Inborn Errors of Immunity: What to Look for Beyond Infections

Fernanda Pinto-Mariz*, Ekaterini Goudouris2

IPPMG-Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil

Inborn errors of immunity (IEI) are a heterogeneous group of more than 400 diseases, mostly genetically determined, whose main clinical manifestations are severe and / or recurrent infections. Despite the efforts of immunology societies worldwide, this group of diseases remains underdiagnosed. The present review attempts to describe, and call the attention of the physicians, for the infectious and non-infectious manifestations related to IEI. The main clinical manifestations, as well as others that are not so frequent, have been reported in this manuscript. In order to facilitate clinical reasoning, we created a table to illustrated some of them and subdivided the main manifestations into infectious, infectious associated with immune dysregulation, only related to dysregulation and others. The dissemination of knowledge about clinical manifestations, especially non-infectious ones, can contribute to early diagnosis of IEI and, consequently, to the reduction of their morbidity and mortality.


Primary immunodeficiencies are a heterogeneous group of diseases with compromise of immune system, mostly genetically determined, first described in the 1950s in patients with severe and / or recurrent infections. Since then, with advances in science, especially genetics, new genes and diseases have been identified, and other clinical manifestations, especially non-infectious ones related to autoimmunity, neoplasia, inflammation, allergy and lymphoproliferation have been described1,2. The identification of manifestations of dysregulation of the immune system in these patients has now led this group of diseases to be called inborn errors of immunity (IEI).

Currently, more than 400 diseases are described, and 430 genetic defects have been identified3, and it is estimated that, together, the prevalence of these diseases is from 1: 1000 to 1: 5000. Predominantly antibody deficiencies are the most frequent, corresponding to approximately 50% of cases4.

In order to facilitate the diagnosis and research of these diseases, the IEI were divided into 10 tables3, according to the classification by the International Union of Immunological Societies (IUIS): 1- Immunodeficiencies affecting cellular and humoral immunity (severe combined immunodeficiency – SCID and combined immunodeficiency - CID), 2- Combined immunodeficiencies with associated or syndromic features, 3- Predominantly antibody deficiencies, 4- Diseases of immune dysregulation, 5- Congenital defects of phagocyte number or function, 6- Defects in intrinsic and innate immunity, 7- Autoinflammatory disorders, 8- Complement deficiencies, 9- Bone marrow failure, 10- Phenocopies of inborn errors of immunity.

Severe and/or recurrent infections by common and/or opportunistic microorganisms that require intravenous antibiotics to resolve are the most common manifestations of IEI diseases5. Despite infections being the most frequent clinical manifestations of this group of diseases and being part the clinical picture of most of them, they are not necessarily the main manifestations. Autoinflammatory disorders, for example, rarely develop infectious conditions and are characterized by persistent or recurrent multisystemic inflammation5.

Some IEI diseases are characterized by well-defined clinical phenotypes such as Wiskott-Aldrich Syndrome, Ataxia telangiectasia, Comèl-Netherton Syndrome, Autosomal dominant HyperIgE Syndrome, among others5.

Warning Signs for Inborn Errors of Immunity

The suspicion of an IEI must start from non-immunologists, that’s why many lists of warning signs have been created. However, the warning signs in use are not able to identify many of the IEI6-8. and studies have shown that family history, need for intravenous antibiotic therapy and failure to thrive are the most efficient signs9.

Warning signs by medical specialties were proposed, focusing on pulmonary, gastrointestinal, cutaneous and other manifestations10, 11, but their greater efficacy in the identification of patients was not demonstrated.

Table I describes the warning signs which, even though we know that they are not sensitive, are the most used in the world.

