Search

Inherited disorders of the inflammasome pathway causes dysregulated inflammasome activation, which presents with inflammation and other clinical features linked to the defective protein. Eight mutations have been previously described in the NLRP1 inflammasome protein, causing different inflammatory skin disorders. Two of these mutations are associated with "autoinflammation with arthritis and dyskeratosis (AIADK)," a novel Mendelian auto-inflammatory disorder, in the 2017 International Union of Immunological Societies phenotypic classification for primary immunodeficiencies. We report a 22-year-old female, with recurrent generalized urticaria, periodic fever and pain abdomen, inflammatory polyarthritis, cutaneous lesions over the extremities, and persistently elevated inflammatory markers. On next-generation sequencing, a heterozygous missense mutation in exon 4 of the NLRP1 gene (chr17:G.5461839C>T) was detected, which results in the amino acid substitution of glutamine for arginine at codon 726 (c.2177G>A; p.Arg726Gln). A probable diagnosis of AIADK, possibly caused by this mutation was proposed, and patient responded well to colchicine. [ABSTRACT FROM AUTHOR]

Neurologic complications of chronic infantile neurologic, cutaneous and articular syndrome (CINCA) are well-known, whereas there are scarce data regarding neurologic features of milder cryopyrin-associated periodic syndrome (CAPS) phenotypes. We aimed to review the neurologic features in detail and summarize the other CAPS-related manifestations in 12 children. All children with CAPS that have been followed-up from pediatric rheumatology outpatient clinic, were enrolled to the study. In addition to the neurologic examination, magnetic resonance imaging (MRI) of brain, electroencephalography, eye examination, hearing test and intellectual assessment were done. Demographic, clinical features, genetic analysis and laboratory tests were noted from patient records and hospital database. The median age of the subjects was 7 years (range 2–19 years), with a female-to-male ratio 2/1. The phenotype was consistent with familial cold autoinflammatory syndrome in 7 patients, Muckle–Wells syndrome in 3 patients and chronic infantile neurologic, cutaneous and articular syndrome in 2 patients. Most frequently noted neurologic clinical manifestation during the entire disease course was headache (n = 4/12) followed by seizures (n = 3/12), papilledema (n = 3/12), intellectual disability (n = 2/12), aseptic meningitis (n = 2/12), hearing loss (n = 2/12) and optic atrophy (n = 1/12). MRI of the brain revealed abnormal lesions in two patients. Uveitis or conjunctivitis were seen in two children. Overall, neurological involvement was detected in 6/12 of our cohort, of which half (n = 3) was in severe form. Half of the children with CAPS exhibited neurologic manifestations with varying degrees of severity. Increased understanding and awareness of this rare but treatable syndrome among neurologists is essential. If remains untreated and unrecognized, this autoinflammatory syndrome could lead to significant morbidity and mortality. Besides complete resolution of systemic symptoms, anti-interleukin-1 treatment may also prevent progression of neurologic findings when initiated in the early stage of the disease. • CAPS is an autoinflammatory syndrome with frequent neurological manifestations. • Management of this multisystemic disease requires a team approach. • Delayed diagnosis leads to significant morbidity and mortality. • Increased awareness of this rare but treatable IL1-associated disease is essential. [ABSTRACT FROM AUTHOR]

Proteasome-associated autoinflammatory syndromes (PRAASs) form a family of recently described rare autosomal recessive disorders of disturbed proteasome assembly and proteolytic activity caused by mutations in genes coding for proteasome subunits. The treatment options for these proteasome disorders consist of lifelong immunosuppressive drugs or Janus kinase inhibitors, which may have partial efficacy and noticeable side effects. Because proteasomes are ubiquitously expressed, it is unknown whether hematopoietic stem cell transplantation (HSCT) may be a sufficient treatment option. Our aim was to report the case of a young boy with a treatment-resistant cutaneous vasculitis that was initially suspected to be associated with a gene variant in SH2D1A. Whole-exome sequencing was performed to identify the genetic defect. Molecular and functional analyses were performed to assess the impact of variants on proteasomal function. The immune characterization led to the decision to perform HSCT on our patient and conduct follow-up over the 7-year period after the transplant. Because loss of myeloid chimerism after the first HSCT was associated with relapse of autoinflammation, a second HSCT was performed. After the successful second HSCT, the patient developed mild symptoms of lipodystrophy, which raised the suspicion of a PRAAS. Genetic analysis revealed 2 novel heterozygous variants in PSMB4 (encoding proteasomal subunit β7). Retrospective analysis of patient cells stored before the first HSCT and patient cells obtained after the second HSCT demonstrated that HSCT successfully rescued proteasome function, restored protein homeostasis, and resolved the interferon-stimulated gene signature. Furthermore, successful HSCT alleviated the autoinflammatory manifestations in our patient. Patients with treatment-resistant PRAAS can be cured by HSCT. [Display omitted] [ABSTRACT FROM AUTHOR]

Systemic autoinflammatory syndromes are a group of inherited and acquired disorders of the innate immunity characterized by recurrence of seemingly unprovoked febrile attacks of variable duration and multidistrict inflammation of different severity. The vast majority of these conditions when observed in pediatrics is caused by mutations in genetic systems involved in the orchestration of inflammation and apoptosis. The group includes hereditary recurrent fevers, idiopathic febrile syndromes, hereditary pyogenic disorders, bone autoinflammatory diseases, immunemediated granulomatous diseases, complement disorders, hemophagocytic and vasculitic syndromes. Diagnostic identification derives from the combination of genotype studies and clinical/ bioumoral data showing the spontaneous activation of cells of the innate immunity in the absence of specific ligands, although diagnosis remains only clinical for idiopathic febrile syndromes such as systemic-onset juvenile idiopathic arthritis and PFAPA syndrome. Meeting the needs of patients with complex chronic diseases as systemic autoinflammatory syndromes requires the provision of collaborative multidisciplinary care and the expertise of a number of health care providers across varied health care settings. [ABSTRACT FROM AUTHOR]

Background: Familial cold autoinflammatory syndrome (FCAS) is characterized by rash, fever, and arthralgia in response to cold exposure. CIAS1, the gene that codes for cryopyrin, is mutated in FCAS. Treatment with anakinra (IL-1 receptor antagonist) prevents symptoms, indicating a crucial role for IL-1 in this disease. Objective: To study cytokine responses to cold exposure in monocytes from subjects with FCAS. Methods: Adherence-enriched monocytes were incubated at 32°C or 37°C. Transcription and release of IL-1β, IL-6, and TNF-α were monitored by quantitative PCR and ELISA. Results: The FCAS monocytes but not control cells responded to 4 h incubation at 32°C with significant secretion of IL-1β. At 16 h, IL-1β, IL-6, and TNF-α were all significantly elevated in FCAS monocytes at 32°C. Increased cytokine transcription was observed in all monocytes at 4 hours, but at 16 hours it was only seen in FCAS monocytes incubated at 32°C. Incubation at 32°C for as little as 1 hour sufficed to induce measurable IL-1β release. Caspase-1 inhibitors prevented the cold-induced IL-1β release, whereas a purinergic antagonist did not. Anakinra had no effect on the early IL-1β release but significantly reduced the late-phase transcription and release of all cytokines. Conclusion: FCAS monocytes respond to mild hypothermia with IL-1β release, which in turn induces autocrine transcription and secretion of IL-6 and TNF-α as well as stimulation of further IL-1β production. Clinical implications: These results confirm the central role of IL-1β in FCAS and support the use of IL-1 targeted therapy in these patients. [Copyright &y& Elsevier]