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Congenital immunodeficiency disorders

Last updated: March 15, 2021

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Congenital immunodeficiency disorders are characterized by a deficiency, absence, or defect in one or more of the main components of the immune system. These disorders are genetically determined and typically manifest during infancy and childhood as frequent, chronic, or opportunistic infections. Classification is based on the component of the immune system that is deficient, absent, or defective. The diagnosis is confirmed with tests such as differential WBC count, absolute lymphocyte count, quantitative immunoglobulin (Ig) measurements, and antibody titers. Treatment usually consists of prophylactic antibiotics to manage and prevent infections. The prognosis in congenital immunodeficiency disorders is variable and depends on the specific disorder.

Congenital B-cell immunodeficiencies

Overview of congenital B-cell immunodeficiencies
Immunodeficiency Etiology Clinical features Diagnostic findings
Bruton agammaglobulinemia
Selective IgA deficiency
Common variable immunodeficiency
  • Clinical symptoms usually develop between 20-40 years of age , but may also manifest during childhood.
  • Recurrent sinopulmonary infections
  • Increased risk of lymphoma, autoimmune disorders, and bronchiectasis

Congenital T-cell immunodeficiencies

Overview of congenital T-cell immunodeficiencies
Immunodeficiency Etiology Clinical features Diagnostic findings
DiGeorge syndrome
Autosomal dominant hyper-IgE syndrome (Job syndrome)
  • Remember the acronym FATED:
    • Fractures and Facies (coarse facial features)
    • Abscesses (mainly staphylococcal)
    • Teeth (retained primary teeth)
    • Hyper-IgE and Eosinophilia
    • Dermatologic features (severe eczema)
IL-12 receptor deficiency
  • Onset varies but usually 1–3 years of age
  • Disseminated disease, especially tuberculosis
  • Fungal infections
Chronic mucocutaneous candidiasis
IPEX syndrome

Congenital combined immunodeficiencies

Overview of congenital combined immunodeficiencies
Immunodeficiency Etiology Clinical features Diagnostic findings
Severe combined immunodeficiency
Wiskott-Aldrich syndrome (WAS)
  • Present at birth
  • Remember the acronym Wis-PER:
    • Wiskott-Aldrich synrome
    • Purpura (due to thrombocytopenia)
    • Eczema
    • Recurrent pyogenic infections (with encapsulated organisms)
  • Increased risk of autoimmune diseases and hematological malignancies
Hyper-IgM syndrome
  • X-linked recessive inheritance
  • Class-switching defect of Th cells (most commonly CD40 ligand deficiency)
Ataxia telangiectasia

Congenital neutrophil and phagocyte disorders

Overview of congenital neutrophil and phagocytes disorders
Immunodeficiency Etiology Clinical features Diagnostic findings
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency type 1
Chédiak-Higashi syndrome
  • Remember the acronym ALPINe
Myeloperoxidase deficiency
  • Often asymptomatic
  • Recurrent Candida infections
Severe congenital neutropenia

Complement disorders

Overview of complement disorders
Immunodeficiency Etiology Clinical features Diagnostic findings
C1 esterase inhibitor deficiency
  • Recurrent angioedemas provoked by triggers (e.g., trauma, surgery, infections, and drugs)
  • Airway edemas can be life-threatening
Early complement deficiencies (C1–C4)
  • Mostly autosomal co-dominant inheritance
  • Most common deficiency: C2 [2]
  • ↑ Risk of recurrent severe infections of the respiratory tract and sinus
  • ↑ Risk of developing SLE
  • ↓ Levels of complement
Terminal complement deficiency
C3 deficiency
  • Deficiency of C3 and its cleaved fragments (e.g., C3b)
  • Impaired opsonization of pathogens → reduced clearance of C3b-bound immune complexes → ↑ susceptibility to type III HSR

B-cell defects (humoral immunity deficiencies) account for 50–60% of all primary immunodeficiencies.

Bruton agammaglobulinemia (X-linked agammaglobulinemia) [3]

Live vaccines (e.g., MMR) are contraindicated in patients with Bruton agammaglobulinemia.

Bruton agammaglobulinemia: Brutal defects in a B cell make little Boys feel unwell.

Selective IgA deficiency (SIgAD) [4][5]

To prevent transfusion reactions, IgA-deficient patients must be given washed blood products without IgA or obtain blood from an IgA-deficient donor.

The Six A's of selective IgA deficiency: Asymptomatic, Airway infections, Anaphylaxis to IgA-containing products, Autoimmune diseases, Atopy

Common variable immunodeficiency (CVID) [7][8][9]

T-cell defects (cellular immunity deficiencies) are responsible for 5–10% of congenital immunodeficiencies.

DiGeorge syndrome (22q11.2 deletion syndrome) [12]

CATCH-22 is the acronym for typical features of DiGeorge syndrome: Cardiac anomalies; Anomalous face; Thymic aplasia/hypoplasia; Cleft palate; Hypocalcemia; Chromosome 22.

Autosomal dominant hyperimmunoglobulin E syndrome (Job syndrome) [13]

FATED is the acronym for the typical features of Autosomal dominant hyper-IgE syndrome: Coarse Facies/Fractures; Abscesses; Retained primary Teeth; Hyper-IgE/Eosinophilia); Dermatologic (severe eczema).

IL-12 receptor deficiency [15][16][17]

Chronic mucocutaneous candidiasis

IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked)

Severe combined immunodeficiency (SCID, Glanzmann–Riniker syndrome, alymphocytosis)

Wiskott-Aldrich syndrome (WAS)

Classic findings of Wiskott-Aldrich syndrome (Wiskott-Aldrich syndrome, Purpura, Eczema, Recurrent infections): WisPER

Hyper-IgM syndrome [20]

Ataxia telangiectasia

Phagocytic defects are characterized by the impaired ability of phagocytic cells (e.g., monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens. These types of defects account for 10–15% of primary immunodeficiencies.

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency type 1 (LAD1)

Chédiak-Higashi syndrome

Classic findings of Chediak-Higashi syndrome (Albinism, Lymphohistiocytosis, Peripheral neuropathy, Infections, Neurodegeneration, Neutropenia): ALPINe

Myeloperoxidase deficiency

Severe congenital neutropenia

Complement deficiencies are rare (≤ 2%) deficiencies of complement components or inhibitors.

C1 esterase inhibitor deficiency (hereditary angioedema)

Terminal complement deficiency (C5–C9 deficiency)

C3 deficiency [22]

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  8. Mary Dell Railey, M.D., Yuliya Lokhnygina, Ph.D., and Rebecca H. Buckley, M.D.. Long Term Clinical Outcome of Patients with Severe Combined Immunodeficiency who Received Related Donor Bone Marrow Transplants without Pre-transplant Chemotherapy or Post-transplant GVHD Prophylaxis. The Journal of Pediatrics. 2009 .
  9. Omenn syndrome. https://rarediseases.info.nih.gov/diseases/8198/omenn-syndrome/cases/34404#:~:text=Infants%20with%20Omenn%20syndrome%20typically,precede%20the%20onset%20of%20infections.. Updated: March 21, 2012. Accessed: February 24, 2021.
  10. X-Linked Hyper IgM Syndrome.
  11. Dihydrorhodamine (DHR) Flow Cytometric Phorbol Myristate Acetate (PMA) Test, Blood. https://www.mayomedicallaboratories.com/test-catalog/Overview/62765. Updated: January 1, 2018. Accessed: July 19, 2018.
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