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

Overview

Congenital B-cell immunodeficiencies

Overview of congenital B-cell immunodeficiencies
Immunodeficiency	Etiology	Clinical features	Diagnostic findings
X-linked (Bruton) agammaglobulinemia	X-linked recessive inheritance BTK gene defect → defective Bruton tyrosine kinase expressed in B cells → complete deficiency of mature B cells	Onset: between 3 and 6 months of age when maternal IgG levels in fetal serum start to decrease Recurrent, severe pyogenic infections, especially by encapsulated bacteria and enteroviruses Hypoplasia of lymphoid tissue (e.g., tonsils, lymph nodes)	Absent or low B cells Normal T-cell count Low immunoglobulins of all classes
Selective IgA deficiency	Unknown Most common primary immunodeficiency	Often asymptomatic May manifest with respiratory infections, and/or chronic diarrhea (e.g., giardiasis) Increased risk of autoimmune diseases like: Gluten-sensitive enteropathy Inflammatory bowel disease Anaphylactic reaction to products containing IgA Atopy	Low serum IgA Normal IgG and IgM
Common variable immunodeficiency	Unknown Phenotypically normal B cells are unable to differentiate into plasma cells → low immunoglobulins of all classes	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	Low IgG, IgA, IgM Low plasma cells Normal B-cell and T-cell counts Poor response to immunizations

Congenital T-cell immunodeficiencies

Overview of congenital T-cell immunodeficiencies
Immunodeficiency	Etiology	Clinical features	Diagnostic findings
DiGeorge syndrome	Microdeletion at 22q11.2 Autosomal dominant inheritance Defective development of the pharyngeal pouches and pharyngeal arches E.g.: Defective development of 3^rd and 4^th pharyngeal pouches → hypoplastic or absent thymus and parathyroids	Variable phenotype Remember the acronym CATCH-22 Cardiac anomalies Anomalous face Thymus aplasia/hypoplasia Cleft palate Hypocalcemia Affected chromosome 22	Detection of 22q11.2 deletion via FISH Low PTH and Ca²⁺ Low T cells CXR: absence of thymic shadow Skin testing: delayed hypersensitivity
Autosomal dominant hyper-IgE syndrome (Job syndrome)	STAT3 gene mutation → ↓ Th17 cells Defective neutrophil chemotaxis	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)	Increased IgE Low IFN-γ Commonly increased eosinophils
IL-12 receptor deficiency	Autosomal recessive inheritance Decreased IL-12 → impaired Th1 response → no release of IFN-γ	Onset varies but usually 1–3 years of age Disseminated disease, especially tuberculosis Fungal infections	Low IFN-γ
Chronic mucocutaneous candidiasis	Several congenital defects (e.g., STAT1 gain of function mutation, AIRE protein deficiency) → impaired T-cell function → impaired or absent immune response to Candida	Noninvasive Candida infections of the skin, nails, and mucous membranes Associated with autoimmune disorders	Usually clinical Cutaneous reaction to Candida antigens is absent. In vitro T-cell proliferation is absent when exposed to Candida antigens.
IPEX syndrome	FOXP3 gene mutation → impaired regulatory T cells → autoimmunity X-linked recessive inheritance	Onset: early infancy Lymphadenopathy, chronic lymphoid tissue hypertrophy Autoimmune skin and endocrine disorders (e.g., type 1 DM especially in boys) Enteropathy Failure to thrive Nail dystrophy	Genetic testing: FOXP3 gene mutations Low or absent CD4⁺CD25⁺regulatory T cells Otherwise normal T-cell populations

