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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, X-linked, T cell-negative, B cell-positive, NK cell-negative; T-B+ severe combined immunodeficiency due to gamma chain deficiency; X-Linked Combined Immunodeficiency Diseases
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: 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.
 
Gene (location): IL2RG (Xq13.1)
 
Monarch Initiative: MONDO:0010315
OMIM®: 300400
Orphanet: ORPHA276

Disease characteristics

Excerpted from the GeneReview: X-Linked Severe Combined Immunodeficiency
The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity). Typical X-SCID. Prior to universal newborn screening (NBS) for SCID most males with typical X-SCID came to medical attention between ages three and six months because of recurrent infections, persistent infections, and infections with opportunistic organisms. With universal NBS for SCID, the common presentation for typical X-SCID is now an asymptomatic, healthy-appearing male infant. Atypical X-SCID, which usually is not detected by NBS, can manifest in the first years of life or later with one of the following: recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications. [from GeneReviews]
Authors:
Eric J Allenspach  |  David J Rawlings  |  Aleksandra Petrovic, et. al.   view full author information

Additional description

From MedlinePlus Genetics
X-linked severe combined immunodeficiency (SCID) is an inherited disorder of the immune system that occurs almost exclusively in males. Children 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. 

If untreated, infants with X-linked SCID can develop poor growth, chronic diarrhea, a fungal infection called thrush, skin rashes, and life-threatening infections. X-linked SCID can be detected shortly after birth by newborn screening, which allows for prompt treatment.  https://medlineplus.gov/genetics/condition/x-linked-severe-combined-immunodeficiency

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size 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 pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Recurrent bronchitis
MedGen UID:
148159
Concept ID:
C0741796
Disease or Syndrome
An increased susceptibility to bronchitis as manifested by a history of recurrent bronchitis.
Agammaglobulinemia
MedGen UID:
168
Concept ID:
C0001768
Disease or Syndrome
A lasting absence of total IgG and total IgA and total IgM in the blood circulation, whereby at most trace quantities can be measured.
Otitis media
MedGen UID:
45253
Concept ID:
C0029882
Disease or Syndrome
Inflammation or infection of the middle ear.
Pneumonia
MedGen UID:
10813
Concept ID:
C0032285
Disease or Syndrome
Inflammation of any part of the lung parenchyma.
Sinusitis
MedGen UID:
20772
Concept ID:
C0037199
Disease or Syndrome
Inflammation of the paranasal sinuses owing to a viral, bacterial, or fungal infection, allergy, or an autoimmune reaction.
Severe combined immunodeficiency disease
MedGen UID:
88328
Concept ID:
C0085110
Disease or Syndrome
A type of primary immune deficiency that is characterized by a more severe defect in both the T- and B-lymphocyte systems.
Decreased circulating IgA level
MedGen UID:
57934
Concept ID:
C0162538
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
Decreased circulating total IgM
MedGen UID:
116095
Concept ID:
C0239989
Finding
An abnormally decreased level of immunoglobulin M (IgM) in blood.
Hypoplasia of the thymus
MedGen UID:
146347
Concept ID:
C0685891
Congenital Abnormality
Underdevelopment of the thymus.
Decreased circulating IgE
MedGen UID:
1714318
Concept ID:
C0853668
Finding
An abnormally decreased level of immunoglobulin E (IgE) in blood.
Decreased proportion of CD8-positive T cells
MedGen UID:
374188
Concept ID:
C1839305
Finding
A decreased proportion of circulating CD8-positive, alpha-beta T cells relative to total number of T cells.
Reduced natural killer cell activity
MedGen UID:
333452
Concept ID:
C1839969
Finding
Reduced ability of the natural killer cell to function in the adaptive immune response.
Recurrent fungal infections
MedGen UID:
336166
Concept ID:
C1844384
Disease or Syndrome
Increased susceptibility to fungal infections, as manifested by multiple episodes of fungal infection.
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.
Combined immunodeficiency
MedGen UID:
751396
Concept ID:
C2711630
Disease or Syndrome
A group of phenotypically heterogeneous genetic disorders characterized by profound deficiencies of T- and B-cell function, which predispose the patients to both infectious and noninfectious complications.
T lymphocytopenia
MedGen UID:
419385
Concept ID:
C2931322
Finding
An abnormally low count of T cells.
Abnormal natural killer cell count
MedGen UID:
866689
Concept ID:
C4021036
Finding
Any deviation from the normal overall count of natural killer (NK) cells in the circulation or a deviation from the normal distribution of NK cell subtypes.
Abnormal T cell count
MedGen UID:
866762
Concept ID:
C4021113
Finding
A deviation from the normal count of T cells.
Abnormal B cell count
MedGen UID:
866853
Concept ID:
C4021208
Finding
A deviation from the normal count of B cells, i.e., the cells that are formed in the bone marrow, migrate to the peripheral lymphatic system, and mature into plasma cells or memory cells.
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.
Impaired lymphocyte transformation with phytohemagglutinin
MedGen UID:
871152
Concept ID:
C4025625
Finding
Normal peripheral blood lymphocytes, when stimulated by phytohemagglutinin (PHA) are cytotoxic for homologous and heterologous cells but not for autologous cells in monolayer culture. The cytotoxic effect is thought to be indicative of the immunological competence of the lymphocytes.
Decreased circulating IgG level
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
Decreased proportion of CD4-positive helper T cells
MedGen UID:
1719772
Concept ID:
C5235140
Finding
A decreased proportion of circulating CD4-positive helper T cells relative to total T cell count.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
Pneumocystis carinii pneumonia
MedGen UID:
994080
Concept ID:
CN315554
Finding
Pneumocystis carinii pneumonia is an opportunistic infection that occurs in immunosuppressed populations.

