Classification of Genetically Defined Autoinflammatory Diseases

  • Raphaela Goldbach-ManskyEmail author
  • Adriana A. de Jesus


Autoinflammatory diseases are hyperinflammatory, immune-dysregulatory conditions that typically present in early childhood with fever, rashes and disease-specific patterns of sterile organ inflammation of predominantly innate immune cells. The identification of disease-causing genetic mutations in key innate immune pathways that regulate pro-inflammatory cytokines, paired with the impressive clinical responses to cytokine blocking therapies has led to the concept that cytokine activation drives “cytokine amplification loops” that lead to the development of systemic and organ-specific disease manifestations of autoinflammatory diseases. While the initial discoveries of the genetic causes of autoinflammatory diseases and the clinical treatment successes centered around conditions that were presumed to be caused by interleukin (IL)-1 overproduction and signaling, more recent studies are providing insights into proinflammatory cytokine dysregulation, that includes Type-I interferon (IFN), IL-17, IL-18 or IL-36 and more generally ubiquitination disorders that affect nuclear factor kappa B (NF-kB) dysregulation. Characteristic clinical findings such as fever patterns, type of skin lesions and pattern of organ inflammation track with specific innate immune pathways. In this chapter we use two different classification systems of the known genetically-defined autoinflammatory diseases, a clinical classification system based on skin lesions, other characteristic clinical features and the pattern of the inflammatory episodes (i.e. fever pattern), and a pathophysiological classification based on innate immune sensor and cytokine pathways that are dysregulated. The clinical and pathophysiological classification systems can be integrated.


Classification Autoinflammatory diseases Dermatologic manifestations Key inflammatory and regulatory pathways Interleukin (IL)-1 Type-I interferon (IFN) IL-18 IL-23/IL-12/IL-17 axis Tumor necrosis factor (TNF) Nuclear factor kappa B (NF-kB) 



Acrodermatitis continua of Hallopeau


Aicardi-Goutières syndrome


Absent in melanoma


Autoinflammatory syndrome associated with lymphedema


AP1S3 mediated psoriasis


PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation


Apoptosis related speck-like protein containing CARD


CARD14-mediated psoriasis


Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures


Cryopyrin-associated periodic syndromes


Caspase activation and recruitment domains


Chronic infantile neurologic, cutaneous and articular syndrome


Cytotoxic CD8+ T cells


Deficiency of adenosine deaminase 2


Dendritic cells


Deficiency of the interleukin 1 receptor antagonist


Deficiency of the interleukin 36 receptor antagonist




Familial cold autoinflammatory syndrome


Familial cold autoinflammatory syndrome 2


Food and Drug Administration


Familial keratosis lichenoides chronica


Familial hemophagocytic lymphohistiocytosis


Familial Mediterranean fever




Generalized pustular psoriasis


Haploinsufficiency of A20


Hyperimmunoglobulinemia D and periodic fever syndrome


Hemophagocytic lymphohistiocytosis


Hematopoietic stem cell transplantation




IL-1 receptor antagonist




Interferon regulatory factor


IFN response gene signature


Interferon stimulated gene factor


Janus kinase


Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy


Laccase (multicopper oxidoreductase) domain-containing 1






Leucine-rich repeat


Linear ubiquitination chain assembly complex


Mitogen-activated protein


Macrophage activation syndrome


Melanoma differentiation-associated protein 5


MyoD family inhibitor domain containing


Mevalonate kinase deficiency




Multiple self-healing palmoplantar carcinoma


Muckle-Wells syndrome


NLRP1-associated autoinflammation with arthritis and dyskeratosis


NLR family apoptosis inhibitory protein


NEMO deleted exon 5 autoinflammatory syndrome—X-linked


NF-κB essential modulator


Nuclear factor kappa B


Neonatal inflammatory skin and bowel disease-1


Natural killer


NOD-like receptor


NOD-like receptor family CARD domain containing


NOD-like receptor family pyrin domain containing


Nucleotide-binding oligomerization domain


Neonatal-onset multisystem inflammatory disease


Non-steroidal anti-inflammatory drugs


Otulin-related autoinflammatory syndrome/Otulipenia


Pyrin-associated autoinflammation with neutrophilic dermatosis


Pathogen-associated molecular pattern


Pyogenic arthritis, pyoderma gangrenosum and acne (syndrome)