Congenital combined immunodeficiencies

Overview of congenital combined immunodeficiencies
Immunodeficiency	Etiology	Clinical features	Diagnostic findings
Severe combined immunodeficiency	Various mutations resulting in impaired function of B cells and T cells X-linked recessive inheritance: defective IL-2R gamma chain (most common variant) Autosomal recessive inheritance: adenosine deaminase deficiency Human RAG mutations: defective VDJ recombination	Asymptomatic at birth Recurrent bacterial, viral, fungal (thrush), and protozoal infections Chronic diarrhea Failure to thrive Lymph nodes and tonsils may be absent	Quantitative PCR: low TRECs Absent T cells (X-linked variant); absent T cells, B cells, and NK cells (AR variant) CXR: absent thymic shadow Lymph node biopsy: absent germinal centers
Wiskott-Aldrich syndrome (WAS)	X-linked recessive inheritance WAS gene mutation→ ↓ WAS protein synthesis → impaired remodeling of T-cells actin cytoskeleton → defective antigen presentation	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	Normal or low IgG and IgM Increased IgE and IgA Thrombocytopenia with small platelets Genetic analysis: mutated WAS gene
Hyper-IgM syndrome	X-linked recessive inheritance Class-switching defect of Th cells (most commonly CD40 ligand deficiency)	Recurrent sinopulmonary infections Commonly infections with Pneumocystis jirovecii, Histoplasma, Cryptosporidium, and CMV Failure to thrive	Low IgG, IgA, and IgE Normal or increased IgM Lymph node biopsy: absent germinal centers
Ataxia telangiectasia	Autosomal recessive inheritance ATM gene defect → failure to recognize and repair dsDNA breaks → no cell cycle arrest → continuous replication of damaged DNA	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., non-Hodgkin lymphoma and leukemia) Increased sensitivity to radiation, therefore x-ray exposure should be avoided in these individuals.	MRI: cerebellar (vermis) atrophy Increased AFP levels Low IgA, IgG, and IgE Lymphopenia

Congenital neutrophil and phagocyte disorders

Overview of congenital neutrophil and phagocytes disorders
Immunodeficiency	Etiology	Clinical features	Diagnostic findings
Chronic granulomatous disease (CGD)	X-linked (most common) or autosomal recessive inheritance Defective phagocytic NADPH oxidase Defective ROS production by neutrophils and macrophages Decreased respiratory burst in neutrophils	Recurrent, severe infections with catalase-positive organisms [1] Lymphadenopathy Possible skin granulomas	Abnormal DHR test: absent or decreased green fluorescence Negative nitroblue tetrazolium dye reduction test Anemia Genotyping is confirmatory
Leukocyte adhesion deficiency type 1	Autosomal recessive inheritance Absent LFA-1 (CD18) protein → impaired leukocyte chemotaxis and migration	Recurrent nonsuppurative bacterial infections of skin and mucosa Impaired wound healing Delayed separation of the umbilical cord Periodontitis	Leukocytosis; however, neutrophils are absent at the site of infection Flow cytometry: absent CD18
Chédiak-Higashi syndrome	Autosomal recessive inheritance LYST gene defect → defective neutrophil chemotaxis and microtubule polymerization dysfunction → defective phagosome-lysosome fusion	Remember the acronym ALPINe Partial Albinism Lymphohistiocytosis Peripheral neuropathy Recurrent pyogenic Infections (S. pyogenes, S. aureus, and Pseudomonas spp.) Progressive Neurodegeneration (and Neutropenia)	Peripheral smear: giant cytoplasmic granules in granulocytes and platelets Mild coagulation abnormalities Pancytopenia
Myeloperoxidase deficiency	Autosomal recessive inheritance Mutation in MPO gene → partial or complete deficiency of MPO in phagocytes	Often asymptomatic Recurrent Candida infections	Positive nitroblue tetrazolium test (intact NADPH oxidase) Absent MPO on staining Genetic analysis: MPO gene mutation
Severe congenital neutropenia	Autosomal dominant, autosomal recessive, or X-linked recessive inheritance Bone marrow failure of myeloid lineage	Recurrent bacterial infections, e.g. gingivitis, otitis media, respiratory infections, and cellulitis (Streptococcus and Staphylococcus) Oral ulcerations	Absolute neutropenia, relative monocytosis Bone marrow aspirate: normal or decreased cellularity; arrest of myeloid lineage

