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X-linked severe combined immunodeficiency(SCIDX1)

MedGen UID:
220906
Concept ID:
C1279481
Disease or Syndrome
Synonyms: IMMUNODEFICIENCY 4; SCIDX1; Severe combined immunodeficiency T- B+ due to gamma chain deficiency; Severe combined immunodeficiency T- B+, X-linked; Severe combined immunodeficiency, X-linked, T cell-negative, B cell-positive, NK cell-negative; X-Linked Combined Immunodeficiency Diseases; X-linked SCID
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
X-linked recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: X-linked severe combined immunodeficiency (203592006); XSCID - X-linked severe combined immunodeficiency (203592006); SCID - X-linked severe combined immunodeficiency (203592006); Thymic epithelial hypoplasia (203592006); X-linked lymphopenic agammaglobulinemia (203592006)
 
Gene (location): IL2RG (Xq13.1)
OMIM®: 300400

Definition

X-linked severe combined immunodeficiency (X-SCID) is a combined cellular and humoral immunodeficiency caused by a hemizygous pathogenic variant in IL2RG. In typical X-SCID lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes. X-SCID is almost universally fatal in the first two years of life unless reconstitution of the immune system is achieved through bone marrow transplant or gene therapy. In the absence of family history of X-SCID and prior to newborn screening for X-SCID, most males with typical X-SCID come to medical attention between ages three and six months with failure to thrive, oral/diaper candidiasis, absent tonsils and lymph nodes, recurrent infections, infections with opportunistic organisms such as Pneumocystis, and persistence of infections despite conventional treatment. Additional common features include rashes, diarrhea, cough and congestion, fevers, pneumonia, sepsis, and other severe bacterial infections. Males with atypical X-SCID may have immune dysregulation and autoimmunity associated with rashes, gastrointestinal malabsorption, and short stature. [from GTR]

Additional descriptions

From GeneReviews
X-linked severe combined immunodeficiency (X-SCID) is a combined cellular and humoral immunodeficiency caused by a hemizygous pathogenic variant in IL2RG. In typical X-SCID lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes. X-SCID is almost universally fatal in the first two years of life unless reconstitution of the immune system is achieved through bone marrow transplant or gene therapy. In the absence of family history of X-SCID and prior to newborn screening for X-SCID, most males with typical X-SCID come to medical attention between ages three and six months with failure to thrive, oral/diaper candidiasis, absent tonsils and lymph nodes, recurrent infections, infections with opportunistic organisms such as Pneumocystis, and persistence of infections despite conventional treatment. Additional common features include rashes, diarrhea, cough and congestion, fevers, pneumonia, sepsis, and other severe bacterial infections. Males with atypical X-SCID may have immune dysregulation and autoimmunity associated with rashes, gastrointestinal malabsorption, and short stature.  https://www.ncbi.nlm.nih.gov/books/NBK1410
From GHR
X-linked severe combined immunodeficiency (SCID) is an inherited disorder of the immune system that occurs almost exclusively in males. Boys with X-linked SCID are prone to recurrent and persistent infections because they lack the necessary immune cells to fight off certain bacteria, viruses, and fungi. Many infants with X-linked SCID develop chronic diarrhea, a fungal infection called thrush, and skin rashes. Affected individuals also grow more slowly than other children. Without treatment, males with X-linked SCID usually do not live beyond infancy.  https://ghr.nlm.nih.gov/condition/x-linked-severe-combined-immunodeficiency

