]]
* Decreased levels of [[interferon gamma]] (IFN-gamma)
|-
|[[Severe combined immunodeficiency|'''Severe combined immunodeficiency (SCID)''']]
|
* Defective [[Interleukin-2 receptor|interleukin-2 receptor gamma chain]] 
* [[Adenosine deaminase]] deficiency
* Reg 1 and Reg 2 [[nonsense mutations]]
|
* [[Interleukin 20 receptor, alpha subunit|IL-2R]] disease is [[X-linked]]
* [[Adenosine deaminase|ADA]] deficiency and reg mutations are typically [[autosomal recessive]]
|
* [[Failure to thrive]]
* [[Chronic diarrhea]]
* [[Thrush]]
* Recurrent [[bacterial]], [[viral]] and [[protozoal]] infections
* Treatment is [[bone marrow]] [[transplant]]
|
* Decreased [[T cell]] receptor excision circles (TRECs)
* Abscence of [[thymic]] shadow on [[Chest X-ray|chest X-Ray]]
* Absent [[germinal centers]] of [[lymph node biopsy]]
* Absent [[T cells]] on [[flow cytometry]]
|-
|[[Ataxia telangiectasia|'''Ataxia Telangiectasia''']]
|
* Defect in [[ATM|ATM gene]]
* [[DNA]] double stranded breaks leading to [[cell cycle]] arrest
|
* Hypersensitivity to [[X-Ray|X-Rays]]
|
* Triad of:
** [[Ataxia]]
** Spider [[Angioma|angiomas]] (Nests of distended [[capillaries]])
** [[IgA deficiency]]
|
* Increased [[alpha fetoprotein]] ([[Alpha-fetoprotein|AFP]])
* Decreased [[IgA]], [[IgG]] and [[IgE]]
* [[Lymphopenia]]
* [[Cerebellar]] atrophy
|-
|[[Hyper IgM Syndrome Type 1|'''Hyper IgM Syndrome''']]
|
* Defective [[CD40L]] ([[CD40L|CD40 ligand]]) on [[T helper cell|Th cells]] leading to [[class switching]] defect
|
* [[X-linked recessive]] pattern of inheritance
|
* Severe pyogenic infections in early life
* Opportunistic infection with:
** [[Pneumocystis jiroveci]]
** [[Cryptosporidium]]
** [[Cytomegalovirus]] ([[Cytomegalovirus infection|CMV]])
|
* Increased [[Immunoglobulin M|IgM]]
* Decreased [[Immunoglobulin G|IgG]], [[IgA]] and [[Immunoglobulin E|IgE]]
* No [[germinal centers]]
|-
|[[Wiskott-Aldrich syndrome|'''Wiskott-Aldrich Syndrome''']]
|
* [[Mutation]] in [[WAS]] [[gene]]
* [[T cells]] unable to reorganize [[actin]] [[microfilaments]] ([[microfilament]] defect) 
|
* [[X-linked recessive]] pattern of inheritance 
* Increased risk of [[autoimmune disease]] and [[malignancy]]
|
* [[Thrombocytopenic purpura]]
* [[Eczema]]
* Recurrent [[infections]]
|
* Decreased to normal [[Immunoglobulin G|IgG]] and [[Immunoglobulin M|IgM]]
* Increased [[Immunoglobulin E|IgE]] and [[IgA]]
* Fewer and smaller [[platelets]]
|}
:*Malignancy: can cause the reduction in the immunoglobulin production.<ref>{{Cite journal
 | author = [[T. Zenone]], [[P. J. Souquet]], [[C. Cunningham-Rundles]] & [[J. P. Bernard]]
 | title = Hodgkin's disease associated with IgA and IgG subclass deficiency
 | journal = [[Journal of internal medicine]]
 | volume = 240
 | issue = 2
 | pages = 99–102
 | year = 1996
 | month = August
 | pmid = 8810936
}}</ref>
*Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia.. 
*Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.<ref>{{Cite journal
 | author = [[W. B. Klaustermeyer]], [[M. E. Gianos]], [[M. L. Kurohara]], [[H. T. Dao]] & [[D. C. Heiner]]
 | title = IgG subclass deficiency associated with corticosteroids in obstructive lung disease
 | journal = [[Chest]]
 | volume = 102
 | issue = 4
 | pages = 1137–1142
 | year = 1992
 | month = October
 | pmid = 1343817
}}</ref>
*Other causes of primary humoral immunodeficiencies.
*Smoking: may cause IgG2 subclass deficiency.<ref>{{Cite journal
 | author = [[I. Qvarfordt]], [[G. C. Riise]], [[B. A. Andersson]] & [[S. Larsson]]
 | title = IgG subclasses in smokers with chronic bronchitis and recurrent exacerbations
 | journal = [[Thorax]]
 | volume = 56
 | issue = 6
 | pages = 445–449
 | year = 2001
 | month = June
 | pmid = 11359959
}}</ref>
*Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

