Browsing by Author "Alsina, L"
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- Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 MutationsPublication . 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, BBackground: 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.
- Primary Immunodeficiency Associated with Chromosomal Aberration - an ESID SurveyPublication . Schatorjé, E; van der Flier, M; Seppänen, M; Browning, M; Morsheimer, M; Henriet, S; Neves, JF; Vinh, D; Alsina, L; Grumach, A; Soler-Palacin, P; Boyce, T; Celmeli, F; Goudouris, E; Hayman, G; Herriot, R; Förster-Waldl, E; Seidel, M; Simons, A; de Vries, EPatients with syndromic features frequently suffer from recurrent respiratory infections, but little is known about the spectrum of immunological abnormalities associated with their underlying chromosomal aberrations outside the well-known examples of Down and DiGeorge syndromes. Therefore, we performed this retrospective, observational survey study.