The Clinical Chameleon of Autoinflammatory Diseases in Children

Abstract

The very first line of defense in humans is innate immunity, serving as a critical strongpoint in the regulation of inflammation. Abnormalities of the innate immunity machinery make up a motley group of rare diseases, named ‘autoinflammatory’, which are caused by mutations in genes involved in different immune pathways. Self-limited inflammatory bouts involving skin, serosal membranes, joints, gut and other districts of the human body burst and recur with variable periodicity in most autoinflammatory diseases (ADs), often leading to secondary amyloidosis as a long-term complication. Dysregulated inflammasome activity, overproduction of interleukin (IL)-1 or other IL-1-related cytokines and delayed shutdown of inflammation are pivotal keys in the majority of ADs. The recent progress of cellular biology has clarified many molecular mechanisms behind monogenic ADs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome (or ‘autosomal dominant familial periodic fever’), cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. A long-lasting history of recurrent fevers should require the ruling out of chronic infections and malignancies before considering ADs in children. Little is known about the potential origin of polygenic ADs, in which sterile cytokine-mediated inflammation results from the activation of the innate immunity network, without familial recurrency, such as periodic fever/aphthous stomatitis/pharyngitis/cervical adenopathy (PFAPA) syndrome. The puzzle of febrile attacks recurring over time with chameleonic multi-inflammatory symptoms in children demands the inspection of the mixture of clinical data, inflammation parameters in the different disease phases, assessment of therapeutic efficacy of a handful of drugs such as corticosteroids, colchicine or IL-1 antagonists, and genotype analysis to exclude or confirm a monogenic origin.

Nakajo-Nishimura Syndrome: The First African Case

“… 5 NNS, like other autoinflammatory syndromes, can cause AA amyloidosis through chronic inflammation; this may constitute a major cause of death. 6 …”

Identification by Exome Sequencing of Predisposing Variants in Familial Cases of Autoinflammatory Recurrent Fevers

“…The identification of the MEFV gene in familial Mediterranean fever families in 1997 [3,4] led to discoveries of many other genes in different AID conditions. Along with monogenic entities, there are other mixed autoinflammatory disorders, such as Behçet's disease, Kawasaki syndrome, and recurrent pericarditis, with a more complex Genes 2023, 14, 1310 2 of 9 genetic architecture requiring the intervention of multiple variants in more than one gene, along with other endogenous and exogenous factors [5,6]. For this reason, they are rarely transmitted in a Mendelian way.…”

Efficacy and safety of thalidomide in children with monogenic autoinflammatory diseases: a single-center, real-world-evidence study

“…Monogenic AIDs usually present with constitutional symptoms like fever and inflammation-related clinical manifestations of multiple organ systems, including but not limited to the skin, joints, eyes, ears, gastrointestinal tract, respiratory tract, central nervous system and cardiovascular system [ 2 – 4 ]. While several medications have proven partially effective in some conditions, for example, colchicine for familial Mediterranean fever (FMF), interleukin 1 inhibitors for tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), JAK inhibitors for several type 1 interferonopathies, glucocorticoids and conventional immunosuppressive agents for Blau syndrome and pyoderma gangrenosum and acne syndrome [ 5 – 7 ], there is no universal therapeutic agent for all kinds of AIDs, and these conditions are usually steroid-dependent and relapse once the dose is tapered. Another dilemma for monogenic AID patients in China is that some effective targeted biological agents such as canakinumab have not been marketed in China, and the drugs used in off label are also unaffordable.…”