Periodic fever syndromes

Inheritance varies by gene. The classical recurrent fevers illustrate this: mevalonate kinase deficiency is typically autosomal recessive, whereas CAPS and TRAPS are typically autosomal dominant. Familial Mediterranean fever is classically autosomal recessive but exhibits a recognised gene-dosage effect. The remaining conditions show a range of inheritance patterns, including autosomal recessive, autosomal dominant, de novo and somatic disease-causing variants.

Diagnosis rests on clinical recognition of recurrent or persistent sterile inflammation together with molecular genetic testing. Because phenotypes overlap across the spectrum, next-generation sequencing of a multi-gene panel is the recommended approach, with confirmation of variant pathogenicity and, where indicated, assessment for mosaicism and copy-number variants.

Main differential diagnoses include:

• Infectious recurrent fever: identifiable pathogen or focus; not gene-defined.
• Autoimmune and rheumatic disease: distinguished by high-titre autoantibodies or antigen-specific T cells; not gene-defined.
• Neoplastic causes of recurrent fever: identified on haematological or oncological work-up; not gene-defined.
• Syndrome of undifferentiated recurrent fever: autoinflammatory phenotype without an identified monogenic cause; no single causative gene.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Shinar Y, Ceccherini I, Rowczenio D, Aksentijevich I, Arostegui J, Ben-Chetrit E, et al. ISSAID/EMQN best practice guidelines for the genetic diagnosis of monogenic autoinflammatory diseases in the next-generation sequencing era. Clin Chem. 2020;66(4):525-36. doi:10.1093/clinchem/hvaa024. PMID:.
• Broderick L, Hoffman HM. IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting. Nat Rev Rheumatol. 2022;18(8):448-63. doi:10.1038/s41584-022-00797-1. PMID:.
• Moghaddas F. Monogenic autoinflammatory disorders: beyond the periodic fever. Intern Med J. 2020;50(2):151-64. doi:10.1111/imj.14414. PMID:.
• Martorana D, Bonatti F, Mozzoni P, Vaglio A, Percesepe A. Monogenic autoinflammatory diseases with Mendelian inheritance: genes, mutations, and genotype/phenotype correlations. Front Immunol. 2017;8:344. doi:10.3389/fimmu.2017.00344. PMID:.