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

Congenital T-cell immunodeficiencies

Congenital combined immunodeficiencies

Congenital neutrophil and phagocyte disorders

Complement disorders

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

Bruton agammaglobulinemia (X-linked agammaglobulinemia)

• Definition: X-linked recessive disease that causes a complete deficiency of mature B lymphocytes
• Epidemiology: occurs mainly in boys
• Etiology: defect of Bruton tyrosine kinase (BTK) expressed in B cells
• Clinical features
  • Onset is > 4 months after birth because of the continual decrease of maternal IgG in fetal serum.
  • Hypoplasia of tonsils and other lymphoid tissue
  • Recurrent, severe pyogenic infections (e.g., pneumonia, otitis media), especially with encapsulated organisms (S. pneumoniae, N. meningitidis, and H. influenzae)
  • Hepatitis virus and enterovirus (e.g., Coxsackie virus) infection
• Diagnosis
  • Flow cytometry
    • Absent or low levels of B cells (marked by CD19, CD20, and CD21)
    • Normal or high T cells
  • Absent lymphoid tissue (e.g., tonsils)
• Treatment
  • IV immunoglobulins
  • Prophylactic antibiotics

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

Selective IgA deficiency (SIgAD)

• Definition: most common primary immunodeficiency that is characterized by a 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 (Giardiasis)
  • Associated with gluten-sensitive enteropathy, inflammatory bowel disease, atopy
  • Anaphylactic reaction to products containing IgA
• Diagnosis
  • Decreased serum IgA levels (< 7 mg/dL)
  • Normal IgG and IgM levels
  • Increased susceptibility to Giardia infection
• Treatment
  • Treatment of infections
  • Prophylactic antibiotics
  • Intravenous infusion of IgA is not recommended because of the risk of anaphylactic reactions (caused by the production of anti-IgA antibodies).

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)

• Definition: primary immunodeficiency with low serum levels of all immunoglobulins despite phenotypically normal B cells
• Epidemiology
  • Sex: ♀ = ♂
  • Onset: presents later than other B-cell defects (usually at 20–35 years of age)
• Etiology: B cells are phenotypically normal but are unable to differentiate into Ig-producing cells, resulting in low immunoglobulins of all classes.
• Clinical features
  • Recurrent pyogenic respiratory infections, e.g., sinopulmonary infections (in rare cases, enteroviral meningitis)
  • Associated with a high risk of lymphoma, gastric cancer, bronchiectasis, and autoimmune disorders (e.g., rheumatoid arthritis, autoimmune hemolytic anemia, immune thrombocytopenia, vitiligo)
• Diagnosis
  • Quantitative immunoglobulin levels: low levels of IgG, IgA, and IgM
  • Decreased number of plasma cells
  • Flow cytometry shows subsets of normal B and T cells
  • Poor response to immunizations
• Treatment
  • Treatment of infections
  • Prophylactic antibiotics
  • IV immunoglobulins

References:^{[1][2][3][4][5][6][7]}

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

DiGeorge syndrome (22q11.2 deletion syndrome)

• Definition: : syndrome characterized by defective development of the third and fourth pharyngeal pouches leading to hypoplastic thymus and parathyroids
• Etiology: autosomal dominant; microdeletion at chromosome 22 (22q11.2)
• Clinical features
  • Cardiac anomalies
    • Conotruncal abnormalities (e.g., tetralogy of Fallot or persistent truncus arteriosus)
    • Ventricular septal defect (VSD)
    • Atrial septal defect (ASD)
  • Anomalous face
    • Prominent nasal bridge
    • Hypoplastic wing of the nose
    • Dysplastic ears
    • Micrognathia; (small lower jaw) and/or retrognathia
  • Thymus aplasia/hypoplasia: recurrent infections (viral/fungal/PCP pneumonia) due to T-cell deficiency
  • Cleft palate
  • Hypoparathyroidism: hypocalcemia with tetany
• Diagnosis
  • Detection of 22q11.2 deletion via fluorescence in situ hybridization (FISH)
  • ↓ PTH and Ca²⁺
  • ↓ Absolute T-lymphocyte count
  • Delayed hypersensitivity skin testing
  • CXR: absence of thymic shadow
• Treatment
  • Immune deficiency treatment
    • Antibiotics, virostatics, and antimycotics
    • PCP prophylaxis
    • Consider bone marrow transplant and/or IVIG
  • Possible thymus transplantation
• Prognosis: poor if not treated (patients usually do not survive beyond childhood)

