Paediatric Behçet's Disease: A Comprehensive Review with an Emphasis on Monogenic Mimics

Abstract

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.

Keywords: A20 haploinsufficiency; Behçet’s disease; NF-κB pathway; inflammatory vasculitis; monogenic mimics; next-generation sequencing; paediatric Behçet’s; whole-exome sequencing.

Figure 1

STRING app [39] physical subnetwork visualisation with Cytoscape Software [40] for: (A) HLA-B from within Behcet disease–related genes (the resulting network consists of 21 functional associations between 9 proteins with a confidence cut-off of 0.4 (PPI enrichment p-value: 7.02 × 10⁻⁷)); (B) A20 protein (the resulting network consists of 29 functional associations between 11 proteins with a confidence cut-off of 0.4 (PPI enrichment p-value: 0.000522)); (C) RELA protein (the resulting network consists of 36 functional associations between 11 proteins with a confidence cut-off of 0.4 (PPI enrichment p-value: 1.11 × 10⁻⁷)).

Figure 2

Overview of the canonical NF-κB signalling pathway and the role of A20 and OTULIN proteins (created by Biorender). Mutations in proteins that can result in BD-like phenotypes are shown in bold. Induction of the pathway by Toll-like receptors (TLRs), T-cell receptors (TCRs), B-cell receptors (BCRs) and cytokine receptors (TNFα, IL-1β, IL-6, etc.) initiates a cascade, followed by the stimulation of IκB kinase (IKK) complex, which consists of three subunits: IKKα, IKKβ, and IKKγ (NEMO, NF-κB essential modulator). Activation of IκBα via phosphorylation leads to release of NF-κB1, which is essentially a dimer composed of RelA/p65 and p50. RelA/p50 complex subsequently translocates to the nucleus, leading to activation of the NF-κB pathway, regulation of genes and, ultimately, transcription of proinflammatory cytokines. Linear ubiquitin chain assembly complex (LUBAC) that consists of HOIL-1, HOIP and SHARPIN activates NF-κB pathway by ligation of linear ubiquitin chains to NEMO and RIP1. OTU deubiquitinase with linear linkage specificity (OTULIN) functions as a deubiquitinating enzyme that catalyzes linear ubiquitin chains from proteins modified by the LUBAC, thereby controlling overactivation of the NF-κB pathway. Similarly, A20 protein is also shown to contain deubiquitinase and E3 ligase domains, which also results in deubiquitination of NF-κB upstream proteins, hence negatively regulating inflammation. These findings may elucidate the mechanisms by which mutations in A20 and OTULIN result in overactivation of the NF-κB signalling pathway and, consequently, enhanced inflammatory response. Abbreviations: IKKα and IKKβ, inhibitor of nuclear factor kappa kinase subunit α and β; LUBAC, linear ubiquitin chain assembly complex; NEMO, NF-κB essential modulator; NF-κB, nuclear factor kappa-B; RIPK1, the death domain-containing protein kinase receptor-interacting protein 1; TNFα, tumour necrosis factor-alpha; TNFR, tumour necrosis factor receptor; TRADD, tumour necrosis factor receptor-1-associated death domain protein. TRAF 2/5:TNF receptor-associated factor 2 and 5.