Primary immunodeficiencies and skin Primäre Immundefekte Hautveränderungen; Primary immunodeficiencies and skin;

Primary immunodeficiencies: The term "primary immunodeficiencies, synonym: PID/immune deficiency syndromes/immune deficiency diseases" covers more than 400 different diseases of the immune system, which are characterized by a temporary or permanent disturbance of the immune function, in which the immune deficiency is congenital, occurs in families and/or can be inherited (see under primary immunodeficiencies/overview and classification).
Clinically, primary immunodeficiencies are usually, but not always (e.g. fever syndromes), manifested by a pathological susceptibility to infections. PGDs can manifest in all organs, with surface epithelia in the skin, lungs, intestines, and genitourinary tract most commonly affected.

Among PIDs,common variable immunodeficiency, or CVID, is the most common. Typical warning signs are hidden behind the acronyms:

• ELVIS (pathogen: unusual; localization: atypical; course: long; intensity: severe; total: very common)

and

• GARFIELD (granulomas, autoimmunity, recurrent fever, eczema, lymphoproliferation, intestinal inflammation).

The following table gives an alphabetically listed overview of skin changes that can occur in connection with primary immunodeficiencies:

Primary immunodeficiencies and skin lesions- A-Z - Table varies n. Schremel S/Berneburg M
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Skin abscess formation/recurrent/severe

• Leukocyte adhesion deficiency syndrome/mutationin ITGB2 gene
• Hyper IgE syndrome 1-5/mutationsin versch. STAT genes
• Hyper-IgE syndrome with mutations in: DOCK8, ZNF431, IL6ST, IL6R.
• IL10 defects (perianal abscesses)
• Papillon-Lefèvre syndrome with palmoplantar hperkeratoses
• Hereditary (primary) agammaglobulinemias
• X-linked inhibitor of apoptosis deficiency
• Wiskott-Aldrich syndrome (WAS)

Alopecia

• Anhidrotic ectodermal dysplasia with immunodeficiency /mutation in NFKBIA
• Cartilage hair hypoplasia/mutation in RMPR
• X-linked ectodermal dysplasia with immunodeficiency/mutation in NEMO
• OMENN syndrome/mutation in RAG1/RAG2
• T-cell immunodeficiency with congenital alopecia and nail dystrophy(T-cell immunodeficiency, congenital thymic aplasia, signs of SCID) mutation in FOXN1
• IPEX syndrome/mutation in FOXP3
• NFKB1 defect/autoimmune cytopenias, alopecia and autoimmune thyroiditis
• NFKB2 defect/alopecia, vilitigo, autoimmune thyroiditis, trachyonychia, endocrinopathies such as NNR insufficiency or ACTH deficiency

Anaphylactic reactions

• TACI defect/mutations in TNFRSF13B gene/selective IgA deficiency type2; in case of IgA antibodies, risk of anaphylactic reactions in case of serum or blood transfusions
• Hereditary angioedema /mutations in the C1 esterase inhibitor gene (11q11-q13.1). Deficiency of C1 esterase inhibitor leads to activation of the complement system, which in turn leads to low plasma concentrations of complement factor C2 (see also Angioedema Hereditary/Overview) .

Atopic diathesis

• CARD11 defect/mutation in CARD11 gene/recurrent respiratory and cutaneous viral infections, atopic diathesis, eosinophilia, food-middle-gel allergies, lymphoma.
• Comel-Netherton syndrome /mutation in SPINK5 gene; congenital ichthyosis, bamboo hair, atopic diathesis, bacterial infections, failure to thrive. IgE elevated.

Candidiasis mucocutaneous

• Polyglandular autoimmune syndrome type 1 /mutation in AIRE
• AD-HIES (Hyper-IgE syndrome 1)/mutation in STAT3
• AR-HIES (Hyper-IgE syndrome 2)/mutation in DOCK8
• Chronic mucocutaneous candidiasis (AIRE/CARD9/CANDN/CLEC7A/IL17RA/IL17)
• Dectin1 deficiency/mutation in Dectin1
• DiGeorge syndrome/mutation in TBX1
• IL12/23 deficiency/mutation in IL12B/Il12RB1
• SCID =Severe combined Immunodeficiency (mutations in the genes: ADA/IL2RG/IL7RA/JAK3/DCRE1C/RAG1/RAG2/SMARCAL1)
• T-lymphocyte defects/mutations in IL2/IL2RG