Table I : Warning signs for inborn errors of immunity in newborns, children and adults


Severe and/or persistent fungal, viral, or bacterial infections 

Adverse reaction to Live vaccine specially BCG

Persistent diabetes mellitus or other autoimmune and/or inflammatory manifestation 

Sepsis-like clinical picture without microbial isolation

Extensive skin lesions

Persistent diarrhea

Congenital heart defects (mainly conotruncal anomalies)

Delayed umbilical cord detachment (>30 days)

Familial history of PID or early deaths caused by infection

Persistent lymphocytopenia 2,500 cells/mm3 or other cytopenia, or leukocytosis without infection

Hypocalcemia with or without seizures

Absence of thymic shadow at X-Ray


Four or more new ear infections within 1 year

Two or more serious sinus infections within 1 year

Two or more months on antibiotics with little effect

Two or more pneumonias within 1 year

Failure of an infant to gain weight or grow normally

Recurrent, deep skin or organ abscesses

Persistent thrush in mouth or fungal skin infection

Need for intravenous antibiotics to clear infections

Two or more deep-seated infections including septicemia

A family history of an inborn error of immunity


Two or more new ear infections within 1 year

Two or more serious sinus infections within 1 year, in the absence of allergy

One pneumonia per year for more than 1 year

Chronic diarrhea with weight loss

Recurrent viral infections (colds, herpes, warts, condyloma)

Recurrent need for intravenous antibiotics to clear infections

Recurrent, deep abscesses of the skin or internal organs

Persistent thrush or fungal infection on skin or elsewhere

Infection with normally harmless tuberculosis-like bacteria

A family history of an inborn error of immunity

Sources: [3,11]

IEI: Other Manifestations Beyond Infections

In general, the sensitivity of the 10 warning signs for the diagnosis of IEI is low, around 60 to 70%, being even lower for less severe diseases6. The medical lack of knowledge about the diseases13 and the predominant focus on infectious manifestations as warning signs can contribute to this scenario. Currently, it is recommended that patients with autoimmune manifestations of early onset and/or refractory to conventional treatments14, severe and difficult to control allergic conditions15, recurrent or persistent inflammatory processes associated or not with fever16 and malignant diseases with early onset and/or unusual presentation17 should be investigated for IEI. The diagnosis of patients with IEI requires a high degree of suspicion, and knowledge of other manifestations besides the infectious ones is essential. Identifying the disease also represents a great challenge. In this sense, the reasoning guided by the main clinical manifestations, pathogens preferentially involved, the main affected sites, and other manifestations that may also be present, facilitate the clinical diagnosis of IEI diseases. Aiming to draw attention to non-infectious manifestations, as well as to facilitate clinical reasoning for the diagnosis of this group of diseases, we created a table that illustrates some of the IEI diseases, highlighting the main clinical manifestations and those that may be associated (Table II). Furthermore, we believe that the division by groups of clinical manifestations (infectious or not), type of pathogen and affected sites is useful for a bedside consultation and could facilitate the diagnosis of IEI diseases. 

Table II: Main clinical presentation and associated manifestations of some of the inborn errors of immunity.

Main Manifestations/





IUIS Classification

Other manifestations/


Early onset of severe/recurrent bacterial, fungal and víral infections; severe reactions with live microorganism vaccines


Severe combined immunodeficiency



Cytopenias, chondroesternal dysplasia, deafness, dysmorphisms, congenital alopecia + nail dystrophy, lymphoproliferation, failure to thrive granuloma, autoimmunity

Late onset (>1 year of age)


Recurrent bacterial, fungal and viral infections, especially EBV


Less severe than SCID

Combined immunodeficiency



Hepatosplenomegaly, lymph node

swelling, eczema, eosinophilia,

elevated IgE: Omenn syndrome


Severe eczema, cutaneous infections, severe atopy, câncer, high IgE, eosinophilia: DOCK8 deficiency


Autoimmunity, immune dysregulation, granuloma, biliary tract and liver disease

Recurrent/severe bacterial infections (extracellular)


Mainly sinopulmonary infections

Predominantly antibody deficiencies


B cells: decreased or absent, severe reduction in all serum Ig isotypes

(Agammaglobulinemia: XL, AD, AR)

