• Clinical science

Congenital immunodeficiency disorders

Summary

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

Overview

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
  • Often asymptomatic
  • May manifest with respiratory infections, and/or chronic diarrhea/steatorrhea
  • Anaphylactic reaction to products containing IgA
  • Increased risk of gluten-sensitive enteropathy, inflammatory bowel disease, atopy
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
    • Facies: coarse facial features
    • Abscesses: mainly staphylococcal
    • Teeth: retained primary teeth
    • Hyper-IgE (eosinophilia)
    • Dermatologic: severe eczema
IL-12 receptor deficiency
  • Onset varies but usually 1–3 years of age
  • Disseminated disease; especially tuberculosis (e.g., following administration of BCG vaccine)
  • Fungal infections
Chronic mucocutaneous candidiasis
  • Several congenital defects (e.g., AIRE protein deficiency) → impaired T-cell function → dysfunctional or absent immune response to Candida
  • 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)
Hyper-IgM syndrome
Ataxia telangiectasia
  • Onset: early childhood
  • Classic triad of 3 As
    • Progressive ataxia due to cerebellar atrophy
    • Spider angiomas
    • IgA deficiency
  • Susceptibility to infections (e.g., ear infections, sinusitis, pneumonia)
  • Increased risk of malignancy (e.g., lymphoma and leukemia)
  • Increased sensitivity to radiation

Congenital neutrophil and phagocyte disorders

Immunodeficiency Etiology Clinical features Diagnostic findings
Chronic granulomatous disease
  • Recurrent, severe infections with catalase-positive organisms
  • Anemia and lymphadenopathy
  • Possible skin granulomas
  • 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
  • Peripheral smear: giant cytoplasmic granules in granulocytes and platelets
  • Mild coagulation abnormalities
  • Pancytopenia
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
  • Absolute neutropenia, relative monocytosis
  • Bone marrow aspirate: normal or decreased cellularity; arrest of myeloid lineage

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
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)

  • Definition: : the most common primary immunodeficiency; with near or total absence of serum and secretory IgA
  • Epidemiology: approx. 1/220 to 1/1000
  • Etiology: unknown
  • Clinical features
    • Often asymptomatic
    • May manifest with sinusitis or respiratory infections (S. pneumoniae, H. influenzae), chronic diarrhea (Giardia), steatorrhea
    • Associated with gluten-sensitive enteropathy, inflammatory bowel disease
  • Diagnosis: serum IgA level < 7 mg/dL, with normalIgG and IgM levels
  • Treatment

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)

References:[1][2][3][4][5][6][7]

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)

  • Definition: : defect in neutrophil chemotaxis
  • Etiology: STAT3 mutation → decreased Th17 cells → defect in neutrophil/macrophage recruitment
  • Clinical features
    • FATED:
      • Facies coarse
      • Abscesses (recurrent bacterial infections)
      • Retained primary Teeth
      • Hyper-IgE (Eosinophilia)
      • Dermatologic (severe eczema)
  • Diagnosis
  • Treatment
    • Antibiotic treatment and prophylaxis
    • IV immunoglobulin therapy

IL-12 receptor deficiency

  • Definition: impaired Th response due to IL-12 receptors
  • Etiology: autosomal recessive
  • 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)

References:[8][9][10][11][12][13][14][15][16]

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

References:[17][18][19][20]

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

Chédiak-Higashi syndrome

Myeloperoxidase deficiency

  • Definition: deficiency or absence of myeloperoxidase enzyme in phagocytes → preserved respiratory burst (since NADPH oxidase intact) but inability to form hypochlorous acid (HClO)
  • 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

References:[17][18][12][21]

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

References:[17][22][23][24][25]

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last updated 06/18/2019
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