==Epidemiology and Demographics==
* A study using data from newborn screening for SCID in the United States found an incidence of 1 in 58,000 livebirths for SCID, inclusive of typical SCID, leaky SCID, and Omenn syndrome. <ref>{{Cite journal
 | author = [[Antonia Kwan]], [[Roshini S. Abraham]], [[Robert Currier]], [[Amy Brower]], [[Karen Andruszewski]], [[Jordan K. Abbott]], [[Mei Baker]], [[Mark Ballow]], [[Louis E. Bartoshesky]], [[Francisco A. Bonilla]], [[Charles Brokopp]], [[Edward Brooks]], [[Michele Caggana]], [[Jocelyn Celestin]], [[Joseph A. Church]], [[Anne Marie Comeau]], [[James A. Connelly]], [[Morton J. Cowan]], [[Charlotte Cunningham-Rundles]], [[Trivikram Dasu]], [[Nina Dave]], [[Maria T. De La Morena]], [[Ulrich Duffner]], [[Chin-To Fong]], [[Lisa Forbes]], [[Debra Freedenberg]], [[Erwin W. Gelfand]], [[Jaime E. Hale]], [[I. Celine Hanson]], [[Beverly N. Hay]], [[Diana Hu]], [[Anthony Infante]], [[Daisy Johnson]], [[Neena Kapoor]], [[Denise M. Kay]], [[Donald B. Kohn]], [[Rachel Lee]], [[Heather Lehman]], [[Zhili Lin]], [[Fred Lorey]], [[Aly Abdel-Mageed]], [[Adrienne Manning]], [[Sean McGhee]], [[Theodore B. Moore]], [[Stanley J. Naides]], [[Luigi D. Notarangelo]], [[Jordan S. Orange]], [[Sung-Yun Pai]], [[Matthew Porteus]], [[Ray Rodriguez]], [[Neil Romberg]], [[John Routes]], [[Mary Ruehle]], [[Arye Rubenstein]], [[Carlos A. Saavedra-Matiz]], [[Ginger Scott]], [[Patricia M. Scott]], [[Elizabeth Secord]], [[Christine Seroogy]], [[William T. Shearer]], [[Subhadra Siegel]], [[Stacy K. Silvers]], [[E. Richard Stiehm]], [[Robert W. Sugerman]], [[John L. Sullivan]], [[Susan Tanksley]], [[Millard L. 4th Tierce]], [[James Verbsky]], [[Beth Vogel]], [[Rosalyn Walker]], [[Kelly Walkovich]], [[Jolan E. Walter]], [[Richard L. Wasserman]], [[Michael S. Watson]], [[Geoffrey A. Weinberg]], [[Leonard B. Weiner]], [[Heather Wood]], [[Anne B. Yates]], [[Jennifer M. Puck]] & [[Vincent R. Bonagura]]
 | title = Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States
 | journal = [[JAMA]]
 | volume = 312
 | issue = 7
 | pages = 729–738
 | year = 2014
 | month = August
 | doi = 10.1001/jama.2014.9132
 | pmid = 25138334
}}</ref> The incidence of autosomal-recessive SCID is higher in cultures in which consanguineous marriage is common.<ref>{{Cite journal
 | author = [[Waleed Al-Herz]] & [[Hamoud Al-Mousa]]
 | title = Combined immunodeficiency: the Middle East experience
 | journal = [[The Journal of allergy and clinical immunology]]
 | volume = 131
 | issue = 3
 | pages = 658–660
 | year = 2013
 | month = March
 | doi = 10.1016/j.jaci.2012.11.033
 | pmid = 23321211
}}</ref>

