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Combined immunodeficiency due to ZAP70 deficiency(IMD48)

MedGen UID:
1809040
Concept ID:
C5575025
Disease or Syndrome
Synonyms: IMD48; Immunodeficiency 48; Severe combined immunodeficiency, atypical
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ZAP70 (2q11.2)
 
Monarch Initiative: MONDO:0010023
OMIM®: 269840
Orphanet: ORPHA911

Disease characteristics

Excerpted from the GeneReview: ZAP70-Related Combined Immunodeficiency
ZAP70-related combined immunodeficiency (ZAP70-related CID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling. Affected children usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower-respiratory infections and oral candidiasis are common. Affected children usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT). [from GeneReviews]
Authors:
Kelly Walkovich  |  Mark Vander Lugt   view full author information

Additional description

From MedlinePlus Genetics
ZAP70-related severe combined immunodeficiency (SCID) is an inherited disorder that damages the immune system. ZAP70-related SCID is one of several forms of severe combined immunodeficiency, a group of disorders with several genetic causes. Children with SCID lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. Often the organisms that cause infection in people with this disorder are described as opportunistic because they ordinarily do not cause illness in healthy people. Infants with SCID typically experience pneumonia, chronic diarrhea, and widespread skin rashes. They also grow much more slowly than healthy children. If not treated in a way that restores immune function, children with SCID usually live only a year or two.

Most individuals with ZAP70-related SCID are diagnosed in the first 6 months of life. At least one individual first showed signs of the condition later in childhood and had less severe symptoms, primarily recurrent respiratory and skin infections.  https://medlineplus.gov/genetics/condition/zap70-related-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.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Eczema
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
Pneumonia
MedGen UID:
10813
Concept ID:
C0032285
Disease or Syndrome
Inflammation of any part of the lung parenchyma.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Panhypogammaglobulinemia
MedGen UID:
233072
Concept ID:
C1328587
Finding
A reduction in the circulating levels of all the major classes of immunoglobulin. is characterized by profound decreases in all classes of immunoglobulin with an absence of circulating B lymphocytes.
Recurrent candida infections
MedGen UID:
348028
Concept ID:
C1860128
Finding
An increased susceptibility to candida infections, as manifested by a history of recurrent episodes of candida infections.
Absence of CD8-positive T cells
MedGen UID:
870742
Concept ID:
C4025197
Finding
Lack of detectible CD8-positive T cells

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCombined immunodeficiency due to ZAP70 deficiency

Professional guidelines

PubMed

Soyak Aytekin E, Keskin A, Tan C, Yalçın E, Dogru D, Ozcelik U, Kiper N, Tezcan I, Cagdas D
Scand J Immunol 2021 Oct;94(4):e13084. Epub 2021 Jul 28 doi: 10.1111/sji.13084. PMID: 34780073

Recent clinical studies

Etiology

Soyak Aytekin E, Keskin A, Tan C, Yalçın E, Dogru D, Ozcelik U, Kiper N, Tezcan I, Cagdas D
Scand J Immunol 2021 Oct;94(4):e13084. Epub 2021 Jul 28 doi: 10.1111/sji.13084. PMID: 34780073
Aluri J, Desai M, Gupta M, Dalvi A, Terance A, Rosenzweig SD, Stoddard JL, Niemela JE, Tamankar V, Mhatre S, Bargir U, Kulkarni M, Shah N, Aggarwal A, Lashkari HP, Krishna V, Govindaraj G, Kalra M, Madkaikar M
Front Immunol 2019;10:23. Epub 2019 Feb 4 doi: 10.3389/fimmu.2019.00023. PMID: 30778343Free PMC Article
Cuvelier GD, Rubin TS, Wall DA, Schroeder ML
J Clin Immunol 2016 Oct;36(7):713-24. Epub 2016 Jul 20 doi: 10.1007/s10875-016-0316-z. PMID: 27438785
Hauck F, Blumenthal B, Fuchs S, Lenoir C, Martin E, Speckmann C, Vraetz T, Mannhardt-Laakmann W, Lambert N, Gil M, Borte S, Audrain M, Schwarz K, Lim A, Schamel WW, Fischer A, Ehl S, Rensing-Ehl A, Picard C, Latour S
Clin Immunol 2015 Dec;161(2):103-9. Epub 2015 Jul 14 doi: 10.1016/j.clim.2015.07.002. PMID: 26187144
Roifman CM, Somech R, Kavadas F, Pires L, Nahum A, Dalal I, Grunebaum E
J Allergy Clin Immunol 2012 Jul;130(1):177-83. Epub 2012 Jun 2 doi: 10.1016/j.jaci.2012.04.029. PMID: 22664165