Clinical features

Hypoplasia of the thymus
MedGen UID:
146347
Concept ID:
C0685891
Congenital Abnormality
Underdevelopment of the thymus.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Recurrent bacterial meningitis
MedGen UID:
375697
Concept ID:
C1845604
Disease or Syndrome
An increased susceptibility to bacterial meningitis as manifested by a medical history of recurrent episodes of bacterial meningitis.
Agammaglobulinemia
MedGen UID:
168
Concept ID:
C0001768
Disease or Syndrome
Absence of the gamma fraction of serum globulin
Pneumonia
MedGen UID:
10813
Concept ID:
C0032285
Disease or Syndrome
An acute, acute and chronic, or chronic inflammation focally or diffusely affecting the lung parenchyma, due to infections (viruses, fungi, mycoplasma, or bacteria), treatment (e.g. radiation), or exposure (inhalation) to chemicals. Symptoms include cough, shortness of breath, fevers, chills, chest pain, headache, sweating, and weakness.
Agammaglobulinemia
MedGen UID:
168
Concept ID:
C0001768
Disease or Syndrome
Absence of the gamma fraction of serum globulin
Skin rash
MedGen UID:
8732
Concept ID:
C0015230
Finding
A red eruption of the skin.
Pneumonia
MedGen UID:
10813
Concept ID:
C0032285
Disease or Syndrome
An acute, acute and chronic, or chronic inflammation focally or diffusely affecting the lung parenchyma, due to infections (viruses, fungi, mycoplasma, or bacteria), treatment (e.g. radiation), or exposure (inhalation) to chemicals. Symptoms include cough, shortness of breath, fevers, chills, chest pain, headache, sweating, and weakness.
Severe combined immunodeficiency disease
MedGen UID:
88328
Concept ID:
C0085110
Disease or Syndrome
Group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. It is inherited as an X-linked or autosomal recessive defect. Mutations occurring in many different genes cause human Severe Combined Immunodeficiency (SCID).
Hypoplasia of the thymus
MedGen UID:
146347
Concept ID:
C0685891
Congenital Abnormality
Underdevelopment of the thymus.
Recurrent fungal infections
MedGen UID:
336166
Concept ID:
C1844384
Finding
Increased susceptibility to fungal infections, as manifested by recurrent episodes of fungal infection.
Chronic oral candidiasis
MedGen UID:
870166
Concept ID:
C4024599
Disease or Syndrome
Chronic accumulation and overgrowth of the fungus Candida albicans on the mucous membranes of the mouth, generally manifested as associated with creamy white lesions on the tongue or inner cheeks, occasionally spreading to the gums, tonsils, palate or oropharynx.
Agammaglobulinemia
MedGen UID:
168
Concept ID:
C0001768
Disease or Syndrome
Absence of the gamma fraction of serum globulin
Skin rash
MedGen UID:
8732
Concept ID:
C0015230
Finding
A red eruption of the skin.
Chronic oral candidiasis
MedGen UID:
870166
Concept ID:
C4024599
Disease or Syndrome
Chronic accumulation and overgrowth of the fungus Candida albicans on the mucous membranes of the mouth, generally manifested as associated with creamy white lesions on the tongue or inner cheeks, occasionally spreading to the gums, tonsils, palate or oropharynx.
Hypoplasia of the thymus
MedGen UID:
146347
Concept ID:
C0685891
Congenital Abnormality
Underdevelopment of the thymus.

Term Hierarchy

Recent clinical studies

Etiology

Shigemura T, Motobayashi M, Matsuda K, Shimodaira T, Kurata T, Kobayashi N, Agematsu K, Nakazawa Y
J Pediatr Hematol Oncol 2017 Nov;39(8):e470-e472. doi: 10.1097/MPH.0000000000000892. PMID: 28678090
Bai QL, Liu N, Kong XD, Xu XJ, Zhao ZH
Genet Mol Res 2015 Jun 11;14(2):6164-72. doi: 10.4238/2015.June.9.2. PMID: 26125817
Lee YW, Yang EA, Kang HJ, Yang X, Mitsuiki N, Ohara O, Miyawaki T, Kanegane H, Lee JH
J Investig Allergol Clin Immunol 2013;23(1):65-7. PMID: 23653982
Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debré M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana-Calvo M
N Engl J Med 2010 Jul 22;363(4):355-64. doi: 10.1056/NEJMoa1000164. PMID: 20660403Free PMC Article
Mustillo P, Bajwa RP, Termuhlen AM, Nicol K, Scherzer R, Jaffe R, Filipovich AH, Gross TG
Pediatr Blood Cancer 2008 Nov;51(5):706-9. doi: 10.1002/pbc.21651. PMID: 18615703

Diagnosis

Shigemura T, Motobayashi M, Matsuda K, Shimodaira T, Kurata T, Kobayashi N, Agematsu K, Nakazawa Y
J Pediatr Hematol Oncol 2017 Nov;39(8):e470-e472. doi: 10.1097/MPH.0000000000000892. PMID: 28678090
Mou W, He J, Chen X, Zhang H, Ren X, Wu X, Ni X, Xu B, Gui J
Immunogenetics 2017 Jan;69(1):29-38. Epub 2016 Aug 26 doi: 10.1007/s00251-016-0949-3. PMID: 27566612
Bai QL, Liu N, Kong XD, Xu XJ, Zhao ZH
Genet Mol Res 2015 Jun 11;14(2):6164-72. doi: 10.4238/2015.June.9.2. PMID: 26125817
Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T, Shimizu N, Kurahashi H, Yoshikawa T, Katano H, Inoue N, Imai K, Takagi M, Morio T, Mizutani S
Clin Infect Dis 2014 Aug 15;59(4):545-8. Epub 2014 May 6 doi: 10.1093/cid/ciu323. PMID: 24803376
Zhang C, Zhang ZY, Wu JF, Tang XM, Yang XQ, Jiang LP, Zhao XD
World J Pediatr 2013 Feb;9(1):42-7. Epub 2011 Nov 21 doi: 10.1007/s12519-011-0330-4. PMID: 22105576