==Risk Factors==
* There are no established risk factors for SCID, however, the incidence of autosomal-recessive SCID is higher in cultures in which consanguineous marriage is common.<ref>{{Cite journal
 | author = [[Waleed Al-Herz]] & [[Hamoud Al-Mousa]]
 | title = Combined immunodeficiency: the Middle East experience
 | journal = [[The Journal of allergy and clinical immunology]]
 | volume = 131
 | issue = 3
 | pages = 658–660
 | year = 2013
 | month = March
 | doi = 10.1016/j.jaci.2012.11.033
 | pmid = 23321211
}}</ref>

==Screening==
* Preferably, SCID can be diagnosed in a newborn before the beginning of infections, with one well-documented example by screening of T cell–receptor excision circles (TRECs). Since the goal of newborn screening is to detect treatable disorders that are threatening to life or long-term health before they become symptomatic and prompt treatment of SCID may notably reduce mortality and morbidity among patients. Infants with SCID without reconstitution of a functioning immune system generally die of overwhelming infection by one year of age.

* T cell receptor excision circles (TRECs) as a biomarker of naïve T cells, is a sensitive and specific, as well as cost effective, method for SCID newborn screening.<ref>{{Cite journal
 | author = [[Kee Chan]] & [[Jennifer M. Puck]]
 | title = Development of population-based newborn screening for severe combined immunodeficiency
 | journal = [[The Journal of allergy and clinical immunology]]
 | volume = 115
 | issue = 2
 | pages = 391–398
 | year = 2005
 | month = February
 | doi = 10.1016/j.jaci.2004.10.012
 | pmid = 15696101
}}</ref>

==Natural History, Complications, and Prognosis==
===Natural History===
* Patients with severe combined immunodeficiency (SCID) may present with multiple recurrent severe [[Infection|infections]], [[chronic diarrhea]], and [[failure to thrive]] ([[FTT]]) In the past, SCID was often diagnosed after children acquired serious infections, such as [[pneumonia]] due to [[Pneumocystis jirovecii pneumonia|Pneumocystis jiroveci]] . <ref>{{Cite journal
 | author = [[Linda M. Griffith]], [[Morton J. Cowan]], [[Luigi D. Notarangelo]], [[Jennifer M. Puck]], [[Rebecca H. Buckley]], [[Fabio Candotti]], [[Mary Ellen Conley]], [[Thomas A. Fleisher]], [[H. Bobby Gaspar]], [[Donald B. Kohn]], [[Hans D. Ochs]], [[Richard J. O'Reilly]], [[J. Douglas Rizzo]], [[Chaim M. Roifman]], [[Trudy N. Small]] & [[William T. Shearer]]
 | title = Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management
 | journal = [[The Journal of allergy and clinical immunology]]
 | volume = 124
 | issue = 6
 | pages = 1152–1160
 | year = 2009
 | month = December
 | doi = 10.1016/j.jaci.2009.10.022
 | pmid = 20004776
}}</ref>

===Complications===
* Patients are at risk for infections from  opportunistic infections usually follow more common infections. [[Pneumocystis jirovecii pneumonia|P. jiroveci]] and [[Fungal pneumonia|fungal pneumonias]] cause death in classic cases. [[Cytomegalovirus infection|CMV]], [[Varicella zoster virus|VZV]], and [[Herpes simplex virus|HSV]] infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other [[Enterovirus|enteroviruses]] impedes stem cell reconstitution.

