Combined immunodeficiency

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Overview

Classification

Immunodeficiency Affecting Cellular and Humoral Immunity

Combined Immunodeficiency

Predominantly Antibody Deficiency

Diseases of Immune Dysregulation

Congenital Defects of Phagocytes

Defects in Intrinsic and Innate Immunity

Auto-inflammatory Disorders

Complement Deficiencies

Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2], Anmol Pitliya, M.B.B.S. M.D.[3] Anum Gull M.B.B.S.[4]

Overview

Classification

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Combined Immunodeficiency Diseases with associated or syndromic features
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Congenital thromocytopenia
 
 
DNA Repair Defects
 
 
Immuno-osseous dysplasias
 
 
Thymic Defects with additional congenital anomalies
 
 
Hyper-IgE syndromes(HIES)
 
 
Dyskeratosis congenita (DKC)
 
 
Defects of Vitamin B12 and Folate metabolism
 
 
Anhidrotic Ectodermodysplasia with ID
 
 
Others
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wiskott Aldrich Syndrome
 
 
 
Ataxia telangiectasia
 
 
 
Cartilage Hair Hypoplasia
 
 
 
DiDeorge Syndrome
 
 
 
Job Syndrome
 
 
 
Dyskeratosis congenita
 
 
 
Transcobalmin 2 deficiency
 
 
 
NEMO deficiency
 
 
 
Purine nucleoside phosphorylase deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XL thrombocytopenia
 
 
 
Nijmegen breakage Syndrome
 
 
 
Schimke Syndrome
 
 
 
TBX1 deficiency
 
 
 
Comel Netherton Syndrome
 
 
 
COATS plus syndrome
 
 
 
Deficiency causing hereditary folate malabsorption
 
 
 
EDA-ID due to IKBA GOF mutation
 
 
 
ID with multiple intestinal atresias
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WIP deficiency
 
 
 
Bloom syndrome
 
 
 
MYSM1 deficiency
 
 
 
Chromosome 10p13-p14 deletion Syndrome
 
 
 
PGM3 deficiency
 
 
 
SAMD9
 
 
 
Methylene-tetrahydrofolate-dehydrogenase 1 deficiency
 
 
 
 
 
 
 
 
Hepatic veno-occlusive disease with immunodeficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARPC1B deficiency
 
 
 
PMS2 deficiency
 
 
 
MOPD1 deficiency
 
 
 
CHARGE Syndrome
 
 
 
 
 
 
 
 
SAMD9L
 
 
 
 
 
 
 
 
 
 
 
 
 
Vici Syndrome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunodeficiency with centromeric instability and facial anomalies(ICF1, ICF2, ICF3, ICF4)
 
 
 
EXTL3 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HOIL1 deficiency, HOIP1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MCM4 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calcium Channel Defects(ORAI-1 deficiency, STIM1 deficiency)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNF168 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hennekam-lymphangiectasia-lymphedema syndrome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
POLE1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STAT5b deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
POLE2 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kabuki Syndrome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NSMCE3 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ERCC6L2(Hebo deficiency)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ligase 1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GINS1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Wiskott-Aldrich Syndrome

  • Wiskott–Aldrich syndrome (WAS) is a rare X-linked Recessive primary immunodeficiency disorder characterized by the triad of eczema, microthrombocytopenia, and often recurrent infections caused by mutation of WASp gene.[1]

X-linked thrombocytopenia (XLT)

Presents with mild eczema and/or infections, it is suspected to be a variant of WAS.Patients with XLT shown to have mutations in the (WAS)Wiskott-Aldrich syndrome protein gene.

X-linked thrombocytopenia (XLT) should be suspected in a male with:

  • Congenital thrombocytopenia (5,000-50,000 platelets/mm3)
  • Small platelet size (platelet volume <7.5 fL)
  • Absence of other clinical findings of Wiskott-Aldrich syndrome
  • Family history of one or more maternally related males with a WAS-related phenotype or disorder
  • Decreased or absent WASP by flow cytometry or western blotting
  • Some affected individuals have near-normal amounts of WAS

WIP DEFICIENCY

(WIP)WISKOTT-ALDRICH-INTERACTING PROTEIN; gene :WIPF1 is located on 2q31.1 . lymphocytes, WASP is almost totally complexed with the WASP-interacting protein (WIP). A major function of WIP is to stabilize WASP and prevent its degradation. WASP protein levels, but not mRNA levels, are severely reduced in T cells [4]

