Congenital immunodeficiency disorders

Last updated: October 30, 2023

Summarytoggle arrow icon

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.

Overviewtoggle arrow icon

Congenital B-cell immunodeficiencies

Overview of congenital B-cell immunodeficiencies
Immunodeficiency Etiology Clinical features Diagnostic findings
X-linked (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
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 syndrome
    • 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, C2, and C4 deficiency
  • ↑ Risk of recurrent severe infections of the respiratory tract and sinus
  • ↑ Risk of developing SLE
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
Terminal complement deficiency

Congenital B-cell immunodeficienciestoggle arrow icon

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

X-linked (Bruton) agammaglobulinemia [3]

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

X-linked (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]

Transient hypogammaglobulinemia of infancy (THI) [12][13]

Congenital T-cell immunodeficienciestoggle arrow icon

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

DiGeorge syndrome (22q11.2 deletion syndrome) [14]

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) [15]

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 [17][18][19]

Chronic mucocutaneous candidiasis

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

Congenital mixed immunodeficienciestoggle arrow icon

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 [23]

Ataxia telangiectasia

Congenital neutrophil and phagocyte disorderstoggle arrow icon

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

Congenital complement deficienciestoggle arrow icon

Complement component deficiencies

Complement component deficiencies are a group of rare inherited genetic conditions characterized by absent or abnormal complement component proteins, which increases the risk of recurrent bacterial infections and autoimmune conditions.

Overview of complement component deficiencies
Classification Classical pathway component deficiencies Alternative pathway component deficiencies Terminal complement deficiency (C5–C9) [25]
C1q deficiency [26][27] C1r deficiency and/or C1s deficiency C2 deficiency [28] C3 deficiency [29] C4 deficiency [30]
  • Very rare [26]
  • Extremely rare [31]
  • 1:20,000 in individuals of Western European descent [32]
  • Most common genetically determined complement deficiency
  • Very rare [33]
  • Very rare [30]
  • C5, C6, and C8 deficiency are the most common
  • Decreased or abnormal (i.e., low-molecular weight) C1q protein, ↓ C1r and/or ↓ C1s → inability to form the C1 complex → disruption of the classical pathway cascade
  • Decreased or absent C4 protein → ↓ activation of the classical and lectin complement pathway [34]
Clinical features
  • Increased risk of bacterial infections
  • Recurrent skin lesions that worsen with excessive UV light exposure
  • Cataracts
  • Hair loss (eyelashes, eyebrows, scalp hair)
  • High frequency of sinopulmonary infections (especially with S. pneumonia)
  • Asymptomatic in the majority of cases
  • Increased risk of viral infections
  • Increased risk of recurrent Neisseria spp. infections
Complications [2]
  • Risk of infection and subsequent potentially life-threatening sepsis increases with course of the disease.
  • Extremely high risk of SLE or SLE-like disease
    • Usually manifests with severe symptoms during childhood
    • Prominent cutaneous manifestations
    • Neuropsychiatric symptoms (e.g., seizures, psychosis, ataxia)
  • High risk of SLE or SLE-like disease
  • 10–30% of affected individuals develop SLE
  • Very high risk of developing SLE or SLE-like diseases

C1 esterase inhibitor deficiency (hereditary angioedema)

Mannose-binding lectin deficiency (MBL deficiency) [35]

  • Definition: an inherited genetic condition characterized by low levels of MBL associated with increased susceptibility to infections
  • Epidemiology: common; affects an estimated 10–30% of the population worldwide
  • Etiology: mutations in the MBL2 gene
  • Pathophysiology: genetic mutations → ↓ production of MBL subunits or impaired subunit assembly into functional MBL↓ activation of the lectin complement pathway → ↑ susceptibility to infections [36]
  • Clinical features: symptoms of recurrent infections
  • Diagnostics
  • Management and complications: see C1q deficiency

Referencestoggle arrow icon

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