• T-cell immunodeficiency with congenital alopecia and nail dystrophy (T-cell immunodeficiency, congenital thymic aplasia, signs of SCID) Mutation in FOXN1

Dermatofibrosarcoma protuberans

• SCID/mutation in ADA

Eczematous skin lesions

• X-linked agammaglobulinemia/mutation in BTK
• Comel-Netherton syndrome/mutation in SPINK5
• Hyper-IgE syndromes/mutations in STAT3 and DOCK8
• Wiskott-Aldrich syndrome/mutation in WAS
• Ataxia teleangiectatica /Louis Bar syndrome/Mutation in ATM/ Seborrheic eczema
• Common variable immunodeficiency/mutations in genes:CD9; CD81; CR3; ICOS; IL21; LRBA; MS4A1; NFKB2; TNFRSF13B/C
• IPEX syndrome/mutation in FOXP3 - seborrheic eczema,
• CVID (selective IgA deficiency)/mutation in IGHA1/2.
• Growth hormone insensitivity syndrome with immune dysregulation1/mutation in STAT5b
• Loeys-Dietz syndrome (recurrent respiratory infections, atopic dermatitis)/mutation in TGFBR1 or TGFBR2 genes
• STAT5b deficiency (disorder of T and NK cell function/eczema, high IgE)/defect in STAT5b gene

Eosinophilia (hematoeosinophilia)

• Hyper-IgE syndrome 1 (eosinophilia, abscess formation, chronic candidiasis)/mutations in STAT3
• Hyper IgE syndrome5 (very high IgE)/mutations in IL6 receptor gene
• Hyper IgE syndrome4 (very high IgE)/mutations in IL6ST gene
• Hyper IgE syndrome3 (very high IgE)/mutations in the ZNF431 gene
• Hyper IgE syndrome 2 (very high IgE)/ (mutations in the DOCK8 gene
• PGM3 defect (eosinophilia, increased IgE)/ mutation in PGM3 gene

Dermatomyositis

• Agammaglobulinemia 3, mutation in CD79A (CD79A)

Erythroderma

• IPEX syndrome/mutation in FOXP3
• Comel-Netherton syndrome/mutation in SPINK5
• OMENN syndrome/mutation in RAG1/2
• SCID/ mutations in the genes: ADA/ CD3delta/epsilon/ IL7R/ JAK3/ PNP/ RAG1/2 (mutations in these genes cause SCID with exanthem tendency)

Exanthema

• Agammaglobulinemia X-linked/ mutation in IL2RG
• MVK defect (urticarial exanthema.recurrent febrile crises)/mutation in MVK gene
• Muckle-Wells syndrome (urticarial exanthema)/mutation in NLRP3
• Pustularexanthema/mutation in ADAM17
• Pustularexanthema/mutation in IL1RN
• Sweet syndrome/mutation in LPIN2
• Candle syndrome/mutation in PSMB8/anular erythema, eyelid and lip edema, progressive peripheral lipodystrophy
• OTULIN defect (fever, diarrhea and inflammatory exanthema - see below. autoinflammation- panniculitis- dermatosis syndrome) mutation in OTULIN/
• FamilialBehcet-like autoinflammatory syndrome-1/mutation in TNFAIP3
• FamilialBehcet-like autoinflammatory syndrome-2/mutation in ELF4

Granulomas of the skin

• Ataxia teleangiectatica/mutation in ATM
• Chronic granulomatosis/mutation in CYBA/CYBB/ NCF1/2/4
• SCID (Common variable immunodeficiency) mutations in CD9; CD81; CR3; ICOS; IL21; LRBA; MS4A1; NFKB2; TNFRSF13B/C
• Cartilage hair hypoplasia/mutation in RMPR
• MHC class I deficiency/mutation in TAP1/2; TAPBP
• OMENN syndrome (RAG1/2)
• Agammaglobulinemia X-linked/mutation in BTK

Folliculitides

• IL10 defects/mutations in the genes: IL10;IL10RA/B
• IL17F defects/mutation in IL17F
• TIRAP defects (staphylococcal infections) Mutation in TIRAP/

Acne-like skin symptoms (hidradenitis suppurativa)