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)

• Definition: defect in neutrophil chemotaxis
• Etiology: autosomal dominant; STAT3 mutation → decreased Th17 cells → reduced neutrophil/macrophage chemotaxis
• Clinical features
  • Coarse Facies
  • Noninflamed Abscesses, recurrent bacterial (staphylococcal) infections
  • Retained primary Teeth
  • Hyper-IgE (Eosinophilia)
  • Dermatologic (severe eczema)
  • Other features: Decreased bone density increases the risk of bone fractures following minor trauma. ^[8]
• Diagnosis
  • ↑ IgE
  • (Variable) eosinophilia
  • ↓ IFN γ
  Treatment
  • Antibiotics and prophylaxis (with penicillinase-resistant antibiotics)
  • IV immunoglobulin therapy

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
    • Mycobacterial infections (e.g., developing tuberculosis after BCG vaccination)
    • Fungal infections
• Diagnosis: ↓ IFN-γ
• Treatment: antibiotics and IFN-γ therapy

Chronic mucocutaneous candidiasis

• Definition: impaired or absent T-cell response to Candida antigens
• Etiology
  • Several congenital defects that result in impaired T-cell function
  • The majority of cases are caused by autoimmune regulator (AIRE protein) deficiency.
• Pathophysiology: defects in IL-17 and IL-17 receptors →; insufficient cell-mediated immune response to Candida infections
• Clinical features
  • Persistent or, less commonly, recurrent noninvasive Candida infections of the skin, mucous membranes, and nails
  • Associated autoimmune disorders (e.g., immune thrombocytopenic purpura, rheumatoid arthritis)
• Diagnosis
  • Usually clinical
  • Absent in vitro T-cell proliferation when exposed to Candida antigen
  • Absent cutaneous reaction to Candida antigen
• Treatment
  • Antifungal therapy
  • Treatment of associated conditions

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

• Definition: : A syndrome characterized by a dysfunctional regulatory T-cell lineage that leads to autoimmunity as a result of disrupted tolerance to self-antigens.
• Etiology
  • X-linked recessive type of inheritance
  • Mutation in transcription factor FOXP3 → unchecked activation of T cells against host tissues
• Clinical features
  • Classically presents in early infancy
  • Lymphadenopathy and/or chronic lymphoid tissue hypertrophy (e.g., enlarged tonsils)
  • Eczema; , possibly accompanied by other autoimmune dermatologic conditions
  • Autoimmune endocrine conditions (e.g., hyperthyroidism or hypothyroidism, type 1 diabetes mellitus in male individuals)
  • Enteropathy, manifesting as e.g., chronic diarrhea
  • Nail dystrophy
  • Failure to thrive
• Diagnosis
  • Primarily based on clinical examination and family history
  • Genetic testing: mutations in FOXP3
  • Flow cytometry: severely reduced or absent CD4+CD25+ regulatory T cells with otherwise normal T-cell populations
• Treatment
  • Nutritional support
  • Immunosuppression: tacrolimus, cyclosporine, or sirolimus
  • Rituximab
  • Bone marrow transplant

References:^{[9][10][11][12][13][14][15][16][17]}

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

• Definition: : A rare genetic condition caused by numerous genetic mutations that result in the defective development of functional B cells and T cells.
• Etiology: various mutations, the most common of which are:
  • X-linked recessive: mutations in the gene encoding the common gamma chain → defective IL-2R gamma chain receptor linked to JAK3 (most common SCID mutation)
  • Autosomal recessive
    • Adenosine deaminase (ADA) deficiency → accumulation of toxic metabolites (deoxyadenosine and dATP) and disrupted purine metabolism → accumulation of dATP inhibits function of ribonucleotide reductase → impaired generation of deoxynucleotides
    • Janus-associated kinase 3 (JAK3) deficiency
• Clinical features
  • Normal at birth
  • Severe, recurrent infections: bacterial diarrhea, chronic candidiasis (thrush), viral and protozoal infections
  • Failure to thrive
  • Chronic diarrhea
  • Lymph nodes and tonsils may be absent
• Diagnosis
  • Quantitative PCR: ↓ T-cell receptor excision circles (TRECs)
  • Flow cytometry: absent T cells
  • CXR: absent thymic shadow
  • Lymph node biopsy: absent germinal centers
• Treatment
  • IV immunoglobulins
  • PCP prophylaxis
  • Bone marrow transplant or stem cell transplantation
  • Avoidance of live vaccines
  • Confinement to sterile environments (hence “bubble boy disease”)
• Prognosis: often fatal in the first year of life if left untreated ^[18][19]