Complement disorders

Overview of complement disorders
Immunodeficiency		Etiology	Clinical features	Diagnostic findings
C1 esterase inhibitor deficiency		Autosomal dominant inheritance Unregulated activation of kallikrein → ↑ bradykinin → angioedema See bradykinin-mediated angioedema in angioedema.	Recurrent angioedemas provoked by triggers (e.g., trauma, surgery, infections, and drugs) Airway edemas can be life-threatening	CH50 assay screening test ↑ Bradykinin levels Low C4 levels Strong contraindication for ACE inhibitors
Early complement deficiencies	C1, C2, and C4 deficiency	Mostly autosomal recessive inheritance Most common deficiency: C2 [2]	↑ Risk of recurrent severe infections of the respiratory tract and sinus ↑ Risk of developing SLE	CH50 assay screening test ↓ Levels of complement
Early complement deficiencies	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	Recurrent, severe infections with encapsulated bacteria (e.g., Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae) Associated with autoimmune diseases (e.g., SLE)
Terminal complement deficiency		Autosomal recessive inheritance Most common deficiencies: C5, C6, and C8 Inability to form membrane attack complex	Recurrent Neisseria (e.g. meningococcal) or gonococcal pyogenic infections Life-threatening sepsis is possible. Associated with SLE and glomerulonephritis

Congenital B-cell immunodeficiencies

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

X-linked (Bruton) agammaglobulinemia [3]

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 → complete deficiency of mature B cells
Clinical features:
Symptoms develop between 3 and 6 months of age when maternal IgG levels in fetal serum start to decrease.

Hypoplasia of lymphoid tissue (e.g., tonsils, lymph nodes)

Recurrent, severe, pyogenic infections (e.g., pneumonia, otitis media), especially with encapsulated bacteria (S. pneumoniae, N. meningitidis, and H. influenzae)

Hepatitis virus and enterovirus (e.g., Coxsackie virus) infections
Diagnosis
- Flow cytometry
  
  Absent or low levels of B cells (marked by CD19, CD20, and CD21)
  
  Normal or high T cells
- Low immunoglobulins of all classes
- Absent lymphoid tissue, i.e., no germinal centers and primary follicles
Treatment
- IV immunoglobulins
- Prophylactic antibiotics

Bruton agammaglobulinemia fact sheet

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]

Definition: most common primary immunodeficiency; that is characterized by a near or total absence of serum and secretory IgA
Epidemiology: approx. 1:220 to 1:1,000
Etiology: unknown
Clinical features
- Often asymptomatic
- May manifest with sinusitis or respiratory infections (S. pneumoniae, H. influenzae)
- Chronic diarrhea, partially due to elevated susceptibility to parasitic infection; (e.g. by Giardia lamblia)
- Associated with autoimmune diseases (e.g., gluten-sensitive enteropathy, inflammatory bowel disease, immune thrombocytopenia) and atopy
- Anaphylactic reaction to products containing IgA (e.g., intravenous immunoglobulin)
Diagnosis
- Decreased serum IgA levels (< 7 mg/dL)
- Normal IgG and IgM levels
- False-positive pregnancy tests [6]
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.

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]

Definition: primary immunodeficiency with low serum levels of all immunoglobulins despite phenotypically normal B cells
Epidemiology
- Sex: ♀ = ♂
- Onset: later than other B-cell defects (typically at 20–40 years of age) [10]
Etiology: Most cases are sporadic with no known family history.
Pathophysiology: 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) [11]
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

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

Definition: an age-related delay in immunoglobulin production despite having normal levels of B cells
Epidemiology
- Approx. 1:1000 live births [13]
- Onset: > 6 months of age; Ig levels typically increase and normalize at 2–6 years of age. [12]
Clinical features
- Recurrent infections (most common: sinopulmonary infections, otitis media, bronchitis, tonsillitis, diarrhea)
- Atopic manifestations (e.g., asthma, food allergies)
- Failure to thrive and/or developmental delay
- Can be asymptomatic
- Severe and/or invasive infections, such as meningitis and bacteremia (rare)
Diagnosis
- Quantitative
  immunoglobulin levels
  
  IgG is ≤ 2 SD of age-appropriate levels.
  
  Levels of IgA and IgM may be low.
  
  Flow cytometry shows subsets of normal B and T cells.
- Presence of specific
  antibodies
  
  Post-exposure IgG antibodies (e.g., rubella, varicella)
  
  Post-immunization IgG antibodies (e.g., tetanus toxoid, pneumococcal polysaccharide)
  
  Isohemagglutinins (anti-A, anti-B)
Treatment
- Prophylactic antibiotics in patients with recurrent infections
- IV immunoglobulins in patients who develop severe and/or invasive infections or recurrent infections despite prophylaxis
- Appropriate treatment in patients with atopic manifestations (e.g., bronchodilators)
- Routine immunization schedule should be continued.

