Combined immunodeficiency

Immunodeficiency Main Page
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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]

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.

• WASp is involved in actin polymerization and associated coupling of receptor engagement, signaling events, and cytoskeletal rearrangement.
• Allogeneic stem cell transplantation is the only curative treatment for Wiskott-Aldrich syndrome.

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

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 .
• 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

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 .
• 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.
• also called Bloom-Torre-Machacek syndrome or congenital telangiectatic erythema (MIM 210900), is a rare autosomal recessive inherited disorder characterized by genomic instability and predisposition to the development all types of cancer.

The most prominent features include growth deficiency of prenatal onset, mild immunodeficiency, excessive photosensitivity with facial lupus-like skin lesions, type 2 diabetes mellitus and hypogonadism

• Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM .