Monogenic Autoinflammatory diseases and skin

The terms "autoinflammation" and "autoinflammatory diseases", or "AiDs" for short, have existed for around 25 years and were conceived as distinct from autoimmune diseases. In 1997, the French Consortium for Familial Mediterranean Fever (The International FMF Consortium 1997) reported for the first time on a monogenic disease characterized by fever and multisystem inflammation caused by MEFV mutations. The term "autoinflammation" itself, dates back to 1999 and McDermott, who discovered germline mutations in the tumor necrosis factor receptor superfamily 1, familial fever syndrome, TRAPS.

Group of inflammatory, monogenic, autoinflammatory diseases with associated dermatological symptoms that are non-infectious, non-allergic, non-autoimmunological in nature. This definition is supplemented by the term autoinflammatory keratinization disorders(AiKDs).

Monogenic autoinflammatory diseases with associated dermatological symptoms classified according to immunodeficiencies

Inflammasomopathies

1. FMF (Familial Mediterranean fever)(MEFV gene/AR/pyrin/GOF mutation, exon 10 of the MEFV gene)
2. TRAPS (TNF receptor-associated periodic fever syndrome)(TNFRSF1A gene/ AD/ TNF receptor 1/LOF)
3. HIDS/MKD(hyper-IgD syndrome/maculo-papular exanthema) (MVK gene/AR mevalonate kinase/ LOF)
4. CAPS (cryopyrin-associated periodic syndrome)(NLRP3 gene/ AD NLRP3/cryopyrin/ GOF)
5. Muckle-Wells syndrome(NLRP3 gene=CIAS1 gene/AD/cryopyrin/ GOF)
6. FCAS1 (Familial cold autoinflammatory syndrome 1/ CAP )(NLRP3 gene)
7. FCAS2 (Familial cold autoinflammatory syndrome 2)(NLRP12 gene/pyrin-like protein)
8. FCAS3 (Familial cold autoinflammatory syndrome 3)(PLCG2 gene/AD)
9. NLRC4-AD (Familial autoinflammatory cold syndrome 4/ FACS 4)(NLRC4 gene/ AD/ NLRC4/ GOF)
10. Vibrator urticaria(ADGRE2 gene/AD/ADGRE2 protein, epidermal growth factor/LOF)
11. PAPA(PSTPIP1 gene/ AD/ CD2BP1/ GOF)
12. DIRA (interleukin-1 receptor antagonist deficiency syndrome)(IL1RN gene/ AR/ IL-1 receptor antagonist/ LOF)
13. Majeed syndrome(LPIN2 gene/ AR/ lipin-2/ LOF)
14. PAAND (pyrin-associated autoinflammation with neutrophilic dermatosis)(MEFV gene/ AD/ pyrin/ GOF)
15. NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)(NLRP1 gene/AR/AD/ NLRP1 protein/ LOF)
16. PFIT (autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia)(WDR1 gene/ AR/ WD40 repeat protein/ LOF)
17. CAIN (CEBPE-associated autoinflammation and immunological impairment of neutrophils)(CEBPE gene/ AR/ CEBPepsilon/ GOF)

NF-κB associated diseases

1. Blue syndrome/early-onset sarcoidosis(NOD2 gene/ AD/ NOD2/ GOF)
2. Yao syndrome (NOD2-associated autoinflammatory disease = polygenic, autoinflammatory disease characterized by periodic fever, dermatitis, arthritis and swelling of the distal extremities as well as gastrointestinal and sicca-like symptoms).
3. NLRP12-AD (NLRP12-associated systemic autoinflammatory disease-syn. FCAS2 = cold-induced autoinflammatory syndrome 2)(NLRP12 gene/ AD/ Monarch1/ LOF)
4. Otulipenia/ORAS (autoinflammatory panniculitis dermatosis syndrome)(OTULIN gene/AR/ otulin, a Met-1 specific deubiquitinase/LOF)
5. HA20 (ubiquinopathy - Behcet-like familial autoinflammatory syndrome)(TNFAIP3 gene/ AD/ A20/ LOF)
6. HOIL-1 deficiency syndrome (ubiquinopathy)(RBCK1 gene/ AR/ HOIL1/ LOF)
7. CARD-14 psoriasis/CAPE(CARD14-associated papulosquamous eruption, also known as atypical juvenile type in pityriasis rubra pilaris)(CARD14 gene/ AD/ CARD14/ GOF)
8. NFKB1-AD (immunodeficiency, common variable, 12, with autoimmunity; NFKB1-associated sterile familial autoinflammatory necrotizing fasciitis; pyoderma gangraenosum may also be associated)(NFKB1 gene/ AD/ p50/p105/ LOF)
9. RELA haploinsufficiency (RELA gene/ AD/ RelA/ LOF)
10. ADAM17 deficiency (ADAM17 plays an important role in the biology of interleukin-6, the mutation of the gene can be associated with pustular psoriasis)(ADAM17 gene/AR/ TACE/ LOF)