IBD (p110δ deficiency), cytopenias (p85 deficiency), blistering, dermatosis, failure to thrive (ZIP7 deficiency), thrombocytopenia, facial dysmorphism, limb anomalies (Hoffman Sd)

Predominantly antibody deficiencies


B cells: decreased or N, severe reduction in at least 2 serum Ig isotypes (IgG and IgA)

 (CVID phenotype)

Polyclonal, lymphoproliferation, autoimmune

cytopenias, granulomatous disease, lymphadenopathy, splenomegaly, lymphoma


EBV ±CMV viremia: APDS1



delay: APDS2, PTEN deficiency


Glomerulonephritis: CD19 and CD81 deficiencies


Congenital sideroblastic anemia, deafness,

developmental delay: TRNT1 deficiency

Bacterial respiratory tract infections




Enlarged lymph nodes (AID and UNG deficiency)

Predominantly antibody deficiencies


B cells: N

IgG and IgA: severe reduction

IgM: N or elevated (Hyper IgM)

Café-au-lait skin spots, hypopigmented skin áreas, family or personal history of câncer (MSH6 deficiency)



Autoimmunity (AID and UNG deficiency)

Recurrent or severe bacterial infection, mainly respiratory (specific antibody deficiency)


Mild bacterial respiratory and gastrointestinal tract infections or asymptomatic (selective IgA deficiency)


Usually not associated with significant infections, resolution around 4 years old (transient hypogammaglobulinemia of infancy)

Predominantly antibody deficiencies


Isotype, Light Chain, or Functional Deficiencies

B cells: N in general

Atopic dermatitis, asthma (specific antibody deficiency)


Autoimmunity (selective IgA deficiency)




Recurrent and severe infections


Skin infections evolve to large ulcers;


S. aureus and Gram-negative organisms; fungal infections (some patients)


Absence of pus


Leukocytosis with neutrophilia

Congenital defects of phagocyte (function)


Leukocyte adhesion deficiency (LAD1)

Delayed separation of the umbilical cord


Severe gingivitis, periodontitis


Impaired wound healing


Failure to thrive






Recurrent bacterial infections – pneumonia, otitis media, cellulitis, periodontitis


Skin infections without pus


Milder infections than in LAD1

Congenital defects of phagocyte (function)



Bombay blood phenotype, mental retardation, short stature, distinctive facial appearance



Recurrent and severe bacterial and fungal infections – similarly to LAD1


Absence of pus


Leukocytosis with neutrophilia

Congenital defects of phagocyte (function)



Delayed separation of the umbilical cord, impaired wound healing, bleeding tendency


Osteopetrosis-like state (some patients)

Recurrent bacterial infections (skin, oropharynx and lung)


Aphthous stomatitis and gingivitis


Gram positive and Gram negative bacterial infections


Absence of pus


Severe congenital neutropenia

Congenital defects of phagocyte (number)


MDS/leucemia (Elastase deficiency*)


Mental retardation and seizures (Kostmann disease)


MDS (X-linked neutropenia)


Intestinal inflammation

Ear sinopulmonary, skin and soft tissue bacterial infections


HPV (warts)


Hypogammaglobulinemia, Neutropenia (myelokathexis)

Defects in intrinsic and innate immunity



Tetralogia of Fallot, urogenital abnormalities


HPV-induced cancers


Tooth loss


Mycobacterial, fungal and candida infections

Predisposition to invasive bacterial infections (pyogens), mainly meningitis

S. pneumoniae > S. aureus and P. aeruginosa


Pus formation, little/no increase in body temperature


Low CRP levels, normal levels of total leukocytes and neutrophils during infections


Improves with age

Defects in intrinsic and innate immunity


IRAK4/MyD88 deficiencies

Delayed separation of the umbilical cord




Non invasive bacterial infections (skin and upper respiratory tract infections) usually necrotizing; S. aureus > P. aeruginosa > S. pneumoniae

