• Clinical science

Congenital immunodeficiency disorders


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

Immunodeficiency Etiology Clinical features Diagnostic findings
Bruton agammaglobulinemia
  • Onset: > 4 months after birth
  • Recurrent, severe pyogenic infections, especially by encapsulated organisms
  • Hypoplasia of lymphoid tissue
Selective IgA deficiency
Common variable immunodeficiency
  • Onset later than other B-cell defects (usually 20–35 years of age)
  • Recurrent sinopulmonary infections
  • Increased risk of lymphoma, autoimmune disorders, and bronchiectasis

Congenital T-cell immunodeficiencies

Immunodeficiency Etiology Clinical features Diagnostic findings
DiGeorge syndrome
Autosomal dominant hyper-IgE syndrome (Job syndrome)
  • Remember the acronym FATED
IL-12 receptor deficiency
  • Onset varies but usually 1–3 years of age
  • Disseminated disease, especially tuberculosis
  • Fungal infections
Chronic mucocutaneous candidiasis
  • Noninvasive Candida infections of the skin, nails, and mucous membranes
  • Associated with autoimmune disorders
IPEX syndrome

Congenital combined immunodeficiencies

Immunodeficiency Etiology Clinical features Diagnostic findings
Severe combined immunodeficiency
Wiskott-Aldrich syndrome (WAS)
  • Normal or low IgG and IgM
  • Increased IgE and IgA
  • Thrombocytopenia with small platelets
  • Genetic analysis: mutated WASp gene
Hyper-IgM syndrome
Ataxia telangiectasia

Congenital neutrophil and phagocyte disorders

Immunodeficiency Etiology Clinical features Diagnostic findings
Chronic granulomatous disease (CGD)
  • Abnormal DHR test: absent or decreased green fluorescence
  • Negative nitroblue tetrazolium dye reduction test
  • Genotyping is confirmatory
Leukocyte adhesion deficiency type 1
Chédiak-Higashi syndrome
Myeloperoxidase deficiency
  • Often asymptomatic
  • Recurrent Candida infections
  • Positive nitroblue tetrazolium test (intact NADPH oxidase)
  • Absent MPO on staining
  • Genetic analysis: MPO gene mutation
Severe congenital neutropenia

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.
Terminal complement deficiency
  • Recurrent Neisseria (e.g. meningococcal) or gonococcal pyogenic infections
  • Life-threatening sepsis is possible.
  • Associated with SLE and glomerulonephritis
C3 deficiency

Congenital B-cell immunodeficiencies

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

Bruton agammaglobulinemia (X-linked agammaglobulinemia)

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

Selective IgA deficiency (SIgAD)

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

Common variable immunodeficiency (CVID)


Congenital T-cell immunodeficiencies

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

DiGeorge syndrome (22q11.2 deletion syndrome)

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)

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

  • Definition: impaired Th1 response due to IL-12 receptors
  • Etiology: autosomal recessive
  • Pathophysiology
    • Normally, antigen-presenting macrophages release IL-12 Th cells transformation to T1 type → release of IFN-γ to activate macrophages
    • Defective IL-12 receptors: macrophages cannot be activated by IFN-γ → no cytotoxicity in cells infected with intracellular pathogens (e.g., Mycobacteria, Salmonella)
    • IL-12 receptor deficiency is the underlying pathology in most cases of high Mendelian susceptibility to mycobacterial disease (MSMD)
  • Clinical features
    • The age of onset varies (depends on the age at exposure to causative pathogens): ∼ 1–3 years of age
    • Features of disseminated disease
  • Diagnosis: IFN-γ
  • Treatment: antibiotics and IFN-γ therapy

Chronic mucocutaneous candidiasis

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


Congenital mixed immunodeficiencies

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

Wiskott-Aldrich syndrome (WAS)

WIPE is the acronym for the classic triad seen in Wiskott-Aldrich syndrome: Wiskott-Aldrich, Infections, Purpura, Eczema.

Hyper-IgM syndrome

Ataxia telangiectasia


Congenital neutrophil and phagocyte disorders

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)