"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Variants in autoinflammatory diseases-related genes in a family with cold-induced autoinflammatory syndrome.

OBJECTIVES: To characterise what immunogenetic alterations are present in a Spanish family having several members with a familial cold-induced autoinflammatory syndrome (FCAS), a kind of autoinflammatory disease (AID). METHODS: We present the case of two sisters (cases 1 and 2) with a similar clinical picture since their childhood. The symptoms start after exposure to cold and consist of recurrent fever, papules or urticaria, and oedema in hands and fingers. The mother had similar symptomatology as her daughters, which remitted after her first pregnancy, whereas the father is healthy. Patients and their parents were genotyped in a panel of 14 candidate genes using Next-Generation Sequencing (NGS). Real-time PCR was used to quantify IL1ß mRNA levels from LPS-stimulated monocytes. ELISA was used to measure the IL1ß and IL18 concentrations in supernatants and sCD25 levels in sera. IL1ß, IL4, IL6, IL8, IL10, IL17A, IL18 and TNF-α serum levels were assessed using xMAP® Technology. RESULTS: All the genetic variants found in this family are benign with two exceptions: NLRC4 p.Leu339Pro (present in both cases and their mother) and PSTPIP1 p.Gln219His (present in Case 1 and her father). The monocytes stimulated of the individuals with the NLRC4 variant produce higher levels of IL1ß (protein and mRNA). Levels of TNF-α, IL4, and IL6 were higher in Case 1 than in the age-matched controls. CONCLUSIONS: The familial segregation and the clinical picture compatible with FCAS suggest that NLRC4 p.Leu339Pro causes the AIDs syndrome diagnosed in several family members.

Distinct Laboratory and Clinical Features of Secondary Hemophagocytic Lymphohistiocytosis in Pediatric Visceral Leishmaniasis: A Retrospective Analysis of 127 Children in Andalusia, Spain (2004-2019).

BACKGROUND: Visceral leishmaniasis (VL) is an endemic in Southern Europe. However, details regarding disease burden, clinical presentations, laboratory markers, management and outcome in children are scarce. METHODS: Medical records of children (<14 years) admitted with VL to 10 pediatric units in Andalusia (2004-2019) were retrospectively reviewed. VL diagnosis was based on clinical presentation, serology, microscopy and molecular methods. Diagnosis of secondary hemophagocytic lymphohistiocytosis (sHLH) was established using the hemophagocytic lymphohistiocytosis-2004 criteria. RESULTS: A total of 127 patients were identified. Median age was 14.5 months; the main clinical presentations were fever and splenomegaly (95.3% each). Cytopenias were the most common laboratory abnormalities. Diagnostics as well as treatment regimens varied over time and the participating centers. Liposomal amphotericin B was prescribed in 97.6%; relapses as well as adverse events were rarely observed (3.1% each). Thirty-seven patients, diagnosed with sHLH required longer hospital admission (P = 0.001), an increased number of platelet (P < 0.006) and red blood cell (P = 0.0001) transfusions and pediatric intensive care unit admission (P = 0.007). Monocytopenia (P = 0.011) and high C-reactive protein levels (P = 0.031), variables not included in the hemophagocytic lymphohistiocytosis-2004 criteria, were associated with sHLH. One patient deceased in the context of the Leishmania infection. CONCLUSIONS: We report data on the largest pediatric VL cohort from Europe, commonly associated with sHLH. Raised C-reactive protein levels and monocytopenia appear to be associated with sHLH. The latter may help to identify these patients and to guide decisions regarding need of additional supportive clinical care and immunomodulatory therapies. The observed high rate of heterogeneity in terms of diagnosis and management warrants the establishment of appropriate guidelines.