===Prognosis===
* SCID is fatal, generally within the first year of life, unless the underlying defect is corrected.Early diagnosis through population-wide newborn screening  and early transplantation in the absence of infectious complications may improve [[hematopoietic cell]] [[Organ transplant|transplantation]] (HCT) outcomes.  Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent. <ref>{{Cite journal
 | author = [[Jennifer Heimall]], [[Brent R. Logan]], [[Morton J. Cowan]], [[Luigi D. Notarangelo]], [[Linda M. Griffith]], [[Jennifer M. Puck]], [[Donald B. Kohn]], [[Michael A. Pulsipher]], [[Suhag Parikh]], [[Caridad Martinez]], [[Neena Kapoor]], [[Richard O'Reilly]], [[Michael Boyer]], [[Sung-Yun Pai]], [[Frederick Goldman]], [[Lauri Burroughs]], [[Sharat Chandra]], [[Morris Kletzel]], [[Monica Thakar]], [[James Connelly]], [[Geoff Cuvelier]], [[Blachy J. Davila Saldana]], [[Evan Shereck]], [[Alan Knutsen]], [[Kathleen E. Sullivan]], [[Kenneth DeSantes]], [[Alfred Gillio]], [[Elie Haddad]], [[Aleksandra Petrovic]], [[Troy Quigg]], [[Angela R. Smith]], [[Elizabeth Stenger]], [[Ziyan Yin]], [[William T. Shearer]], [[Thomas Fleisher]], [[Rebecca H. Buckley]] & [[Christopher C. Dvorak]]
 | title = Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study
 | journal = [[Blood]]
 | volume = 130
 | issue = 25
 | pages = 2718–2727
 | year = 2017
 | month = December
 | doi = 10.1182/blood-2017-05-781849
 | pmid = 29021228
}}</ref>

==Diagnosis==
===Diagnostic Criteria===
The diagnosis of SCID is made when patient is less than two years of age with either an absolute CD3 T cell count of less than 300/mm3, or an absolute CD3 T cell count of greater than 300/mm3 with absent naïve CD3/CD45RA T cells, at least one of the following  diagnostic criteria are met:<ref>{{Cite journal
 | author = [[Capucine Picard]], [[Waleed Al-Herz]], [[Aziz Bousfiha]], [[Jean-Laurent Casanova]], [[Talal Chatila]], [[Mary Ellen Conley]], [[Charlotte Cunningham-Rundles]], [[Amos Etzioni]], [[Steven M. Holland]], [[Christoph Klein]], [[Shigeaki Nonoyama]], [[Hans D. Ochs]], [[Eric Oksenhendler]], [[Jennifer M. Puck]], [[Kathleen E. Sullivan]], [[Mimi L. K. Tang]], [[Jose Luis Franco]] & [[H. Bobby Gaspar]]
 | title = Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015
 | journal = [[Journal of clinical immunology]]
 | volume = 35
 | issue = 8
 | pages = 696–726
 | year = 2015
 | month = November
 | doi = 10.1007/s10875-015-0201-1
 | pmid = 26482257
}}</ref>
* Male with deleterious mutation in the X-linked ''IL2RG'' gene encoding the cytokine receptor common gamma chain (gamma-c).
* Male or female patient with deleterious homozygous or compound heterozygous mutations in any of the genes listed in the Gene Defects table other than ''IL2RG''.
* ADA activity of less than 2% of control or mutations in both alleles of the ''ADA'' gene.
* Engraftment of transplacentally acquired maternal T cells.

===History and Symptoms===
Clinically, most patients present before age 3 months. The diagnosis of SCID should be suspected in children with any of the following:
* Positive newborn screening result for SCID
* Unexplained lymphopenia
* Recurrent fevers
* Failure to thrive (FTT)
* Chronic diarrhea
* Recurrence of severe episodes of thrush, mouth ulcers, respiratory syncytial virus (RSV), herpes simplex virus (HSV), varicella zoster virus (VZV), measles, influenza, or parainfluenza 3
* Adverse reactions (infections) caused by live vaccines, such as Bacillus Calmette-Guérin (BCG), rotavirus vaccine, or varicella vaccine
* A family history of SCID (seen in <20 percent of cases)

