Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases

Abstract

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.

Computational Modeling of NLRP3 Identifies Enhanced ATP Binding and Multimerization in Cryopyrin-Associated Periodic Syndromes

“…As observed in other studies (136,141), we found that mutations with the lowest p-weighted scores (log(p w ) < −2, corresponding to p w < 0.01), which are expected to be the most severely-disruptive to NLRP3 structure and function, occur in the NACHT domain between Glu250 and Arg550 with a mutational hotspot including the Arg262 site ( Figure 2A). Arg262 is the most cited mutation site (17, 59-61, 64, 66, 69, 93, 96, 136), is shared between all CAPS, and has a wide variance of reported substitutions.…”

Clinical benefits of TNF‐α inhibitors in Chinese adult patients with NLRP3‐associated autoinflammatory disease

“…Considering the heterogeneity of the clinical manifestations and the existence of overlapping phenotypes, early diagnosis of NLRP3 ‐AID is a big challenge for most physicians in real‐life scenarios as for other monogenic AIDs; thus, algorithms for the differential diagnosis of these conditions have been recently proposed [15]. In this study, we found that the duration of diagnosis delay was approximately 20 years, which indicated that NLRP3 ‐AID may be underdiagnosed in the Chinese population.…”

The everchanging framework of autoinflammation

“…1) with a variable modality of recurrence, alternating with periods of complete wellness [2]. The description of tardive manifestations, veiled phenotypes and atypical clinical signs beginning in adulthood has been more and more reported in recent times for different AIDs, requiring that many specialists become confident with concepts, details and management of autoinflammation [3].…”