Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.
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Lorenzini Tiziana, Fliegauf Manfred, Klammer Nils, Frede Natalie, Proietti Michele, Bulashevska Alla, Camacho-Ordonez Nadezhda, Varjosalo Markku, Kinnunen Matias, de Vries Esther, van der Meer Jos W M, Ameratunga Rohan, Roifman Chaim M, Schejter Yael D, Kobbe Robin, Hautala Timo, Atschekzei Faranaz, Schmidt Reinhold E, Schröder Claudia, Stepensky Polina, Shadur Bella, Pedroza Luis A, van der Flier Michiel, Martínez-Gallo Mónica, Gonzalez-Granado Luis Ignacio, Allende Luis M, Shcherbina Anna, Kuzmenko Natalia, Zakharova Victoria, Neves João Farela, Svec Peter, Fischer Ute, Ip Winnie, Bartsch Oliver, Barış Safa, Klein Christoph, Geha Raif, Chou Janet, Alosaimi Mohammed, Weintraub Lauren, Boztug Kaan, Hirschmugl Tatjana, Dos Santos Vilela Maria Marluce, Holzinger Dirk, Seidl Maximilian, Lougaris Vassilios, Plebani Alessandro, Alsina Laia, Piquer-Gibert Monica, Deyà-Martínez Angela, Slade Charlotte A, Aghamohammadi Asghar, Abolhassani Hassan, Hammarström Lennart, Kuismin Outi, Helminen Merja, Allen Hana Lango, Thaventhiran James E, Freeman Alexandra F, Cook Matthew, Bakhtiar Shahrzad, Christiansen Mette, Cunningham-Rundles Charlotte, Patel Niraj C, Rae William, Niehues Tim, Brauer Nina, Syrjänen Jaana, Seppänen Mikko R J, Burns Siobhan O, Tuijnenburg Paul, Kuijpers Taco W, NIHR BioResource, Warnatz Klaus, Grimbacher Bodo, NIHR BioResource
Аннотация
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.