Wiskott-Aldrich syndrome (WAS)

• Definition: genetic condition characterized by impaired function of T cells and thrombocytopenia
• Etiology: mutated WASp gene (X-linked recessive inheritance) → impaired signaling to actin cytoskeleton reorganization → defective antigen presentation
• Epidemiology: : occurs primarily in males
• Clinical features
  • Onset of symptoms: from birth
  • Classic triad
    • Eczema (high risk of atopic disorders)
    • Bleeding diathesis
    • Recurrent opportunistic infections with encapsulated organisms ; in the first years of life (e.g., otitis media)
  • Increased risk of autoimmune diseases and hematological malignancies (e.g., lymphoma, leukemia)
• Diagnosis
  • Normal or ↓ IgG and IgM
  • ↑ IgE and IgA
  • Thrombocytopenia with small platelets
  • Genetic analysis (confirmatory test): mutated WASp gene
• Treatment
  • IV immunoglobulin therapy
  • Prophylactic antibiotics
  • Platelet transfusions
  • Stem cell transplantation may be curative.
• Prognosis: : shortened life expectancy

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

Hyper-IgM syndrome

• Definition: : A group of syndromes characterized by a class-switching defect of Th cells.
• Epidemiology: CD40 ligand deficiency is the most common form.
• Etiology
  • X-linked recessive inheritance
  • Abnormal interaction between CD4 T cells and cells that express CD40
• Clinical presentation
  • Recurrent sinopulmonary infections (commonly Pneumocystis jirovecii and Histoplasma)
  • Cryptosporidium enteritis (which may lead to biliary disease, cirrhosis, and cholangiocarcinoma)
  • CMV hepatitis
  • Failure to thrive
• Diagnosis
  • ↓ IgG, IgA, IgE
  • Normal or ↑ IgM
  • Lymph node biopsy: absent germinal centers
• Treatment
  • IV immunoglobulin therapy
  • Prophylactic antibiotics
  • Recombinant human granulocyte-colony stimulating factor
  • Stem cell transplantation may be curative.

Ataxia telangiectasia

• See ataxia telangiectasia for details.

References:^{[18][20][21][22][23]}

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)

• Definition: deficiency of superoxide production by polymorphonuclear neutrophils and macrophages
• Etiology
  • X-linked recessiveor autosomal recessive inheritance (2:1)
  • Defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
  • Defective ROS production: impaired ability to deactivate or kill ingested microorganisms
  • Decreased respiratory burst in neutrophils
• Clinical features
  • Recurrent, severe infections (chronic skin, lymph node, bone, respiratory, GI, and urinary tract infections) with catalase-positive organisms ; (S. aureus; , Nocardia spp., Escherichia coli, Candida, Klebsiella, Pseudomonas, Aspergillus; , Serratia)
  • Anemia
  • Lymphadenopathy
  • Granulomas of the skin and GI/GU tract
• Diagnosis
  • Neutrophil assay
    • Dihydrorhodamine test (DHR): flow cytometry test showing abnormal NADPH oxidase activity (inability to metabolize dihydrorhodamine to fluorescent product, rhodamine → decreased green fluorescence) ^[24]
    • Nitroblue tetrazolium dye reduction test: negative.
  • Hypergammaglobulinemia
  • Genotyping is confirmatory
• Treatment
  • Treatment of infections
  • Life-long prophylactic antibiotics, e.g., TMP-SMX (for catalase-positive infections)
  • Glucocorticoids for severe inflammation
  • IFN-γ therapy
  • Bone marrow transplant
  • Possibly gene therapy

Leukocyte adhesion deficiency type 1 (LAD1)

