Table 3.

Inborn errors of immunity with atopic phenotypes.

Disease	Genetic defect	Inheritance	Main Features	Distinguishing features from common allergic disorders
Hyper-IgE syndromes (HIES)
AD-HIES STAT3 deficiency (Job syndrome)	STAT3	AD LOF	Eczema, skin abscesses, CMC, recurrent pneumonias leading to pneumatocoeles, and skeletal and connective tissue abnormalities	Early-onset eczema; peculiar thickened texture of the facial skin, retroauricular fissures, and severe folliculitis of the axillae and groin; cold abscesses; distinctive facial, and skeletal features, low frequency of allergy
DOCK8 deficiency	DOCK8	AR	Severe eczema, severe allergies, immunodeficiency with increased susceptibility to bacterial and viral infections, autoimmunity, and increased risk for malignancies	Severe eczema associated with warts, severe skin and sinopulmonary infections
ZNF341 deficiency	ZNF341	AR	Phenocopy of AD-HIES	Same as AD-HIES
IL6 signal transducer (IL6ST) deficiency	IL6ST	AR or AD LOF	Largely overlapping with AD-HIES: eczema, recurrent skin and pulmonary infections, craniosynostosis, neurodevelopmental delay	Severe eczema, recurrent cutaneous and pulmonary infections, distinctive skeletal features
IL6 receptor deficiency	IL6R	AR	Partially overlapping with AD-HIES: no skeletal abnormalities	Recurrent pyogenic infections, cold abscesses
ERBIN deficiency	ERBB2IP	AD LOF	Eczema, eosinophilic esophagitis, skeletal and connective tissue abnormalities like STAT3-HIES	Skeletal and connective tissue abnormalities
Loeys-Dietz syndrome (TGFBR deficiency)	TGFBR1 TGFBR2	AD	Marfan-like syndrome, high prevalence of allergic diseases	Skeletal and connective tissue abnormalities
PGM3 deficiency	PGM3	AR	Skeletal dysplasia, immunodeficiency and tendency to bone marrow failure, severe atopy, neurodevelopmental delay; some patients display renal, intestinal, and heart defects.	Complex syndromic phenotype associated with atopy
Comel-Netherton syndrome	SPINK5	AR	Congenital ichthyosis, bamboo hair, atopic diathesis; increased bacterial infections; enteropathy, failure to thrive	Congenital ichthyosis
TYK2 deficiency	TYK2	AR	Susceptibility to intracellular bacteria (mycobacteria, Salmonella) and viruses; dermatitis	Peculiar susceptibility to infections
Omenn syndrome
OS is associated with multiple genetic abnormalities	RAG1, RAG2, IL2RG, IL7R, LIG4, ADA, DCLRE1C, RMRP, CHD7, ZAP70, 22q11del and more	AR, XL	Erythroderma, lymphadenopathy, eosinophilia, and combined immunodeficiency	Erythroderma or neonatal eczematous rash; immunodeficiency
Wiskott-Aldrich syndrome (WAS) and WAS-like conditions
Wiskott-Aldrich syndrome	WAS	XL	Thrombocytopenia, recurrent infections, eczema, bloody diarrhea, haematological malignancies, autoimmune manifestations	Eczema associated with thrombocytopenia and recurrent infections
WIP deficiency	WIPF1	AR	Thrombocytopenia with or without small platelets, recurrent infections, eczema, bloody diarrhea	WAS-like phenotype
ARPC1B deficiency	ARPC1B	AR	Mild thrombocytopenia, recurrent infections, autoimmunity; dermatitis	WAS-like phenotype
NOCARH	CDC42	AD	Neonatal-onset cytopenia, autoinflammation, rash, and episodes of hemophagocytic lymphohistiocytosis; wide phenotypic heterogeneity	Autoinflammation, cytopenia, episodes of HLH
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like conditions
IPEX	FOXP3	XL	Autoimmune enteropathy, early onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, severe early-onset dermatitis, recurrent severe infections, elevated IgE and IgA	Severe early-onset dermatitis associated with multiorgan autoimmunity
CD25 deficiency	IL2RA	AR	IPEX-like syndrome; chronic viral, fungal, and bacterial infections	IPEX-like syndrome
STAT5b deficiency	STAT5B	AR or AD LOF	Growth-hormone insensitive dwarfism; dysmorphic features; eczema; prominent autoimmunity Growth-failure; eczema (no immune defects compared to AR STAT5b deficiency)	IPEX-like syndrome, dwarfism, dysmorphic features
STAT1 GOF	STAT1	AD GOF	CMC, infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy	CMC, autoimmunity
ITCH deficiency	ITCH	AR	Autoimmunity, failure to thrive, developmental delay, dysmorphic facial features	Autoimmunity, dysmorphic facial features
CBM-opathies
CADINS	CARD11	AD LOF	Atopic disease, respiratory tract infections and cutaneous viral infections Increased IgE, eosinophilia, Th-2 skewed immune response	Severe atopic disease associated with susceptibility to infections and immune dysregulation
CARD14 deficiency	CARD14	AD LOF	Atopic disease, recurrent pyogenic and viral skin infections and respiratory tract infections	See CARD11
MALT1 deficiency	MALT1	AR	Recurrent infections of the skin and of the respiratory and gastrointestinal tracts, failure to thrive, periodontal disease and inflammatory gastrointestinal disease	Recurrent infections and inflammatory gastrointestinal disease
Other IEI presenting with atopic phenotypes
Selective IgA deficiency (SIgAD)	Unknown	Unknown	Frequently asymptomatic. Susceptibility to infections, autoimmunity and allergy Serum IgA levels (<0.07 g/L), normal serum IgG and IgM on at least two determinations	Isolated IgA deficiency
RLTPR deficiency	CARMIL2	AR	Recurrent infections, EBV lymphoproliferation and other malignancy, atopy	Infections, atopy, malignancies
JAK1 GOF	JAK1	AD GOF	Eosinophilia, hepatosplenomegaly, eosinophilic enteritis, poor growth, viral infections	Hypereosinophilic syndrome
MyD88 deficiency	MYD88	AR	Bacterial infections (pyogens), high IgE levels	Peculiar susceptibility to pyogenic infections
EDA-ID due to IKBKG (NEMO) deficiency	IKBKG (NEMO)	XL	Anhidrotic ectodermal dysplasia; susceptibility to infections (bacteria, mycobacteria, viruses, fungi)	Peculiar phenotype of anhidrotic ectodermal dysplasia
NFKB1 deficiency	NFKB1	AD	Recurrent respiratory infections, EBV proliferation, autoimmunity	Susceptibility to infections, autoimmunity (cytopenias, alopecia, thyroiditis)
NFKB2 deficiency	NFKB2	AD	Recurrent respiratory infections, autoimmunity	Susceptibility to infections, autoimmunity (alopecia and endocrinopathies)
Hypereosinophilic syndrome due to somatic mutations in STAT5b	STAT5B (GOF) – somatic mutations	–	Eosinophilia, atopic dermatitis, urticarial rash, diarrhea	Hypereosinophilic syndrome

AR, autosomal recessive; AD, autosomal dominant; CADINS, CARD11-associated atopy with dominant interference of NF-kB signaling; CMC, chronic mucocutaneous candidiasis; EDA-ID, Anhidrotic Ectodermal Dysplasia with ImmunoDeficiency; GOF, gain of function; HLH, hemophagocytic lymphohistiocytosis; LOF, loss of function; XL, X-linked