Diagnosis

Soyak Aytekin E, Keskin A, Tan C, Yalçın E, Dogru D, Ozcelik U, Kiper N, Tezcan I, Cagdas D
Scand J Immunol 2021 Oct;94(4):e13084. Epub 2021 Jul 28 doi: 10.1111/sji.13084. PMID: 34780073
Aluri J, Desai M, Gupta M, Dalvi A, Terance A, Rosenzweig SD, Stoddard JL, Niemela JE, Tamankar V, Mhatre S, Bargir U, Kulkarni M, Shah N, Aggarwal A, Lashkari HP, Krishna V, Govindaraj G, Kalra M, Madkaikar M
Front Immunol 2019;10:23. Epub 2019 Feb 4 doi: 10.3389/fimmu.2019.00023. PMID: 30778343Free PMC Article
Cuvelier GD, Rubin TS, Wall DA, Schroeder ML
J Clin Immunol 2016 Oct;36(7):713-24. Epub 2016 Jul 20 doi: 10.1007/s10875-016-0316-z. PMID: 27438785
Karaca E, Karakoc-Aydiner E, Bayrak OF, Keles S, Sevli S, Barlan IB, Yuksel A, Chatila TA, Ozen M
Gene 2013 Jan 10;512(2):189-93. Epub 2012 Nov 2 doi: 10.1016/j.gene.2012.10.062. PMID: 23124046
Roifman CM, Somech R, Kavadas F, Pires L, Nahum A, Dalal I, Grunebaum E
J Allergy Clin Immunol 2012 Jul;130(1):177-83. Epub 2012 Jun 2 doi: 10.1016/j.jaci.2012.04.029. PMID: 22664165

Therapy

Soyak Aytekin E, Keskin A, Tan C, Yalçın E, Dogru D, Ozcelik U, Kiper N, Tezcan I, Cagdas D
Scand J Immunol 2021 Oct;94(4):e13084. Epub 2021 Jul 28 doi: 10.1111/sji.13084. PMID: 34780073
Ling E, Broides A, Ling G, Shubinsky G, Hadad N, Nahum A, Simon AJ, Lev A, Somech R
Immunol Res 2021 Feb;69(1):100-106. Epub 2021 Jan 23 doi: 10.1007/s12026-021-09172-w. PMID: 33484432
Cuvelier GD, Rubin TS, Wall DA, Schroeder ML
J Clin Immunol 2016 Oct;36(7):713-24. Epub 2016 Jul 20 doi: 10.1007/s10875-016-0316-z. PMID: 27438785
Karaca E, Karakoc-Aydiner E, Bayrak OF, Keles S, Sevli S, Barlan IB, Yuksel A, Chatila TA, Ozen M
Gene 2013 Jan 10;512(2):189-93. Epub 2012 Nov 2 doi: 10.1016/j.gene.2012.10.062. PMID: 23124046
Santos A, Dias A, Cordeiro A, Cordinhã C, Lemos S, Rocha G, Faria E
J Microbiol Immunol Infect 2010 Dec;43(6):530-7. doi: 10.1016/S1684-1182(10)60082-5. PMID: 21195982

Prognosis

Cuvelier GD, Rubin TS, Wall DA, Schroeder ML
J Clin Immunol 2016 Oct;36(7):713-24. Epub 2016 Jul 20 doi: 10.1007/s10875-016-0316-z. PMID: 27438785

Clinical prediction guides

Aluri J, Desai M, Gupta M, Dalvi A, Terance A, Rosenzweig SD, Stoddard JL, Niemela JE, Tamankar V, Mhatre S, Bargir U, Kulkarni M, Shah N, Aggarwal A, Lashkari HP, Krishna V, Govindaraj G, Kalra M, Madkaikar M
Front Immunol 2019;10:23. Epub 2019 Feb 4 doi: 10.3389/fimmu.2019.00023. PMID: 30778343Free PMC Article
Liu J, Guo K, Hu L, Luo T, Ma Y, Zhang Y, Lai W, Guo Z
Mol Immunol 2019 Mar;107:21-28. Epub 2019 Jan 10 doi: 10.1016/j.molimm.2019.01.001. PMID: 30639475
Hoshino A, Takashima T, Yoshida K, Morimoto A, Kawahara Y, Yeh TW, Okano T, Yamashita M, Mitsuiki N, Imai K, Sakatani T, Nakazawa A, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Ogawa S, Kojima S, Morio T, Kanegane H
J Infect Dis 2018 Jul 24;218(5):825-834. doi: 10.1093/infdis/jiy231. PMID: 29684201
Kaur M, Singh M, Silakari O
Cell Signal 2014 Nov;26(11):2481-92. Epub 2014 Jul 15 doi: 10.1016/j.cellsig.2014.06.017. PMID: 25049080
Roifman CM, Somech R, Kavadas F, Pires L, Nahum A, Dalal I, Grunebaum E
J Allergy Clin Immunol 2012 Jul;130(1):177-83. Epub 2012 Jun 2 doi: 10.1016/j.jaci.2012.04.029. PMID: 22664165

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