**Bruton agammaglobulinemia fact sheet**
BTK: B-cell tyrosine kinase

© AMBOSS

Congenital T-cell immunodeficiencies

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

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

Definition: genetic disorder, which is characterized by a microdeletion at the 22q11.2 region resulting in a range of developmental abnormalities
Epidemiology: ∼ 1 in 2,000 to 7,000 live births
Etiology: microdeletion at chromosome 22 (22q11.2); de novo mutation (∼ 90%), autosomal dominant (∼ 10%)
Pathophysiology
- The TBX1 gene in the 22q11.2 region is the main gene responsible for the DiGeorge phenotype
- Deletions in TBX1 lead to
  malformations in the
  pharyngeal apparatus, which results in abnormalities of the:
  
  Bones and muscles of the face and neck → abnormal facies, cleft palate
  
  Outflow tract of the heart → heart defects (e.g., ToF)
  
  3rd and 4th pharyngeal pouches → thymus hypoplasia (T-cell immunodeficiency) and parathyroid hypoplasia (hypocalcemia)
Clinical features
- Cardiac anomalies in DiGeorge syndrome
  
  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: mostly normal life expectancy with appropriate medical care

CATCH-22 is the acronym for typical features of DiGeorge syndrome: Cardiac anomalies; Anomalous face; Thymic aplasia/hypoplasia; Cleft palate; Hypocalcemia; Chromosome 22.

DiGeorge syndrome (22q11.2 deletion syndrome) fact sheet Facial features in DiGeorge syndrome

Autosomal dominant hyperimmunoglobulin E syndrome (Job syndrome) [15]

Definition: defect in neutrophil chemotaxis
Etiology: autosomal dominant; STAT3 mutation → ↓ Th17 cells → ↓ neutrophil chemotaxis
Clinical features
- Coarse Facies
- Recurrent, cold 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. [16]
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).

Autosomal dominant hyper-IgE syndrome fact sheet

IL-12 receptor deficiency [17][18][19]

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)
  
  Affected individuals have defects in IFN-γ mediated immunity.
  
  This increases susceptibility to infection with weakly virulent mycobacteria (e.g., environmental mycobacteria, BCG vaccine).
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
- Autoimmune regulator (AIRE protein) deficiency is a common cause.
- The majority of cases are caused by a gain of function mutation in the STAT1 gene. [20]
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

**DiGeorge syndrome (22q11.2 deletion syndrome) fact sheet**
© AMBOSS

**Facial features in DiGeorge syndrome**
Broad nasal bridge and nasal tip, ocular hypertelorism, dysplastic and low-set ears as well as micrognathia.

Source: “Figure 1, in: Towards a safety net for management of 22q11.2 deletion syndrome: guidelines for our times” by A. Habel, R. Herriot, D. Kumararatne et al., Springer Link, licensed under CC BY 4.0. Modifications: person anonymized.

**Physeo - DiGeorge Syndrome**
Original title: “Genetics: Section 12.3 - DiGeorge Syndrome”. Created by: Physeo™.

**Autosomal dominant hyper-IgE syndrome fact sheet**
© AMBOSS

Congenital mixed immunodeficiencies

Severe combined immunodeficiency (SCID, 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 the function of ribonucleotide reductase → impaired generation of deoxynucleotides
  
  Janus-associated kinase 3 (JAK3) deficiency
- RAG mutation results in faulty VDJ recombination (see “Immunoglobulin properties”).
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
Subtype:
Omenn syndrome (an
autosomal recessive form of
SCID) [21]

Etiology: mutations of RAG gene or ILRA7 gene

Clinical features

Onset before 3 months of age

Erythroderma, adenopathy, and hepatosplenomegaly

Severe, recurrent infections

Failure to thrive

Diagnosis: oligoclonal T cells, eosinophilia, ↑ IgE levels
Diagnosis
- Quantitative PCR: ↓ T-cell receptor excision circles (TRECs); detection of TRECs is used in the newborn screening for SCID
- 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
- Prognosis: often fatal in the first year of life if left untreated [22]