===Physical Examination===
Physical findings are multisystemic. The patient may present with the following:
* Fever
* Failure to thrive
* Dehydration due to chronic diarrhea
* Acute otitis media
* Absent lymphatic tissue
* Extensive candidiasis in the mouth and diaper area
* Recurrent skin abscesses and/or other severe skin infections

===Laboratory Findings===
Lymphopenia is the typical hallmark of severe combined immunodeficiency (SCID). Although, normal or even elevated lymphocyte counts may be observed in a remarkable number of patients. which makes the diagnosis a challenge especially in patients with Omenn syndrome, bare lymphocyte syndrome, and interleukin (IL)–2 deficiency.  Obtaining lymphocyte subpopulations as determined by flow cytometry and evaluation of T cell proliferative responses to mitogens are laboratory findings which can help to diagnose among patients  lymphopenia is not frankly detected.

The classic laboratory findings in SCID include low to absent T cell count and function, as evaluated by T cell enumeration by flow cytometry and T cell proliferation to mitogens such as phytohemagglutinin (PHA) and concanavalin A (ConA). <ref>{{Cite journal
 | author = [[Brian T. Kelly]], [[Jonathan S. Tam]], [[James W. Verbsky]] & [[John M. Routes]]
 | title = Screening for severe combined immunodeficiency in neonates
 | journal = [[Clinical epidemiology]]
 | volume = 5
 | pages = 363–369
 | year = 2013
 | month = 
 | doi = 10.2147/CLEP.S48890
 | pmid = 24068875
}}</ref>

Laboratory findings necessary to confirm the diagnosis and used for diagnostic criteria include an absolute CD3+ T cell count of <300 cells/microL and/or maternal T cells in the circulation.

===Imaging Findings===
A chest x-ray may be helpful in the diagnosis of SCID. The thymic shadow is absent on chest radiography among the majority of patients with SCID, thus, a chest x-ray may be helpful in the newborn suspected of SCID.  In addition, obtaining a chest x-ray may be helpful  to assess pneumonia secondary to SCID.

===Other Diagnostic Studies===
'''Detection of maternal T cell engraftment''' : Since normal or even elevated lymphocyte counts may be observed in a remarkable number of patients, then such patients should be evaluated for maternal T cell engraftment. In some patients with SCID, maternal T cells which cross the placenta and enter the circulation of a fetus engraft subsequently may expand to levels >8000 cells/microL, that causes the total T cell count to appear incorrectly normal.<ref>{{Cite journal
 | author = [[S. M. Muller]], [[M. Ege]], [[A. Pottharst]], [[A. S. Schulz]], [[K. Schwarz]] & [[W. Friedrich]]
 | title = Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients
 | journal = [[Blood]]
 | volume = 98
 | issue = 6
 | pages = 1847–1851
 | year = 2001
 | month = September
 | pmid = 11535520
}}</ref> A majority of the maternally engrafted T cells express CD45RO while normal infant T cells are predominantly naïve and express CD45RA. These surface markers can be enumerated by flow cytometry.<ref>{{Cite journal
 | author = [[Stephen C. Jameson]] & [[David Masopust]]
 | title = Diversity in T cell memory: an embarrassment of riches
 | journal = [[Immunity]]
 | volume = 31
 | issue = 6
 | pages = 859–871
 | year = 2009
 | month = December
 | doi = 10.1016/j.immuni.2009.11.007
 | pmid = 20064446
}}</ref>

==Treatment==
===Medical Therapy===
The mainstay of treatment for all forms of SCID is [[hematopoietic cell]] [[Organ transplant|transplantation]] (HCT). The majority of cases of [[adenosine deaminase deficiency]] require [[enzyme]] replacement therapy (polyethylene glycol-adenosine deaminase [PEG-ADA]) or gene therapy. Gene therapy is also becoming an alternative for X-linked SCID (common gamma-chain deficiency) and other genetic forms of SCID.