• Hidradenitis suppurativa/Mutationsin MEFV
• Hidradenitis suppurativa/Mutationsin NCSTN
• Hidradenitis suppurativa/Mutations in PSEN2

Hair abnormalities

• Silvery shiny hair(Chediak-Higashi syndrome) Mutation in LYST
• Silvery hair(Hermansky-Pudlak syndrome type 2)Mutation in AP3B1
• Fine hair: Schimke-type SCID (combination of spondyloepiphyseal dysplasia with numerous lentigines, a slowly progressive immunodeficiency) Mutation in SMARCAL1
• Trichorrhexis invaginata/nodosa (Comel-Netherton syndrome) Mutation in SPINK5
• Woolly hair: tricho-hepato-enteral syndrome/mutation in TTC37 or SKIV2L
• Wiedemann-Steiner syndrome (hypertrichosis of the elbows) mutation KMT2A
• SLC29A3- defect (hypertrichosis and hyperpigmentation)/mutation in SLC29A

Hypohidrosis

• Anhidrotic ectodermal dysplasia with immunodeficiency 1/ mutation in IKBKG
• Anhidrotic ectodermal dysplasia with immunodeficiency 1/mutation in ORA1 gene

• Anhidrotic ectodermal dysplasia with immunodeficiency 2/mutation in NFKBIA

Ichthyoses

• Comel-Netherton syndrome/mutationin SPINK5
• Anhidrotic ectodermal dysplasia with immunodeficiency 1

Infections, bacterial

• Agammaglobulinemias, autosomal recessive
• Agammaglobulinemia X-linked/mutation in IL2RG
• TIRAP defects (staphylococcal infections)Mutation in TIRAP
• Immunodeficiency 13 and IKZF1 defect (bacterial infection tendency, no mycotic infections) Mutation in IKZF1 (Ikaros defect)
• NFKB2 defect(immunodeficiency 10 and NFKB2 defect) bact. infections, alopecia, vilitigo, autoimmune thyroiditis, trachyonychia, endocrinopathies like NNR insufficiency or ACTH deficiency

Infections, viral (general)

• Wiskott-Aldrich syndrome/mutation in WAS

Infections, viral(herpes virus infections -HSV/EBV/cytomegaly)

• Hyper IgE syndrome/mutation in DOCK8
• MCM4 deficiency/mutation in MCM4
• T-lymphocyte defects/IL2R deficiency
• Immunodeficiency syndrome 14A/B/Mutation in PIK3CD
• PIK3R1 defect (chronic EBV and CMV infections)Mutation in PIK3R1
• Immunodeficiency 20 and mutation in FCGR3A

Infections combined -bacterial, viral, mycotic

• SCID/mutation in ADA
• Artemis deficiency/mutation in DCLRE1C
• ILRA deficiency/mutation in ILRA
• JAK3 deficiency/mutation in JAK3
• RAG1/2 deficiency/mutation in RAG1/2
• Immunoosseous dysplasia according to Schimke (T cell immunodeficiency) Mutation in SMARCAL1
• Immunodeficiency 14A/B/Mutationin PIK3CD
• Jacobsen syndrome (chromosome 11q deletion) mutation in 11q23del
• ICF syndrome (syndrome with immunodeficiency, instability of the centromere region of some chromosomes and facial anomalies) mutation in DNMT3B

• T-cell immunodeficiency with congenital alopecia and nail dystrophy (T-cell immunodeficiency, congenital thymus aplasia, signs of SCID) Mutation in FOXN1

Photosensitivity

• Bloom syndrome/mutation in BLM

Lipodystrophy

• Candle syndrome (anular erythema, eyelid and lip edema, progressive peripheral lipodystrophy) Mutation in PSMB8

Livedo syndromes

• Vasculitis, autoinflammation, immunodeficiency and hematological defects/mutation in ADA2 gene

Lymphomas

• Non-EBV B-cell lymphomas(immunodeficiency 14A/B) Mutation in PIK3CD gene
• Subcutaneous panniculitis-like T-cell lymphoma/association to HAVCR2