Wiskott-Aldrich syndrome (WAS)

Definition: genetic condition characterized by impaired function of T cells and thrombocytopenia
Epidemiology: : occurs primarily in males
Etiology: mutated WAS gene (X-linked recessive inheritance) → impaired signaling to actin cytoskeleton reorganization → defective antigen presentation
Clinical features
- Onset of symptoms: from birth
- Classic triad
  - Purpura (bleeding diathesis)
  - Eczema (high risk of atopic disorders)
  - 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 WAS gene
Treatment
- IV immunoglobulin therapy
- Prophylactic antibiotics
- Platelet transfusions
- Stem cell transplantation may be curative.
Prognosis: : shortened life expectancy

Wiskott-Aldrich syndrome

Classic findings of Wiskott-Aldrich syndrome (Wiskott-Aldrich syndrome, Purpura, Eczema, Recurrent infections): WisPER

Hyper-IgM syndrome [23]

Definition: A group of syndromes characterized by impaired interaction between Th cells and B cells that results in a B cell class-switching defect
Epidemiology: CD40 ligand deficiency is the most common form.
Etiology
- X-linked recessive inheritance
- CD40L deficiency in Th cells leads to abnormal interaction with B cells that express the CD40 receptor, disrupting B-cell class-switching, which leads to depleted immunoglobulins
Clinical features
- Recurrent severe
  pyogenic infections that manifest since childhood
  - Opportunistic 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.

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)

Definition: deficiency of superoxide production by polymorphonuclear neutrophils and macrophages
Etiology
- X-linked recessive or autosomal recessive inheritance (2:1)
- Defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase that results in:
  
  Defective reactive oxygen species (ROS) production (e.g., superoxide) → 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)
- 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, i.e., incubated leukocytes fail to turn blue when exposed to nitroblue tetrazolium
- Hypergammaglobulinemia
- Anemia
- Genotyping is confirmatory
Treatment
- Treatment of infections
- Life-long prophylactic antibiotics, e.g., TMP-SMX (for catalase-positive infections)
- Antifungal prophylaxis (e.g., itraconazole, voriconazole, posaconazole)
- Glucocorticoids for severe inflammation
- IFN-γ therapy
- Bone marrow transplant
- Possibly gene therapy

Chronic granulomatous disease fact sheet

Leukocyte adhesion deficiency type 1 (LAD1)

Definition: : A genetic condition characterized by a defect in the leukocytic chemotaxis that results in decreased phagocyte activity
Etiology
- Autosomal recessive inheritance
- Absence of the β2-integrin leukocyte adhesion surface molecule LFA-1 (CD18) prevents leukocytes from migrating to tissues during infection or inflammation.
Clinical features
- Recurrent nonsuppurative bacterial infections (e.g., skin and mucosal infections) with minimal inflammation due to dysfunctional neutrophils
- Impaired wound healing
- Omphalitis
- Delayed separation of the umbilical cord (> 30 days 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 degeneration of neurons and 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
- Pancytopenia (especially neutropenia)
Treatment: bone marrow transplant

Chediak-Higashi syndrome

Classic findings of Chediak-Higashi syndrome (Albinism, Lymphohistiocytosis, Peripheral neuropathy, Infections, Neurodegeneration, Neutropenia): ALPINe

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/μL 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

**Chronic granulomatous disease fact sheet**
© AMBOSS

**Chediak-Higashi syndrome**
Photomicrograph of peripheral blood smear (Wright-Giemsa stain; very high magnification)
Inclusion bodies (examples indicated by arrows) and polymorphous nuclei (green overlay) can be seen within the leukocytes.
These findings are consistent with Chediak-Higashi syndrome.

Source: “Figure 2, in: Two Novel Mutations Identified in an African-American Child with Chediak-Higashi Syndrome” by Kerry Morrone, Yanhua Wang, Marjan Huizing, Elie Sutton, James G. White, William A. Gahl, and Karen Moody, Case Reports in Medicine, licensed under CC BY 3.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above (© AMBOSS).