Professional guidelines

PubMed

Kuo CY, Kohn DB
Curr Allergy Asthma Rep 2016 May;16(5):39. doi: 10.1007/s11882-016-0615-8. PMID: 27056559Free PMC Article
Farinelli G, Capo V, Scaramuzza S, Aiuti A
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Candotti F
Int J Hematol 2014 Apr;99(4):383-92. Epub 2014 Feb 1 doi: 10.1007/s12185-014-1524-z. PMID: 24488786

Recent clinical studies

Etiology

Zhang L, Li K, Liu Z, An L, Wei H, Pang S, Cao Z, Huang X, Jin X, Ma X
Mol Ther 2024 Jun 5;32(6):1658-1671. Epub 2024 Mar 26 doi: 10.1016/j.ymthe.2024.03.028. PMID: 38532630
Yan KK, Condori J, Ma Z, Metais JY, Ju B, Ding L, Dhungana Y, Palmer LE, Langfitt DM, Ferrara F, Throm R, Shi H, Risch I, Bhatara S, Shaner B, Lockey TD, Talleur AC, Easton J, Meagher MM, Puck JM, Cowan MJ, Zhou S, Mamcarz E, Gottschalk S, Yu J
Sci Adv 2023 Oct 6;9(40):eadg9959. doi: 10.1126/sciadv.adg9959. PMID: 37801507Free PMC Article
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Ghosh S, Gaspar HB
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Cavazzana-Calvo M, Hacein-Bey-Abina S, Fischer A
Curr Opin Allergy Clin Immunol 2002 Dec;2(6):507-9. doi: 10.1097/00130832-200212000-00005. PMID: 14752333

Diagnosis

Cavazzana-Calvo M, Hacein-Bey-Abina S, Fischer A
Curr Opin Allergy Clin Immunol 2002 Dec;2(6):507-9. doi: 10.1097/00130832-200212000-00005. PMID: 14752333
Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M
Int J Hematol 2002 Nov;76(4):295-8. doi: 10.1007/BF02982686. PMID: 12463590
Farner NL, Voss SD, Sondel PM
Clin Diagn Lab Immunol 1995 Sep;2(5):518-23. doi: 10.1128/cdli.2.5.518-523.1995. PMID: 8548528Free PMC Article
Conley ME
Clin Immunol Immunopathol 1991 Nov;61(2 Pt 2):S94-9. doi: 10.1016/s0090-1229(05)80043-1. PMID: 1934618
Schwaber J, Rosen FS
Immunodefic Rev 1990;2(3):233-51. PMID: 1981831

Therapy

Ghosh S, Gaspar HB
Hematol Oncol Clin North Am 2017 Oct;31(5):823-834. Epub 2017 Jun 29 doi: 10.1016/j.hoc.2017.05.003. PMID: 28895850
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
Wang X, Rickert M, Garcia KC
Science 2005 Nov 18;310(5751):1159-63. doi: 10.1126/science.1117893. PMID: 16293754
Cavazzana-Calvo M, Hacein-Bey-Abina S, Fischer A
Curr Opin Allergy Clin Immunol 2002 Dec;2(6):507-9. doi: 10.1097/00130832-200212000-00005. PMID: 14752333
Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M
Int J Hematol 2002 Nov;76(4):295-8. doi: 10.1007/BF02982686. PMID: 12463590

Prognosis

Yan KK, Condori J, Ma Z, Metais JY, Ju B, Ding L, Dhungana Y, Palmer LE, Langfitt DM, Ferrara F, Throm R, Shi H, Risch I, Bhatara S, Shaner B, Lockey TD, Talleur AC, Easton J, Meagher MM, Puck JM, Cowan MJ, Zhou S, Mamcarz E, Gottschalk S, Yu J
Sci Adv 2023 Oct 6;9(40):eadg9959. doi: 10.1126/sciadv.adg9959. PMID: 37801507Free PMC Article
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
Chinen J, Shearer WT
J Allergy Clin Immunol 2005 Aug;116(2):411-8. doi: 10.1016/j.jaci.2005.05.010. PMID: 16083798
Cavazzana-Calvo M, Hacein-Bey-Abina S, Fischer A
Curr Opin Allergy Clin Immunol 2002 Dec;2(6):507-9. doi: 10.1097/00130832-200212000-00005. PMID: 14752333
Schwaber J, Rosen FS
Immunodefic Rev 1990;2(3):233-51. PMID: 1981831

Clinical prediction guides

Ahmed B, Zafar M, Qadir MI
Crit Rev Eukaryot Gene Expr 2019;29(6):511-520. doi: 10.1615/CritRevEukaryotGeneExpr.2019026820. PMID: 32422006
Paiva RA, Ramos CV, Martins VC
FEBS J 2018 Dec;285(24):4565-4574. Epub 2018 Sep 17 doi: 10.1111/febs.14651. PMID: 30187694
Peaudecerf L, Krenn G, Gonçalves P, Vasseur F, Rocha B
Immunol Rev 2016 May;271(1):173-84. doi: 10.1111/imr.12408. PMID: 27088914
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
Schwaber J, Rosen FS
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