Autor(es):
Lorenzini, T ; Fliegauf, M ; Klammer, N ; Frede, N ; Proietti, M ; Bulashevska, A ; Camacho-Ordonez, N ; Varjosalo, M ; Kinnunen, M ; de Vries, E ; van der Meer, JW ; Ameratunga, R ; Roifman, CM ; Schejter, YD ; Kobbe, R ; Hautala, T ; Atschekzei, F ; Schmidt, RE ; Schröder, C ; Stepensky, P ; Shadur, B ; Pedroza, LA ; van der Flier, M ; Martínez-Gallo, M ; Gonzalez-Granado, LI ; Allende, LM ; Shcherbina, A ; Kuzmenko, N ; Zakharova, V ; Neves, JF ; Svec, P ; Fischer, U ; Ip, W ; Bartsch, O ; Barış, S ; Klein, C ; Geha, R ; Chou, J ; Alosaimi, M ; Weintraub, L ; Boztug, K ; Hirschmugl, T ; Dos Santos Vilela, MM ; Holzinger, D ; Seidl, M ; Lougaris, V ; Plebani, A ; Alsina, L ; Piquer-Gibert, M ; Deyà-Martínez, A ; Slade, CA ; Aghamohammadi, A ; Abolhassani, H ; Hammarström, L ; Kuismin, O ; Helminen, M ; Allen, HL ; Thaventhiran, JE ; Freeman, AF ; Cook, M ; Bakhtiar, s ; Christiansen, M ; Cunningham-Rundles, C ; Patel, NC ; Rae, W ; Niehues, T ; Brauer, N ; Syrjänen, J ; Seppänen, MJ ; Burns, SO ; Tuijnenburg, P ; Kuijpers, TW ; Warnatz, K ; Grimbacher, B
Data: 2020
Identificador Persistente: http://hdl.handle.net/10400.17/3743
Origem: Repositório do Centro Hospitalar de Lisboa Central, EPE
Assunto(s): Adult; Aged; Autoimmunity; Biological Variation, Population; Biomarkers; Disease Management; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; NF-kappa B p50 Subunit; Prognosis; Tomography, X-Ray Computed; Genetic Association Studies; Genetic Predisposition to Disease; Heterozygote; Mutation; Phenotype; HDE PED
Descrição
Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
