Monogenic Autoinflammatory diseases and skin

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 14.12.2023

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Autoinflammation syndromes; autoinflammatory diseases; autoinflammatory syndromes

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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.

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Group of inflammatory, monogenic, autoinflammatory diseases with associated dermatologic symptoms that are non-infectious, non-allergic, non-autoimmunologic in nature.

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Monogenic autoinflammatory diseases with associated dermatologic symptoms sorted by dermatologic symptoms

Monogenic autoinflammatory with maculo-papular exanthema/inflammatory plaques

  • FMF (Familial Mediterranean fever/urticarial exanthema) (MEFV gene/AR/ pyrin/GOF mutation, exon 10 of the MEFV gene)
  • TRAPS (TNF receptor-associated periodic fever syndrome/urticarial exanthema) (TNFRSF1A gene/ AD/ TNF receptor 1/LOF)
  • HIDS/MKD(hyper-IgD syndrome) (MVK gene/AR mevalonate kinase/ LOF)
  • HOIL-1 deficiency syndrome (ubiquinopathy) (RBCK1 gene/ AR/ HOIL1/ LOF)

Monogenic autoinflammatory with urticarial exanthema

  • CAPS (cryopyrin-associated periodic syndrome) (NLRP3 gene/ AD NLRP3/cryopyrin/ GOF)
  • NLRP12-AD (NLRP12-associated systemic autoinflammatory disease-syn. FCAS2 = cold-induced autoinflammatory syndrome 2) (NLRP12 gene/ AD/ Monarch1/ LOF)
  • FCAS3 (cold-induced autoinflammatory syndrome 3, familial) (PLCG2 gene/ AD/ PLCγ2/ GOF)
  • Muckle-Wells syndrome (NLRP3 gene=CIAS1 gene/AD /Cryopyrin/ GOF
  • FCAS1 (Familial cold autoinflammatory syndrome 1/ CAP ) (NLRP3 gene)
  • FCAS2 (Familial cold autoinflammatory syndrome 2) (NLRP12 gene/pyrin-like protein)
  • NLRC4-AD (Familial autoinflammatory cold syndrome 4/ FACS 4) (NLRC4 gene/ AD/ NLRC4/ GOF)
  • Vibratory urticaria (ADGRE2 gene/AD/ ADGRE2/ LOF)

Pustular, pyogenic or other neutrophilic monogenic autoinflammatory dermatoses

  • PAPA (PSTPIP1 gene/ AD/ CD2BP1/ GOF)
  • DIRA (interleukin-1 receptor antagonist deficiency syndrome) (IL1RN gene/ AR/ IL-1 receptor antagonist/ LOF)
  • Majeed syndrome (LPIN2 gene/ AR/ lipin-2/ LOF)
  • 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)
  • CARD-14 psoriasis/CAPE (CARD14-associated papulosquamous eruption, also referred to as atypical juvenile type in pityriasis rubra pilaris) (CARD14 gene/ AD/ CARD14/ GOF)
  • PAAND (pyrin-associated autoinflammation with neutrophilic dermatosis) (MEFV gene/ AD/ pyrin/ GOF)
  • SGMRT (Singleton-Merten syndrome I and II) (IFIH1 gene and RIGI gene/AD pattern recognition receptors MDA5 and RIGI/GOF)
  • 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)
  • AP1S3 (and autoinflammatory psoriasis (AP1S3 gene/AD?/AP1S3/LOF)
  • 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)
  • 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).

Monogenic autoinflammatory dermatoses with panniculitis/subcutaneous nodule formation

  • Blue syndrome/early-onset sarcoidosis (NOD2 gene/ AD/ NOD2/ GOF)
  • CANDLE/PRAAS syndrome(perinatal with red plaques, later facial and generalized lipodystrophy)(PSMB8 gene/AR/ β5i subunit of the proteasome/ LOF)
  • Otulipenia/ORAS(autoinflammatory panniculitis dermatosis syndrome) (OTULIN gene/AR/ otulin, a Met-1 specific deubiquitinase/LOF)

Monogenic autoinflammatory with vasculitides/vasculopathies

  • DADA2 (Deficiency of Adenosine Deaminase 2) (CECR1 gene/ AR/ ADA2/ LOF)
  • SAVI (STING-associated vasculopathy) (TMEM173 gene/ AD/ STING/ GOF)
  • Chilblain lupus familial (TREX1 gene, SAMHD1 gene, TMEM173 gene/ AD/ 3-prime repair exonuclease 1 enzyme - dNTPs- STING/ LOF and GOF)
  • 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)
  • ADAR1 (Adenosine deaminases acting on RNA /Aicardi-Goutières syndrome) (ADAR gene and DDX58 gene/ AD/LOF)

Monogenic autoinflammatory hyperkeratotic dermatoses

  • NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis) (NLRP1 gene/AR/AD/ NLRP1 protein/ LOF)

Monogenic autoinflammatory dermatoses with hyperpigmentation

  • H syndrome (histiocytosis-lymphadenopathy-plus-syndrome) ( SLC29A3 gene/ AR/ hENT3/ LOF)

Monogenic autoinflammatory dermatoses with blistering

  • FCAS3 (Familial cold autoinflammatory syndrome 3) (PLCG2 gene/AD)

Monogenic autoinflammatory diseases with aphthae

  • HA20 (ubiquinopathy/Behcet-like familial autoinflammatory syndrome) (TNFAIP3 gene/ AD/ A20/ LOF)
  • PFIT (autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia) (WDR1 gene/ AR/ WD40 repeat protein/ LOF)
  • CAIN (CEBPE-associated autoinflammation and immunological impairment of neutrophils) (CEBPE gene/ AR/ CEBPepsilon/ GOF)
  • RELA haploinsufficiency syndrome (RELA gene/ AD/ RelA/ LOF)

Clinical features
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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.

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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.

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  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.


Please ask your physician for a reliable diagnosis. This website is only meant as a reference.


Last updated on: 14.12.2023