• 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 main 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 primary immunodeficiency disorders is variable and depends on the specific disorder.

Congenital B-cell immunodeficiencies

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

Bruton agammaglobulinemia (X-linked agammaglobulinemia)

Selective IgA deficiency (SIgAD)

Common variable immunodeficiency (CVID)


Congenital T-cell immunodeficiencies

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

DiGeorge syndrome (22q11.2 deletion syndrome)

Autosomal dominant hyperimmunoglobulin E syndrome (Job syndrome)

IL-12 receptor deficiency

  • Definition: impaired Th response due to IL-12 receptors
  • Etiology: autosomal recessive; salmonella infections and mycobacterial infections most common
  • Pathophysiology: Normally, antigen-presenting macrophages release IL-12, which triggers T-helper cells to transform to T1 type. T1-helper cells then release IFN-γ to activate macrophages. If IL-12 receptors are defective, macrophages cannot be activated by IFN-γ to trigger cytotoxicity in cells infected with intracellular pathogens such as mycobacteria and salmonella
  • Clinical features
    • Age at onset varies depending on the age at exposure to causative pathogens (on average 1–3 years of age).
    • Features of disseminated disease, especially tuberculosis; (e.g., following administration of BCG vaccine)
    • Fungal infections
  • Diagnosis: IFN-γ
  • Treatment: antibiotic 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

WIPE → Wiskott-Aldrich, Infections, Purpura, Eczema

Hyper-IgM syndrome

Ataxia telangiectasia


Congenital neutrophil and phagocyte disorders

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

Chronic granulomatous disease (CGD)

Leukocyte adhesion deficiency type 1

Chediak-Higashi syndrome

  • Definition: defect in neutrophil chemotaxis/microtubule polymerization
  • Etiology: autosomal recessive defective lysosomal trafficking regulator gene (LYST)
  • Clinical features
    • Recurrent pyogenic infections (may be extensive if massive infiltration occurs)
    • Partial albinism
    • Progressive neuropathies: tingling and other paresthesias in limbs
  • Diagnosis
    • Peripheral smear shows giant cytoplasmic granules in granulocytes and platelets
    • Mild coagulation abnormalities
  • Treatment: bone marrow transplant

Myeloperoxidase deficiency

  • Definition: deficiency or absence of myeloperoxidase enzyme in phagocytes → preserved respiratory burst (reactive oxygen species) but inability to form hypochlorite
  • Etiology: autosomal recessive mutation in the MPO gene
  • Clinical features
  • Diagnosis
    • Positive nitroblue tetrazolium test (intact NADPH oxidase)
    • Absent myeloperoxidase on staining
    • Mutations in MPO gene on sequencing
  • Treatment: no specific treatment or prophylaxis is indicated. Treating fungal infections with minimal therapy is advised.

Severe congenital neutropenia


Congenital complement deficiencies

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

  • Definition: deficiency of the complement factor C3 and its cleaved fragments (e.g., C3b)
  • Etiology: primary or secondary due to impairment in the regulatory proteins factor I or factor H
  • Pathophysiology: decreased levels of the opsonin C3b → impaired opsonization of pathogens by the innate immune system and reduced clearance of C3b-bound immune complexes
  • Clinical features


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last updated 02/19/2019
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