Therapy

Shigemura T, Motobayashi M, Matsuda K, Shimodaira T, Kurata T, Kobayashi N, Agematsu K, Nakazawa Y
J Pediatr Hematol Oncol 2017 Nov;39(8):e470-e472. doi: 10.1097/MPH.0000000000000892. PMID: 28678090
De Ravin SS, Wu X, Moir S, Anaya-O'Brien S, Kwatemaa N, Littel P, Theobald N, Choi U, Su L, Marquesen M, Hilligoss D, Lee J, Buckner CM, Zarember KA, O'Connor G, McVicar D, Kuhns D, Throm RE, Zhou S, Notarangelo LD, Hanson IC, Cowan MJ, Kang E, Hadigan C, Meagher M, Gray JT, Sorrentino BP, Malech HL
Sci Transl Med 2016 Apr 20;8(335):335ra57. doi: 10.1126/scitranslmed.aad8856. PMID: 27099176Free PMC Article
Cavazzana M, Six E, Lagresle-Peyrou C, André-Schmutz I, Hacein-Bey-Abina S
Hum Gene Ther 2016 Feb;27(2):108-16. doi: 10.1089/hum.2015.137. PMID: 26790362Free PMC Article
Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernández KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ
N Engl J Med 2014 Oct 9;371(15):1407-17. doi: 10.1056/NEJMoa1404588. PMID: 25295500Free PMC Article
van der Loo JC, Swaney WP, Grassman E, Terwilliger A, Higashimoto T, Schambach A, Hacein-Bey-Abina S, Nordling DL, Cavazzana-Calvo M, Thrasher AJ, Williams DA, Reeves L, Malik P
Gene Ther 2012 Aug;19(8):872-6. Epub 2012 May 3 doi: 10.1038/gt.2012.37. PMID: 22551777Free PMC Article

Prognosis

Mou W, He J, Chen X, Zhang H, Ren X, Wu X, Ni X, Xu B, Gui J
Immunogenetics 2017 Jan;69(1):29-38. Epub 2016 Aug 26 doi: 10.1007/s00251-016-0949-3. PMID: 27566612
Wada T, Toma T, Yasui M, Inoue M, Kawa K, Imai K, Morio T, Yachie A
J Investig Allergol Clin Immunol 2016;26(1):63-5. PMID: 27012023
Tan W, Yu S, Lei J, Wu B, Wu C
Immunogenetics 2015 Nov;67(11-12):629-39. Epub 2015 Sep 26 doi: 10.1007/s00251-015-0871-0. PMID: 26409833
Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debré M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana-Calvo M
N Engl J Med 2010 Jul 22;363(4):355-64. doi: 10.1056/NEJMoa1000164. PMID: 20660403Free PMC Article
Huang LH, Shyur SD, Weng JD, Shin-Chi, Huang FY, Tzen CY
Pediatr Dermatol 2006 Nov-Dec;23(6):560-3. doi: 10.1111/j.1525-1470.2006.00309.x. PMID: 17155998

Clinical prediction guides

Shigemura T, Motobayashi M, Matsuda K, Shimodaira T, Kurata T, Kobayashi N, Agematsu K, Nakazawa Y
J Pediatr Hematol Oncol 2017 Nov;39(8):e470-e472. doi: 10.1097/MPH.0000000000000892. PMID: 28678090
Mou W, He J, Chen X, Zhang H, Ren X, Wu X, Ni X, Xu B, Gui J
Immunogenetics 2017 Jan;69(1):29-38. Epub 2016 Aug 26 doi: 10.1007/s00251-016-0949-3. PMID: 27566612
Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernández KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ
N Engl J Med 2014 Oct 9;371(15):1407-17. doi: 10.1056/NEJMoa1404588. PMID: 25295500Free PMC Article
Speckmann C, Pannicke U, Wiech E, Schwarz K, Fisch P, Friedrich W, Niehues T, Gilmour K, Buiting K, Schlesier M, Eibel H, Rohr J, Superti-Furga A, Gross-Wieltsch U, Ehl S
Blood 2008 Nov 15;112(10):4090-7. Epub 2008 Aug 26 doi: 10.1182/blood-2008-04-153361. PMID: 18728247
Ginn SL, Curtin JA, Kramer B, Smyth CM, Wong M, Kakakios A, McCowage GB, Watson D, Alexander SI, Latham M, Cunningham SC, Zheng M, Hobson L, Rowe PB, Fischer A, Cavazzana-Calvo M, Hacein-Bey-Abina S, Alexander IE
Med J Aust 2005 May 2;182(9):458-63. PMID: 15865589

Recent systematic reviews

Trobridge GD
Expert Opin Biol Ther 2011 May;11(5):581-93. Epub 2011 Mar 7 doi: 10.1517/14712598.2011.562496. PMID: 21375467Free PMC Article
Rans TS, England R
Ann Allergy Asthma Immunol 2009 May;102(5):357-62; quiz 363-5, 402. doi: 10.1016/S1081-1206(10)60504-2. PMID: 19492655
Strauss BE, Costanzi-Strauss E
Braz J Med Biol Res 2007 May;40(5):601-13. PMID: 17464421

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