Congenital complement deficiencies

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]
Classification	C1q deficiency [26][27]	C1r deficiency and/or C1s deficiency	C2 deficiency [28]	C3 deficiency [29]	C4 deficiency [30]	Terminal complement deficiency (C5–C9) [25]
Epidemiology	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
Etiology	Autosomal recessive inheritance				Autosomal dominant or autosomal recessive inheritance C4 gene mutations	Autosomal recessive inheritance
Etiology	C1q gene mutations	C1r and/or C1s gene mutations	C2 gene mutations	Primary or secondary due to impairment in the regulatory proteins factor I or factor H		Autosomal recessive inheritance
Pathophysiology	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		Type I C2 deficiency: deletion in C2 gene → impaired translation of the C2 protein → absent C2 protein Type II C2 deficiency: point mutation the C2 gene → ↓ C2 secretion → ↓ plasma levels	Decreased C3b → impaired opsonization of pathogens and ↓ clearance of C3b-bound immune complexes	Decreased or absent C4 protein → ↓ activation of the classical and lectin complement pathway [34]	Impaired formation of the membrane attack complex due to deficiencies in terminal complement factors (C5–C9)
Clinical features	Increased risk of bacterial infections
Clinical features	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	Recurrent, severe childhood infections (e.g., upper respiratory tract infections, pneumonia, meningitis) with encapsulated bacteria (e.g., N. meningitidis, H. influenzae, S. pneumoniae)	Increased risk of viral infections	Increased risk of recurrent Neisseria spp. infections
Diagnosis	Measurement of serum protein levels Confirmatory molecular genetic testing C1q deficiency: neuroimaging may show cerebral vasculitis, brain atrophy, and/or lesions of the basal ganglia CH50 assay screening test Measures total hemolytic complement activity (of the classical complement pathway). Hemolysis of the serum sample will be absent if the patient has a complement deficiency.
Management	No specific treatment available Immunization against the most likely pathogens Antibiotic prophylaxis and treatment of infections Immunosuppression in patients with SLE C1q deficiency: Allogeneic hematopoietic stem cell transplantation can restore physiologic C1q production.
Complications [2]	Associated with renal disease (mesangial proliferative glomerulonephritis, IgA nephropathy) ↑ Risk of autoimmune conditions					Risk of infection and subsequent potentially life-threatening sepsis increases with course of the disease.
Complications [2]	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	Associated with SLE and type III hypersensitivity reactions	Very high risk of developing SLE or SLE-like diseases

C1 esterase inhibitor deficiency (hereditary angioedema)

See “Bradykinin-mediated 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
- Measurement of serum MBL protein levels
- Confirmatory molecular genetic testing
Management and complications: see C1q deficiency