Recurrent pyogenic infections

Complement deficiencies







MASP2 deficiency

Inflammatory lung disease, autoimmunity

Ficolin 3 deficiency


Necrotizing enterocolitis in infancy; selective antibody defect to Pneumococcal polysaccharides; infections with encapsulated organisms

Disseminated Neisserial infections

Complement deficiencies



Properdin and

Factor D deficiency




Fungal, bacterial, and parasitic infections


Systemic adverse effects to BCG


Most severe in XL disease

Congenital defects of phagocyte (function)


Chronic Granulomatous Disease (AR e XL)

Autoinflammatory phenotype, IBD

BCG disease (localized or disseminated)


Mycobacteria, Salmonellae or other intracellular pathogens

Defects in intrinsic and innate immunity


Mendelian susceptibility to mycobacterial disease (MSMD)

Viral infections


Mucocutaneous candidiasis

Severe viral or mycobacterial [NTM] infections



Congenital defects of phagocyte (function)


GATA2 deficiency

Alveolar proteinosis, lymphedema, invasive fungal infections, acute myeloid leukemia

Invasive fungal diseases (mainly Candida and Trichophyton species)

Defects in intrinsic and innate immunity


CARD-9 deficiency



Chronic Mucocutaneous

Candidiasis without ectodermal


Defects in intrinsic and innate immunity



Fungal, bacterial and viral (HSV) infections, auto-immunity (thyroiditis, diabetes, cytopenias), enteropathy

Susceptibility to viral infections:



Severe viral infections

Defects in intrinsic and innate immunity


STAT1 deficiency




Mycobacteria infection

Disseminated vaccine strain measles

STAT2 Deficiency



Severe influenza disease

IRF7 and IRF9 deficiencies

Severe rhinovirus and other RNA viruses

MDA5 deficiency

Herpes simplex encephalitis

UNC93B1 deficiencies


TLR3 deficiencies

Severe pulmonary influenza and VZV

 Epidermodysplasia verruciformis (HPV)



Cancer of the skin

Main Manifestations/




Infections and Immune dysregulation

IUIS Classification

Other manifestations/


Bacterial respiratory tract infection, autoimmunity (cytopenias), enteropathy, splenomegaly



Diseases of immune dysregulation


LRBA deficiency

CTLA-4 haploinsufficiency

Autoimmunity (others than cytopenias), failure to thrive; non-respiratory tract infection, lymphadenopathy, interstitial lung disease, hepatomegaly

Ear/sinopulmonary infections, EBV associated lymphoproliferative disease/lymphoma, lymphadenopathy, splenomegaly

Diseases of immune dysregulation


X-linked magnesium

EBV and neoplasia


Viral infections, gastrointestinal infections, autoimune cytopenias.

Chronic mucocutaneous candidiasis




Addison disease

Diseases of immune dysregulation


Autoimmune polyendocrinopathy with candidiasis

and ectodermal dystrophy (APECED)

Other autoimmunity endocrinopathies


Ectodermal dystrophy




Pernicious anemia

Hemophagocytic lymphohistiocytosis (HLH)


Oculocutaneous albinism


Recurrent infections

Diseases of immune dysregulation

(HLH with hypopigmentation)







Bleeding tendency, progressive neurological dysfunction, neutropenia

Griscelli type 2

Hermansky-Pudlak type 2


Pulmonary fibrosis, increased bleeding, neutropenia

Hermansky-Pudlak type 10

Severe neutropenia, seizures, hearing loss and neurodevelopmental delay

Main Manifestations/




Immune dysregulation

IUIS Classification

Other manifestations/Disease

Familial hemophagocytic lymphohistiocytosis (FHL)

Diseases of immune dysregulation

(FHL without hypopigmentation)




Syntaxin 11 and

STXBP2/Munc18-2 deficiencies









FAAP24 deficiency

EBV-driven lymphoproliferative disease

SLC7A7 deficiency

Lysinuric protein intolerance, bleeding tendency, alveolar proteinosis

Severe and protracted enteropathy with villous atrophy, eczema,

severe, often multiple endocrinopathies (mainly diabetes and thyroiditis)