Viral [[Infection|infections]] are a leading cause of death in patients with SCID, both before and in the first several months after HCT before T cell engraftment has occurred. The most commonly implicated viruses are [[Cytomegalovirus infection|CMV]], [[Epstein Barr virus|EBV]], and [[Adenovirus infection|adenovirus]]. Pharmacologic treatment and [[Prophylaxis|prophylactic]] options for viral infections remain limited and often ineffective, with associated morbidities notably from [[acute kidney injury]] and [[Bone marrow suppression|myelosuppression]]. Treatment may also generate [[Drug resistance|resistance]], and does not confer extended protection leaving patients at risk for viral reactivation.<ref>{{Cite journal
 | author = [[Marcie Tomblyn]], [[Tom Chiller]], [[Hermann Einsele]], [[Ronald Gress]], [[Kent Sepkowitz]], [[Jan Storek]], [[John R. Wingard]], [[Jo-Anne H. Young]] & [[Michael J. Boeckh]]
 | title = Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective
 | journal = [[Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation]]
 | volume = 15
 | issue = 10
 | pages = 1143–1238
 | year = 2009
 | month = October
 | doi = 10.1016/j.bbmt.2009.06.019
 | pmid = 19747629
}}</ref> Adoptive immunotherapy with virus-specific T cells (VST) can be used along with antiviral agents to treat these life-threatening viral infections.<ref>{{Cite journal
 | author = [[Amy Houghtelin]] & [[Catherine M. Bollard]]
 | title = Virus-Specific T Cells for the Immunocompromised Patient
 | journal = [[Frontiers in immunology]]
 | volume = 8
 | pages = 1272
 | year = 2017
 | month = 
 | doi = 10.3389/fimmu.2017.01272
 | pmid = 29075259
}}</ref>

===Primary Prevention===
* There are no established measures for the primary prevention of SCID. 

===Secondary Prevention===
Effective measures for the secondary prevention of SCID include:<ref>{{Cite journal
 | author = [[Linda M. Griffith]], [[Morton J. Cowan]], [[Luigi D. Notarangelo]], [[Jennifer M. Puck]], [[Rebecca H. Buckley]], [[Fabio Candotti]], [[Mary Ellen Conley]], [[Thomas A. Fleisher]], [[H. Bobby Gaspar]], [[Donald B. Kohn]], [[Hans D. Ochs]], [[Richard J. O'Reilly]], [[J. Douglas Rizzo]], [[Chaim M. Roifman]], [[Trudy N. Small]] & [[William T. Shearer]]
 | title = Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management
 | journal = [[The Journal of allergy and clinical immunology]]
 | volume = 124
 | issue = 6
 | pages = 1152–1160
 | year = 2009
 | month = December
 | doi = 10.1016/j.jaci.2009.10.022
 | pmid = 20004776
}}</ref>
* Mothers with a history of a prior affected child with SCID should receive recommended booster [[Vaccine|vaccines]] prior to [[Childbirth|delivery]] to provide [[transplacental]] [[antibodies]]
* Protective [[Isolation (health care)|isolation]] for neonates with suspected SCID before receiving definitive treatment
* All [[blood product]]<nowiki/>s must be irradiated, leukodepleted, and [[cytomegalovirus]] ([[Cytomegalovirus infection|CMV]]) negative
Typical prophylaxis against infection includes:
* [[Antibody|Immune globulin]] replacement therapy
* Prophylaxis for [[Pneumocystis jirovecii|Pneumocystis ''jirovecii'']] pneumonia with [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]].
* Antifungal prophylaxis with [[fluconazole]]
* [[Monoclonal antibodies|Monoclonal antibody]] against [[Human respiratory syncytial virus|respiratory syncytial virus]] (RSV) with [[palivizumab]]
* Antiviral agent for prophylaxis against [[Herpes simplex virus|HSV]], [[Cytomegalovirus infection|CMV]], [[Epstein Barr virus|EBV]]

==References==
{{reflist|2}}

{{Immune disorders}}
{{DNA repair-deficiency disorder}}

[[Category:Immunology]]
[[Category:Hematology]]