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Genetic Fever syndromes

Systemic autoinflammatory diseases comprise an expanding group of diseases, including monogenic diseases caused by inborn errors (also known as periodic fever syndromes) and polygenic diseases such as Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Systemic Juvenile idiopathic arthritis and Adult onset Still diseaseSchnitzler syndrome, idiopathic recurrent autoimmune pericarditis, or Chronic non-bacterial osteomyelitis - also known as CRMO

There can be overlapping clinical features between various disorders and even heterogeneity among patients even with the same genetic disorder, making diagnosis often challenging and can include extensive tests over a period of time. Genetic testing is available for some conditions.

A suggested classification is given below and please note that the list of conditions is not exhaustive !

Polygenic autoinflammatory diseases (exemplars)

  • PFAPA syndrome
  • Chronic recurrent multifocal osteomyelitis (CRMO) - also known as Chronic non-bacterial osteomyelitis (CNO)
  • Still's disease (Juvenile systemic idiopathic arthritis and Adult onset Still disease)
  • Schnitzler syndrome

Monogenic autoinflammatory diseases (exemplars)

  • Inflammasomopathies:
    • Familial Mediterranean fever.
    • Hyperimmunoglobulinaemia D - also known as mevalonic kinase deficiency.
    • Tumour necrosis factor receptor-associated periodic syndrome (TRAPS).
    • The cryopyrinopathies (Familial cold auto-inflammatory syndrome), Muckle – Wells syndrome, chronic infantile neurologic cutaneous and articular syndrome (CINCA) and also known as neonatal onset multi-system inflammatory disease (NOMID).
  • Relopathies:
    • Haploinsufficiency A20
    • Otulipenia
    • LUBAC deficiency
  • Interferonopathies:
    •   Aicardi-Goutiere's syndrome
    •   SAVI syndrome
    •   CANDLE syndrome
    •   COPA syndrome
  • Others: 
    • e.g., DADA2, DIRA, DITRA, Majeed syndrome, Cherubism

summary of the autoinflammatory diseases from the Autoinflammatory Alliance is useful to demonstrate the overlap between the spectrum of disease currently identified. It is likely that more will be identified. 

Treatment options include biological agents for some of these conditions (e.g., IL1 blockade in Cryopyrinopathies) often with dramatic improvement in the quality of life for children.  Patients require long term specialist supervision and support for the family is important. 


Autoinflammatory Alliance: https://www.nomidalliance.com/compchart.php

FMF (Familial Mediterranean Fever) & AID (AutoImmuneDiseases) Global Association: https://www.fmfandaid.org/disease

PRINTO (Paediatric Rheumatology International Trials Organisation) : https://www.printo.it/pediatric-rheumatology/GB/info/sub/11/Autoinflammatory-Diseases - includes information sheets that can be downloaded for families. 

The Autoinflammatory Alliance provides more information and resources for families http://autoinflammatory.org