Interferonopathies

1. CANDLE/PRAAS syndrome(perinatal with red plaques, later facial and generalized lipodystrophy)(PSMB8 gene/AR/ β5i subunit of the proteasome/ LOF)
2. SAVI (STING-associated vasculopathy)(TMEM173 gene/ AD/ STING/ GOF)
3. Chilblain lupus familial(TREX1 gene, SAMHD1 gene, TMEM173 gene/ AD/ 3-prime repair exonuclease 1 enzyme - dNTPs- STING/ LOF and GOF)
4. AGS (Aicardi-Goutières syndrome)(TREX1 gene, RNASEH2A gene, RNASEH2B gene, RNASEH2C gene and SAMHD1 gene/ AR/ proteins involved in intracellular degradation or sensing of nucleic acids/ LOF > GOF)
5. ADAR1 (Adenosine deaminases acting on RNA /Aicardi-Goutières syndrome)(ADAR gene and DDX58 gene/ AD/LOF)
6. SGMRT (Singleton-Merten syndrome I and II) (IFIH1 gene and RIGI gene/AD pattern recognition receptors MDA5 and RIGI/GOF)

Other cytokine-signaled diseases

1. DADA2 (Deficiency of Adenosine Deaminase 2)(CECR1 gene/ AR/ ADA2/ LOF)
2. DITRA (interleukin-36 receptor antagonist deficiency syndrome; mutations in DITRA are found in 80% of sporadic cases of pustular psoriasis)(IL36RN gene/AR/ IL-36 receptor antagonist/ LOF)
3. H syndrome (histiocytosis-lymphadenopathy-plus-syndrome) ( SLC29A3 gene/ AR/ hENT3/ LOF)
4. FCAS3 (cold-induced autoinflammatory syndrome 3, familial)(PLCG2 gene/ AD/ PLCγ2/ GOF)
5. Vibrator urticaria(ADGRE2 gene/AD/ ADGRE2/ LOF)
6. AP1S3 (and autoinflammatory psoriasis(AP1S3 gene/AD?/AP1S3/LOF)
7. PAPA syndrome(PSTPIP1 gene/CD2 binding protein1)
8. Proteasome-associated autoinflammatory syndrome 2 (PRAAS2; mutation in the POMP gene. The mutations in POMP lead to impaired proteasome assembly with reduced 20S proteasome levels, reduced incorporation of proteasome subunits and increased proteasomal precursor complexes. The overall proteasome activity is reduced).

Clinical-dermatological manifestations of autoinflammatory syndromes are usually as follows (see classification):

• Recurrent fever
• Urticarial exanthema
• Pustular, pyogenic or neutrophilic exanthema
• Panniculitis or subcutaneous nodules
• Vasculitis or other vasculopathies
• Hyperkeratotic lesions
• Hyperpigmented lesions
• Blistering lesions
• Aphthous lesions
• Various organ manifestations such as ostitis, periostitis, Crohn's disease, etc.

Initially, the term "autoinflammatory syndromes" was coined for a small group of monogenic familial fever syndromes (see below fever syndromes, hereditary, periodic; see below Immunodeficiency primary/autoinflammatory diseases). In the meantime, this term has been extended to include a larger group of diseases.

1. Braun-Falco M et al (2011) Skin involvement in autoinflammatory syndromes. JDDG 9: 232 - 245
2. Figueras-Nart I et al (2019) Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases. Front Immunol 10:2448.
3. Israeli E (2012) Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA). Lupus 21:190-194.
4. Tufan A et al. (2020) Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turk J Med Sci 50(SI-2):1591-1610.