ARPC1B DEFICIENCY

  • ARPC1B gene (ACTIN-RELATED PROTEIN 2/3 COMPLEX, SUBUNIT 1B) is located on 7q22.1 and its deficieny leads to PLTEID(Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease)
  • The ARP2/3 protein complex is involved in the control of actin polymerization in cells. The human complex consists of 7 subunits, including the actin-related proteins ARP2 and ARP3 .[5]
  • PLTEID is an autosomal recessive immune-mediated inflammatory disease with highly variable manifestations. More severely affected individuals have recurrent infections, vasculitis, and thrombocytopenia, whereas other patients have mild vasculitis and normal numbers of small platelets without severe infections.
  • Laboratory studies show platelets with abnormal shape, decreased dense granules, and impaired spreading ability, as well as immune dysregulation with increased eosinophils, B cells, IgA and IgE, and autoantibodies [6]

ATAXIA-TELANGIECTASIA

  • Ataxia-telangiectasia (AT) is an autosomal recessive characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, radiosensitivity, predisposition to lymphoid malignancies and immunodeficiency
  • The ATM gene is related to a family of genes involved in cellular responses to DNA damage and/or cell cycle control with defects in both cellular and humoral immunity [7].
  • ATM gene is located on 11q22.3.
  • Diagnosis is usually achieved by physical examination and identification of both ataxia and oculo-cutaneous telangiectasia, this is then followed by laboratory tests for low levels of IgA, IgG2, IgG4, and IgE.
  • They may also have a low lymphocyte count and other immunological abnormalities.
  • This can then be followed by cytogenetic and molecular testing to confirm the diagnosis.
  • MRI and CT scans may show signs of cerebellar atrophy.

Nijmegen breakage Syndrome

  • Nijmegen breakage syndrome (NBS) is caused by mutation in the NBS1 gene on chromosome 8q21 which is inherited as an Autosomal Recessive disorder.
  • It is characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer.
  • It is phenotypically indistinguishable from Berlin breakage syndrome.Both are autosomal recessive chromosomal instability syndromes
  • Ataxia-telangiectasia variant-1 is the designation applied to the Nijmegen breakage syndrome

BLOOM SYNDROME

It is caused by the mutation in the BLM gene encoding DNA helicase RecQ protein-like-3 (RECQL3) on chromosome 15q26.* 
It is rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer.[8]* Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM 
  1. Buchbinder D, Nugent DJ, Fillipovich AH (2014). "Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments". Appl Clin Genet. 7: 55–66. doi:10.2147/TACG.S58444. PMC 4012343. PMID 24817816.
  2. Buchbinder D, Nugent DJ, Fillipovich AH (2014). "Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments". Appl Clin Genet. 7: 55–66. doi:10.2147/TACG.S58444. PMC 4012343. PMID 24817816.
  3. Muñoz A, Olivé T, Martinez A, Bureo E, Maldonado MS, Diaz de Heredia C, Sastre A, Gonzalez-Vicent M (September 2007). "Allogeneic hemopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON)". Pediatr Hematol Oncol. 24 (6): 393–402. doi:10.1080/08880010701454404. PMID 17710656.
  4. Pawłowski R (1991). "Distribution of common phenotypes of sperm diaphorase (DIA3) in the Polish population". Hum. Hered. 41 (4): 279–80. doi:10.1159/000154013. PMID 1783416.
  5. Volkmann N, Amann KJ, Stoilova-McPhie S, Egile C, Winter DC, Hazelwood L, Heuser JE, Li R, Pollard TD, Hanein D (September 2001). "Structure of Arp2/3 complex in its activated state and in actin filament branch junctions". Science. 293 (5539): 2456–9. doi:10.1126/science.1063025. PMID 11533442.
  6. Kahr WH, Pluthero FG, Elkadri A, Warner N, Drobac M, Chen CH, Lo RW, Li L, Li R, Li Q, Thoeni C, Pan J, Leung G, Lara-Corrales I, Murchie R, Cutz E, Laxer RM, Upton J, Roifman CM, Yeung RS, Brumell JH, Muise AM (April 2017). "Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease". Nat Commun. 8: 14816. doi:10.1038/ncomms14816. PMC 5382316. PMID 28368018.
  7. Lavin MF, Shiloh Y (1997). "The genetic defect in ataxia-telangiectasia". Annu. Rev. Immunol. 15: 177–202. doi:10.1146/annurev.immunol.15.1.177. PMID 9143686.
  8. Kaneko H, Kondo N (May 2004). "Clinical features of Bloom syndrome and function of the causative gene, BLM helicase". Expert Rev. Mol. Diagn. 4 (3): 393–401. doi:10.1586/14737159.4.3.393. PMID 15137905.