Systemic lupus erythematosus (SLE) and SLE-like HV

• C2 deficiency
• Deficiency in complement fractions: C3-/C4-/C1q-/C1r-/C1s-/C5
• C1 esterase inhibitor deficiency /C1 inhibitor
• IgA deficiency/mutation in IGAD1
• X-linked chronic granulomatous disease/Mutations in the genes:CGD/CYBA/CYBB/NCFI2/4
• CVID/ mutations in the genes: CD19/CD81/CR3/ICOS/LRBA/MS4A1/ NFKB2/ TNFRSF13B/C
• ACP5 defect (SLE-like autoimmunity, with Raynaud's symptoms, vitiligo, thrombocytopenia) Mutation in ACP5
• Familial Chilblain Lupus/Mutation in STING
• Aicardi-Goutieres syndrome/mutation in TREX1 gene
• Aicardi-Goutieres syndrome/mutation in genes: RNASEH2B, RNASEH2C, RNASEH2A. SAMHD1, ADAR
• Chronic granulomatosis/mutations in genes: CYBB; p22phox; p67phox; p47phox.
• DNAse 2 defect/autosomal recessive mutation in DNASE2 gene.
• DNASE1L3 defect(early manifested infantile SLE) mutation in DNASE1L3
• IRAK1 defect (childhood SLE, adult SLE) X-linked recessive mutation in IRAK1 gene

Molluscum contagiosum (severe and persistent)

• Hyper IgE syndrome/mutation in DOCK8
• X-linked recessive hyper IgM syndrome/mutation in CD40LG
• Wiskott-Aldrich syndrome/mutation in WAS
• IL18BP defect(interleukin-18 binding protein; this protein may contribute to the lack of inflammatory response characteristic of molluscum contagiosum virus lesions).

Susceptibility to mycobacteriosis.

• MSDM=Mendelian susceptibility to mycobacteria/mutations in the genes: IFNGR1/ IFNGR2/ STAT1/IL12B/IL12RB1/IRF8/ISG1/IKBKG/CYBB
• NEMO deficiency/mutation in NEMO
• IRF8 defects/mutation in IRF8
• GATA2 defects/mutation in GATA2
• IFNgammaR1 defects/mutation in IFNGR1
• IFNgammaR2 defects/mutation in IFNGR2
• STAT1 defects/mutation in STAT1

Onychodystrophy

• APECED syndrome (see below Chronic mucocutaneous candidiasis) Mutation in AIRE
• HIES/Mutation in STAT3
• Dyskeratosis congenita/Mutationin NOLA2/3
• Dyskeratosis congenita/Mutation in the genes: CTC1/DKC1/NHP2/RTEL1/ NOP10/TCAB1/TERC/TERT/TINF2)
• Dectin1 deficiency/mutation in Dectin1

Panniculitis

• OTULIN defect/mutationin OTUlin gene: fever, diarrhea and inflammatory exanthema (see below autoinflammation- panniculitis- dermatosis syndrome.

Petechiae/Purpura

• Wiskott-Aldrich syndrome/mutation in WAS
• C2-deficiency (Purpura Schönlein)/Mutation in C2
• C4-deficiency (see below Purpura Schönlein-Henoch)Mutation in C4A/B
• Chediak-Higashi syndrome/mutation in LYST
• CVID/Mutationsin the genes:CD19/CD81/CR3/ICOS/IL21/LRBA/MS4A1/NFKB2/TNFRSF13B/ TNFRSF13C
• Dyskeratosis congenita/Mutations in the genes: CTC1/DKC1/NHP2/ RTEL1/NOP10/ TCAB1/TERC/TERT/TINF2
• Fanconi anemia/mutations in the genes: BRIP1/ERCC4/FANCA-G/FANCIL/ FANCIM /PLAB2/RAD51C/SLX4/
• Hepatic venoocclusive disease with immunodeficiency/mutation in SP111
• Hermansky-Pudlak syndrome type2/mutation in AP3B1
• Immunodeficiency 13 and IKZF1 defect (Ikaros defect) Mutation in IKZF1
• Shwachman-Bodian-Diamond syndrome/mutation in SBDS

Palmo-plantar hyperkeratosis

• Clericuzio-type poikiloderma with neutropenia: Genodermatosis with poikiloderma, usually noncyclic permanent neutropenia, recurrent sinopulmonary infections, pachyonychia, and palmo-plantar hyperkeratosis.

Photosensitivity

• Bloom syndrome/mutation in BLM
• Ligase I defect (light and radiation sensitivity) Mutation in LIG1 gene.