References

Fomin AB, Pastorino AC, Kim CA, et al. "DiGeorge Syndrome: a not so rare disease". Clinics. 65(9). :865-869. (2010)
Khan K, Wozniak SE, Giannone AL, Abdulmassih ME. "A boy with relentless pruritus: Job’s Syndrome". Am J Case Rep. 17. :104-110. (2016)
Wissem Hafsi, Talel Badri. "Job Syndrome (Hyperimmunoglobulin E)". StatPearls Publishing. (2019)
Caragol I, Casanova JL. "Inherited disorders of the Interleukin-12/ Interferon-gamma axis: Mendelian predisposition to mycobacterial disease in man". Inmunología. 22(3). :263-276. (2003)
Palamaro L, Giardino G, Santamaria F et al. "Interleukin 12 receptor deficiency in a child with recurrent bronchopneumonia and very high IgE levels". Ital J Pediatr. 38(46). (2012)
Prando C, Samarina A, Bustamante J et al. "Inherited IL-12p40 deficiency". Medicine (Baltimore). 92(2). :109-122. (2013)
Okada S, Puel A, Casanova J-L, Kobayashi M. "Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity". Clin Transl Immunology.. 5(12). :e114. (2016)
"Omenn syndrome". https://rarediseases.info.nih.gov/diseases/8198/omenn-syndrome/cases/34404#:~:text=Infants%20with%20Omenn%20syndrome%20typically,precede%20the%20onset%20of%20infections.. [2012-03-21]
Mary Dell Railey, M.D., Yuliya Lokhnygina, et al. "Long Term Clinical Outcome of Patients with Severe Combined Immunodeficiency who Received Related Donor Bone Marrow Transplants without Pre-transplant Chemotherapy or Post-transplant GVHD Prophylaxis". The Journal of Pediatrics. (2009)
"X-Linked Hyper IgM Syndrome"
"Dihydrorhodamine (DHR) Flow Cytometric Phorbol Myristate Acetate (PMA) Test, Blood". https://www.mayomedicallaboratories.com/test-catalog/Overview/62765. [2018-01-01]
Greenberg DE, Goldberg JB, Stock F, et al. "RecurrentBurkholderiaInfection in Patients with Chronic Granulomatous Disease: 11‐Year Experience at a Large Referral Center". Clinical Infectious Diseases. 48(11). :1577-1579. (2009)
Macedo ACL, Isaac L. "Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway". Frontiers in Immunology. 7. (2016)
Rosain J, Hong E, Fieschi C, et al. "Strains Responsible for Invasive Meningococcal Disease in Patients With Terminal Complement Pathway Deficiencies". J Infect Dis. 215(8). :1331-1338. (2017)
Van Schaarenburg RA, Magro-Checa C, Bakker JA, et al. "C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus". Frontiers in Immunology. 7. (2016)
"C1q deficiency". https://rarediseases.info.nih.gov/diseases/12958/c1q-deficiency. [2016-03-18]
Sullivan KE. "Complement Deficiencies". Elsevier. :90-100.e4. (2015). ISBN: 0323298753
S. Reis E, Falcao DA, Isaac L. "Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H". Scand J Immunol. 63(3). :155-168. (2006)
Wu YL, Hauptmann G, Viguier M, Yu CY. "Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus". Genes & Immunity. 10(5). :433-445. (2009)
Lintner KE, Wu YL, Yang Y, et al. "Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases". Frontiers in Immunology. 7. (2016)
"Complement component 2 deficiency". https://medlineplus.gov/genetics/condition/complement-component-2-deficiency/. [2020-08-18]
Okura Y, Kobayashi I, Yamada M, et al. "Clinical characteristics and genotype-phenotype correlations in C3 deficiency". J Allergy Clin Immunol. 137(2). :640-644.e1. (2015)
Wang H, Liu M. "Complement C4, Infections, and Autoimmune Diseases". Frontiers in Immunology. 12. (2021)
"Mannose-binding lectin protein deficiency". https://rarediseases.info.nih.gov/diseases/10309/mannose-binding-lectin-protein-deficiency#ref_11420. [2016-11-23]
Holdaway J, Deacock S, Williams P, Karim Y. "Mannose-binding lectin deficiency and predisposition to recurrent infection in adults". J Clin Pathol. 69(8). :731-736. (2016)
"Bruton Agammaglobulinemia"
Yel L. "Selective IgA deficiency". J Clin Immunol. 30(1). :1-16. (2010)
"Selective IgA Deficiency". http://www.msdmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/selective-iga-deficiency. [2016-08-01]
Cole LA. "False Positive hCG Assays". Elsevier. :229-236. (2010). ISBN: 9780123849076
"Common Variable Immune Deficiency". https://rarediseases.org/rare-diseases/common-variable-immune-deficiency/. [2017-01-01]
Sneller MC. "New insights into common variable immunodeficiency". Ann Intern Med. 118(9). :720. (1993)
Cunningham-Rundles C. "The many faces of common variable immunodeficiency". Hematology Am Soc Hematol Educ Program. 2012. :301-305. (2012)
Tam JS, Routes JM. "Common Variable Immunodeficiency". American Journal of Rhinology & Allergy. 27(4). :260-265. (2013)
Agarwal S, Cunningham-Rundles C. "Autoimmunity in common variable immunodeficiency". Ann Allergy Asthma Immunol. 123(5). :454-460. (2019)
Kliegman RM, Stanton BF, Geme JS, Schor NF, Behrman RE. "Nelson Textbook of pediatrics". Elsevier (2011). (2011). ISBN: 9781437707557
A Wesley Burks, Stephen Holgate, Robyn O'Hehir, et al. "Middleton's Allergy: Principles and Practice". Elsevier. (2019). ISBN: 9780323546980