The Broad-Ranging Panorama of Systemic Autoinflammatory Disorders With Specific Focus on Acute Painful Symptoms and Hematologic Manifestations in Children

Abstract

Systemic autoinflammatory disorders (SAIDs) are inherited defects of innate immunity characterized by recurrent sterile inflammatory attacks involving skin, joints, serosal membranes, gastrointestinal tube, and other tissues, which recur with variable rhythmicity and display reactive amyloidosis as a potential long-term complication. Dysregulated inflammasome activity leading to overproduction of many proinflammatory cytokines, such as interleukin-1 (IL-1), and delayed shutdown of inflammation are considered crucial pathogenic keys in the vast majority of SAIDs. Progress of cellular biology has partially clarified the mechanisms behind monogenic SAIDs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. Whereas, little is clarified for the polygenic SAIDs, such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome. The puzzle of symptomatic febrile attacks recurring over time in children requires evaluating the mixture of clinical data, inflammatory parameters in different disease phases, the therapeutic efficacy of specific drugs such as colchicine, corticosteroids or IL-1 antagonists, and genotype analysis in selected cases. The long-term history of periodic fevers should also need to rule out chronic infections and malignancies. This review is conceived as a practical template for proper classification of children with recurring fevers and includes tips useful for the diagnostic approach to SAIDs, focusing on the specific acute painful symptoms and hematologic manifestations encountered in childhood.

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

“…However, while asthenia is a nonspecific manifestation identified in many systemic disorders, specific inflammatory features associated with recurrent fever may provide valuable clinical information. In particular, FMF attacks generally last between 6 and 72 hours, while TRAPS patients are characterized by episodes lasting 1 to 3 weeks; CAPS and HIDS manifest with fever generally lasting 4-7 days [8,10,12,56,59]. Of note, also the PFAPA syndrome is characterized by fever episodes resolving in 4-7 days and this disorder should always be taken into account when considering differential diagnosis [136,137].…”

“…Most patients with mAIDs report musculoskeletal manifestations, with FMF and CINCA/NOMID being the most typically involved. Nev-ertheless, patients with MKD and TRAPS may refer joint and muscle symptoms as well [8,10,12,56,59].…”

“…Among mAIDs, neurological manifestations are more closely related to severe CAPS phenotypes. Indeed, while headache and drowsiness are the only neurological symptoms of FCAS during inflammatory bouts, MWS is often complicated by sensorineural deafness and progressive visual loss due to the atrophy of the optic nerve over time [8,12,56,59,91]. The nervous system is severely affected in CINCA/NOMID: suggestive clinical signs include chronic aseptic meningitis, increased intracranial pressure, cerebral atrophy, hydrocephalus or ventriculomegaly, sensorineural hearing loss, and chronic papilledema [91].…”

“…Over the last 20 years, the identification of new putative genes following the extensive use of next-generation sequencing technologies and the remarkable progress of molecular techniques have deepened our knowledge about the pathogenesis of mAIDs, providing novel insights of mechanisms involved in innate immunity regulation [8]. In addition, the discovery of gene modifiers and somatic mosaicisms as well as a better comprehension of the role of epigenetic factors have clarified some aspects of the wide phenotypic heterogeneity of these disorders.…”

When, how, and why do fevers hold children hostage?

“…A comprehensive medical history and asking about travel destinations, including transit points, together with thorough clinical examination, should always be undertaken 26 . Of course, the possibility that systemic autoinflammatory disorders might be concealed behind recurrent fevers cannot be overlooked, as most inherited autoinflammatory disorders are characterized by lifelong spontaneously relapsing bouts of fever and intermittent or subcontinuous systemic inflammation 27,28 . Despite the rather recent nosological characterization, autoinflammatory disorders have afflicted Mankind throughout the past centuries, although they were erroneously believed to be secluded to people living around specific areas of the world, such as the Mediterranean basin countries or North‐West Europe 29 .…”