• Definition: : genetic condition characterized by a defect in the leukocytic chemotaxis that results in decreased phagocyte activity
• Etiology
  • Autosomal recessive inheritance
  • Absence of the ß2-integrin leukocyte adhesion surface molecule LFA-1 (CD18) → Leukocytes are unable to migrate into tissues during infection or inflammation.
• Clinical features
  • Recurrent nonsuppurative bacterial infections (e.g., skin and mucosal infections), impaired wound healing
  • Wounds with minimal inflammation and no pus
  • Omphalitis
  • Delayed separation of the umbilical cord (> 2 weeks postpartum)
• Diagnosis
  • Leukocytosis; however, neutrophils are absent at the site of infection!
  • Flow cytometry: absent CD18, CD11a, CD11b, and CD11c
• Treatment
  • Prevention of further infections (e.g., adequate dental hygiene)
  • Treatment of infections
  • Bone marrow transplant

Chédiak-Higashi syndrome

• Definition: defect in neutrophil chemotaxis and microtubule polymerization dysfunction → defective phagosome-lysosome fusion
• Etiology: autosomal recessive; defective lysosomal trafficking regulator (LYST) gene
• Clinical features
  • Recurrent pyogenic infections
    • May be extensive if massive infiltration occurs
    • Pathogens include S. pyogenes, S. aureus, and Pseudomonas spp.
  • Partial albinism
  • Progressive peripheral neuropathy
  • Hemophagocytic lymphohistiocytosis (can occur in the accelerated phase and is potentially fatal)
• Diagnosis
  • Peripheral smear shows giant cytoplasmic granules in granulocytes and platelets
  • Mild coagulation abnormalities
  • Neutropenia
• Treatment: bone marrow transplant

Myeloperoxidase deficiency

• Definition: : A genetic condition characterized by the deficiency or absence of myeloperoxidase enzyme in phagocytes that are unable to form hypochlorous acid (HClO) but have preserved respiratory burst (since NADPH oxidase is intact.
• Etiology: autosomal recessive mutation in the MPO gene
• Clinical features
  • Recurrent Candida infections (e.g., oral thrush, vulvovaginitis)
  • Many patients are asymptomatic.
• Diagnosis
  • Positive nitroblue tetrazolium test: intact NADPH oxidase
  • Absent myeloperoxidase on staining
  • Mutations in MPO gene on sequencing
• Treatment
  • No specific treatment or prophylaxis
  • Treatment of fungal infections

Severe congenital neutropenia

• Definition: A deficiency of neutrophils that occurs at or around birth due to bone marrow failure of the myeloid lineage.
• Etiology
  • Autosomal dominant, autosomal recessive, or X-linked recessive inheritance
  • Mutations in the neutrophil elastase gene, HAX1 gene, and Wiskott-Aldrich syndrome gene
• Clinical features
  • Recurrent bacterial infections, e.g., gingivitis, otitis media, respiratory infections, and cellulitis due to Streptococcus and Staphylococcus
  • Oral ulcerations are commonly seen by the age of 2 years.
• Diagnosis
  • Absolute neutropenia with relative monocytosis. Absolute neutrophil count is usually < 200/microL in infants.
  • Bone marrow examination
    • Normal or decreased cellularity
    • Arrest of the myeloid lineage at the promyelocyte/myelocyte stage
• Treatment
  • G-CSF
  • Hematopoietic cell transplantation

References:^{[13][20][24][25]}

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

C1 esterase inhibitor deficiency (hereditary angioedema)

See bradykinin-mediated angioedema in angioedema.

Terminal complement deficiency (C5–C9 deficiency)

• Definition: impaired formation of the membrane attack complex due to deficiencies in terminal complement factors (C5–C9)
• Epidemiology: C5, C6, and C8 deficiency are the most common
• Etiology: autosomal recessive pattern
• Clinical features
  • Recurrent pyogenic infections (e.g., meningococcal or gonococcal)
  • Associated with SLE and glomerulonephritis
  • Life-threatening sepsis may occur in prolonged disease.
• Diagnosis: CH50 assay screening test
• Treatment
  • Meningococcal vaccine
  • Prophylactic antibiotics

C3 deficiency

• Definition: deficiency of the complement factor C3 and its cleaved fragments (e.g., C3b)
• 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
  • Recurrent, severe, childhood infections (e.g., upper respiratory tract infections, pneumonia, meningitis) with encapsulated bacteria (e.g., N. meningitidis, H. influenzae, S. pneumoniae)
  • Associated with autoimmune diseases (e.g., SLE) and type III hypersensitivity reactions

References:^{[20][22][26][27][28]}