Periodic fever, immunodeficiency, and thrombocytopenia


Pediatric granulomatous arthritis


PLCG2-associated antibody deficiency and immune dysregulation


Palmoplantar psoriasis


Proteasome-associated autoinflammatory syndrome


Pattern recognition receptors


Pyrin domain


Retinoic acid-inducible gene


RIG-like receptor


STING-associated vasculopathy with onset in infancy


Syndrome of enterocolitis and autoinflammation associated with mutation in NLRC4


Succinate dehydrogenase


Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay


Systemic inflammatory response syndrome


Singleton-Merten syndrome


Spondyloenchondrodysplasia with immune dysregulation


Signal transducer and activator of transcription


Stimulator of IFN genes


TNF-α convertase enzyme


Tumor necrosis factor


Toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex


Tartrate-resistant phosphatase


TNF receptor-associated periodic syndrome


TNFRSF11A-associated hereditary fever disease


Tyrosine kinase


Ubiquitin-specific peptidase


Very early-onset inflammatory bowel disease


X-linked inhibitor of apoptosis

Supplementary material

420188_1_En_10_MOESM1_ESM.xlsx (33 kb)
Supplementary Data 1 Clinical features of Mendelian autoinflammatory diseases. Abbreviations: PRR pattern recognition receptors; IL interleukin; CAPS cryopyrin-associated periodic syndrome; FCAS familial cold autoinflammatory syndrome; MWS Muckle-Wells syndrome; NOMID neonatal-onset mutlisystem inflammatory disease; CINCA chronic infantile neurological cutaneous and articular syndrome; FMF familial Mediterranean fever; PAAND pyrin-associated autoinflammation with neutrophilic dermatosis; HIDS/MKD hyperimmunoglobulinemia D with periodic fever syndrome/mevalonate kinase deficiency; TRAPS tumor necrosis facor receptor-associated periodic syndrome; DIRA deficiency of the interleukin-1 receptor antagonist; SAVI STING-associated vasculopathy with onset in infancy; AGS Aicardi-Goutières syndrome; CANDLE chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; SPENCDI spondyloenchondrodysplasia with immune dysregulation; CAMPS CARD14-mediated psoriasis; AMPS AP1S3 mediated psoriasis; DITRA deficiency of the IL-36 receptor antagonist; ORAS otulin-related autoinflammatory syndrome/otulipenia; NDAS NEMO deleted exon 5 autoinflammatory syndrome—X-linked; HA20 haploinsufficiency of A20; LACC1 laccase (multicopper oxidoreductase) domain-containing 1; MAS macrophage activation syndrome; FHL familial hemophagocytic lymphohistiocytosis; CHS Chediak-Higashi syndrome; PLAID PLCG2-associated antibody deficiency and immune dysregulation; APLAID PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation; PAPA pyogenic arthritis, pyoderma gangrenosum and acne syndrome; PFIT perioidc fever, immunodeficiency, and thrombocytopenia; DADA2 deficiency of adenosine deaminase 2; IBD inflammatory bowel disease; AR autosomal recessive; AD autosomal dominant; URI upper respiratory infection; AIHA autoimmune hemolytic anemia; AITP autoimmune thrombocytopenic purpura; ANA anti-nuclear antibody; IFN interferon; TNF tumor necrosis factor (XLSX 32 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Raphaela Goldbach-Mansky
    • 1
    Email author
  • Adriana A. de Jesus
    • 1
  1. 1.Translational Autoinflammatory Diseases SectionNational Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)BethesdaUSA

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