Diseases of immune dysregulation


IPEX (FOXP3 deficiency)

Hemolytic anemia, thrombocytopenia

IBD and folliculitis

Diseases of immune dysregulation


IL-10 deficiency




Recurrent respiratory diseases, arthritis

IL-10 receptor deficiency

Recurrent respiratory diseases, arthritis, lymphoma




EBV associated HLH, lymphoma, non-malignant lymphoproliferation

Diseases of immune dysregulation


SAP deficiency (XLP1)




Aplastic anemia, vasculitis, colitis

EBV associated HLH, colitis, lymphoproliferation

XIAP deficiency (XLP2)

Recurrent HLH, hepatitis, IBD




Chronic adenopathy


Autoimmune cytopenias

Diseases of immune dysregulation









ALPS-Caspase 10

Bacterial and viral infections




Chronic adenopathy


ALPS-Caspase 8

Bacterial and viral infections

FADD deficiency

Recurrent episodes of encephalopathy and liver dysfunction

Main Manifestations/




SLE-like Syndrome

IUIS Classification

Other manifestations/Disease


Complement deificency

Infections with encapsulated organisms



C1 r

Ehlers Danlos phenotype

C1 s

Ehlers Danlos phenotype, multiple autoimmune diseases


 Vasculitis, polymyositis, atherosclerosis



Main Manifestations/





IUIS Classification

Other manifestations/Disease

Angioedema without urticaria

Complement deficiency




Serpiginous rash

AD: autosomal dominant inheritance, AID: activation-induced cytidine deaminase, ALPS: Autoimmune lymphoproliferative syndrome, APDS: Activated p110δ syndrome, AR: autosomal recessive inheritance, BCG: Bacillus Calmette–Guérin, CID: Combined immunodeficiency, CRP: C-reactive protein, CTLA-4: cytotoxic T lymphocyte antigen 4, CVID: Common variable immunodeficiency, EBV: Epstein-Barr virus, GOF: gain-of-function, HIES: Hyper IgE syndrome; HPV: Human papilloma virus, HSV: Herpes simplex virus, IBD: inflammatory bowel disease, ID: immunodeficiency, Ig: immunoglobulin, IL: interleukin, IPEX: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, IRF: interferon regulatory factor, IUIS: International Union of Immunological Societies, LOF: loss-of-function, LRBA: lipopolysaccharide responsive beige-like anchor protein, MASP: MBL associated serine proteases, MBL: mannose-binding lectin, MDS: Myelodysplastic syndrome, MTHFD1: methylene-tetrahydrofolate dehydrogenase1, N: normal, NTB: non-tuberculous mycobacteria, Sd: syndrome, SLE: Systemic lupus erythematosus, TLR: Toll-like receptor, UNG: uracil-DNA glycosylase, VZV: Varicella zoster virus, XL: X-linked inheritance, XLP: X-linked lymphoproliferative.

* Some patients with elastase deficiency can present with cyclic neutropenia.


Early diagnosis is essential to reduce morbidity and mortality related to this group of diseases4, 18. Suspicion should be made by general practitioners, pediatricians or other medical specialties, so that early referral is made to the clinical immunologist. Therefore, warning signs should be known by all medical specialties and other clinical manifestations, especially non-infectious, cannot be forgotten.

In addition, the incorporation of TREC and KREC count in neonatal screening programs is essential to ensure early identification of severe and fatal forms of IEI19.

Conflict of Interest

All authors declare no conflict of interest related to this manuscript.


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Article Info

Article Notes

  • Published on: August 18, 2021


  • primary immunodeficiency diseases

  • inborn errors of immunity
  • diagnosis
  • clinical manifestations
  • infections
  • immune dysregulation
  • allergy
  • autoimmunity
  • autoinflammation
  • cancer.


*Dr. Pinto-Mariz F,
IPPMG-Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil;