Behçet’s disease (BD) is a polygenic condition with a complex immunopathogenetic background and challenging diagnostic and therapeutic concepts. Advances in genomic medicine have provided intriguing insights into disease pathogenesis over the last decade, especially into monogenic mimics of BD. Although a rare condition, paediatric BD should be considered an important differential diagnosis, especially in cases with similar phenotypes. Emerging reports of monogenic mimics have indicated the importance of genetic testing, particularly for those with early-onset, atypical features and familial aggregation. Treatment options ought to be evaluated in a multidisciplinary setting, given the complexity and diverse organ involvement. Owing to the rarity of the condition, there is a paucity of paediatric trials; thus, international collaboration is warranted to provide consensus recommendations for the management of children and young people. Herein, we summarise the current knowledge of the clinical presentation, immunopathogenetic associations and disease mechanisms in patients with paediatric BD and BD-related phenotypes, with particular emphasis on recently identified monogenic mimics.

Familial Mediterranean Fever (FMF) is the prototype and most common autoinflammatory disease that is particularly frequent in populations originating from the Mediterranean basin. It is characterized by episodes of recurrent inflammation lasting 2–3 days. Colchicine is the mainstay therapy, which decreases the number of attacks and eventually prevents amyloidosis, the most worrisome complication of uncontrolled FMF. It is an autosomal recessive disease. The high rate of MEFV gene mutations in specific populations has been discussed as the result of an evolutionary advantage. Tel-Hashomer criteria were the first set of criteria primarily designed for adults. Recently, the Eurofever/PRINTO group has validated a new set of classification criteria for FMF, including clinical and genetic variables. Colchicine intolerance is an important problem and limits the ability to reach an effective dose. In these groups of patients, adding an alternative biological treatment (anti IL-1 agents) is recommended. Several tools such as FMF50, AIDAI, ADDI, ISSF and MASIF have been proposed to evaluate and quantify the disease activity and organ damage. Ongoing research should clarify the exact mechanisms causing FMF attacks and phenotypic variabilities between the patients; further translational research requires the implementation of proteomics and epigenetics signatures to elucidate the pathogenesis.

Hereditary systemic autoinflammatory diseases (SAIDs) are rare, often severe conditions characterised by mutations in the key regulators of innate immune responses. Dramatic advances in the molecular genetics and next-generation sequencing in the past decade enabled identification of novel mutations that play a pivotal role in the mechanistic pathways of inflammation. Although genetic testing may not always provide straightforward guidance in diagnosis and clinical decision making, through translational research, it sheds light into molecular immunopathogenesis, particularly in IL-1 inflammasome and cytokine signalling pathways. These remarkable insights provided a better understanding of autoinflammatory conditions and their association with the innate and adaptive immune systems, as well as leading to development of cytokine-targetted biologic treatments. Use of targetted therapeutics not only helps control disease flares, reduce acute-phase responses and prevent devastating complications such as amyloidosis, but also improves health-related quality of lives and support patients to pursue almost a normal life. Herein, we discuss the commonest monogenic SAIDs, describe their immunopathology, and summarise the approaches in the management and targetted treatment of these conditions, including presentation of novel data based on a cohort of children with these rare diseases from a single quaternary referral centre in London.