Pigmentary disorders (hypo- and hyperpigmentation/cafe au lait spots)

• Ataxia teleangiectatica/Mutationin ATM
• CHARGE syndrome/mutationin CHD7
• Mismatch repair deficiency syndrome constitutional (infections, café au lait spots, lymphomas)/mutation in PMS2
• Dyschromatosis symmetrica hereditaria (reticular hyperpigmentation on the dorsum of the hands, feet and face) mutation in the ADAR gene
• ACP5 defect (vitiligo, recurrent bacterial and viral infections, SLE-like autoimmunity, with Raynaud's symptom)/mutation in ACP5 gene
• POLA1 defect (hyperpigmentation, amyloidosis)/mutation in POLA1 gene
• SLC29A3 defe ct(hyperpigmentation and hypertrichosis)/SLC29A3 gene
• Dyskeratosis congenita/mutationsin DKC1 gene and about 12 other genes

• Schimke immunoosseous dysplasia (spondyloepiphyseal dysplasia with numerous lentigines, a slowly progressive immunodeficiency) mutation in the SMARCAL1 gene

• Immunodeficiency 10 and NFKB2 defect (vitiligo, autoimmune thyroiditis, endocrinopathies)

Psoriasis and psoriasiform exanthema

• IL10 defects/mutation in IL10RA/IL10RB
• ICF syndrome/mutation in DNMT38/ ZBTB24
• LIG4 syndrome/mutation in LIG4
• Nijmwegen breakage syndrome/mutation in NBS1
• SCID with mutation in NHEJ1
• Vici syndrome (autophagy disorder/albinism) mutation in EPG5 gene
• ADAM17 defect (pustular exanthema)Mutation in ADAM17
• DITR (generalized pustular psoriasis) mutation in IL36RN
• AP1S3 defect (AP1S3 stands for "Adaptor Related Protein Complex 1 Subunit Sigma 3"); mutations associated miLeukocyte Adhesion Deficiency Syndromet AP1S3 lead to: pustular psoriasis as well as pustulosis palmaris et plantaris.
• CAMPS(CARD14 mediated psoriasis) (CARD14); association also with pityriasis rubra pilaris.

Pyoderma gangraenosum

• C7 deficiency (C7)
• Leukocyte adhesion deficiency syndrome (mutations in the genes: ITGB2/SLC35C1/KIND3).

Raynaud's syndrome

• ACP5 defect (ACP5 gene)

Ulcerations (mucocutaneous)

• Congenital (cyclic) neutropenia (mutations in the genes: ELA2/HAX1/VPS4eA/ JAGN1/GF11/ CTSC/WAS)
• Leukocyte adhesion deficiency (mutations in the genes: ITGB2/SLC334C1/FERMT)
• Dyskeratosis congenita (CTC1/DKC1/NHP2/NOP10/TCAB1/TERC/TERT)
• X-linked agammaglobulinemia (BTK)

Urticaria

• Urticaria /recurrent respiratory infections/poststreptococcal glomerulonephritis/mutation in RAC2
• Urticaria/cold urticaria/association with familial cold-induced autoinflammatory syndromes 1-4. The following genotypes belong to this family:

• Cold-inducedautoinflammatory syndrome 1, familial/mutation in NLRP3.

• Cold-inducedautoinflammatory syndrome 2, familial/mutation in NLRP12

• Cold-inducedautoinflammatory syndrome 3, familial/mutation in PLCG2

• Cold-induced autoinflammatory syndrome 4, familial/mutation in NLRC/mutation in NLRC4

Vasculitides of the skin

• CD81 deficiency/CD81 acts together with CLDN1 as co-receptor for hepatitis C virus
• DNASE1L3 defect/ early manifested infantile SLE as well as hypocomplementemic urticarial vasculitis (HUVS)

Warts

• Autosomal recessive HIES/mutation in DOCK8
• Epidermodysplasia verruciformis/mutation in EVER1/EVER2
• ICF syndrome/mutation in DNMT3B/ ZBTB24
• WHIM syndrome/mutation in CXCR4
• Immunodeficiency 20 and FCGR3A defect/ severe human papillomavirus infections (+herpes infections)

Secondary or acquired immunodeficiencies: The primary immunodeficiencies are contrasted with the acquired or secondary immunodeficiencies. The best known example is AIDS (acquired immune deficiency syndrome). However, we are most often concerned with immunodeficiencies induced by immunosuppressive or immunomodulatory therapies.