6533b826fe1ef96bd12846ea

RESEARCH PRODUCT

Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 Mutations

Tiziana LorenziniManfred FliegaufNils KlammerNatalie FredeMichele ProiettiAlla BulashevskaNadezhda Camacho-ordonezMarkku VarjosaloMatias KinnunenEsther De VriesJos W.m. Van Der MeerRohan AmeratungaChaim M. RoifmanYael D. SchejterRobin KobbeTimo HautalaFaranaz AtschekzeiReinhold E. SchmidtClaudia SchröderPolina StepenskyBella ShadurLuis A. PedrozaMichiel Van Der FlierMónica Martínez-galloLuis Ignacio Gonzalez-granadoLuis M. AllendeAnna ShcherbinaNatalia KuzmenkoVictoria ZakharovaJoão Farela NevesPeter SvecUte FischerWinnie IpOliver BartschSafa BarışChristoph KleinRaif GehaJanet ChouMohammed AlosaimiLauren WeintraubKaan BoztugTatjana HirschmuglMaria Marluce Dos Santos VilelaDirk HolzingerMaximilian SeidlVassilios LougarisAlessandro PlebaniLaia AlsinaMonica Piquer-gibertAngela Deyà-martínezCharlotte A. SladeAsghar AghamohammadiHassan AbolhassaniLennart HammarströmOuti KuisminMerja HelminenHana Lango AllenJames E. ThaventhiranAlexandra F. FreemanMatthew CookShahrzad BakhtiarMette ChristiansenCharlotte Cunningham-rundlesNiraj C. PatelWilliam RaeTim NiehuesNina BrauerJaana SyrjänenMikko R.j. SeppänenSiobhan O. BurnsPaul TuijnenburgTaco W. KuijpersKlaus WarnatzBodo GrimbacherZoe AdhyaHana AlachkarAriharan AnantharachaganRichard AntrobusGururaj ArumugakaniSofie AshfordWilliam J. AstleAnthony AttwoodChiara BacchelliJoana BatistaHelen E. BaxendaleClaire BethuneShahnaz BibiMarta BledaBarbara BoardmanClaire BoothJohn R. BradleyGerome BreenMatthew BrownMichael J. BrowningMary BrownlieMatthew S. BucklandSiobhan O. BurnsOliver S. BurrenKeren CarssJohn ChambersAnita ChandraNaomi Clements BrodHayley CliffordNichola CooperLouise C. DaughertyE.g. DaviesSophie DaviesJohn DavisSarah DeacockSri V.v. DeeviJohn DempsterLisa A. DevlinEleanor F. DewhurstKate DownesElizabeth DreweDaniel DuarteJ. David M. EdgarKaren EdwardsWilliam EgnerTariq El-shanawanyMarie ErwoodDebra FletcherJames FoxAmy J. FraryMattia FrontiniAbigail FurnellH. Bobby GasparRohit GhuryeKimberly C. GilmourNicholas S. GleadallSarah GoddardPavels GordinsStefan GräfLuigi GrassiDaniel GreeneSofia GrigoriadouScott HackettRosie HagueMatthias HaimelLorraine HarperGrant HaymanArchana HerwadkarFengyuan HuStephen HughesAarnoud P. HuissoonRoger JamesStephen JollesJennifer JolleyJulie JonesYousuf KarimMary A. KasanickiPeter KelleherCarly KempsterSorena KianiNathalie KingstonNigel KleinMyrto KostadimaRoman KreuzhuberTaco W. KuijpersDinakantha KumararatneJames LaffanHana Lango AllenSara E. LearRachel LingerHilary LonghurstLorena E. LorenzoPaul A. LyonsJesmeen MaimarisAnia MansonRutendo MapetaJennifer MartinMark I. MccarthyElizabeth M. McdermottHarriet MckinneyStuart MeachamKaryn MegyHazel MillarAnoop MistryValerie MorrissonSai H.k. MurngIman NasirSergey NejentsevSadia NooraniEric OksenhendlerWillem H. OuwehandSofia PapadiaChristopher J. PenkettRomina PetersenMark J. PonsfordWaseem QasimEllen QuinnIsabella QuintiF. Lucy RaymondPaula J. Rayner-matthewsAlex RichterNilesh SamaniCrina SamarghiteanAlba Sanchis-juanRavishankar B. SargurSinisa SavicSuranjith L. SeneviratneW.a. Carrock SewellDenis SeyresFiona ShackleyOlga ShamardinaIlenia SimeoniMichael A. SimpsonKenneth G.c. SmithSimon StainesEmily StaplesHannah StarkHans StaussCathal L. SteeleJonathan StephensKathleen E. StirrupsJames E. ThaventhiranDavid ThomasMoira J. ThomasPatrick ThomasAdrian J. ThrasherTobias TillyCatherine TittertonPaul TreadawaySalih TunaErnest TurroRafal UrniazJulie Von ZiegenweidtNeil WalkerChristopher WattSteven B. WelchDeborah WhitehornLisa WillcocksNicholas W. WoodYvette WoodSarita WorkmanAusten WorthKatherine YatesNigel YeatmanPatrick F.k. YongTimothy YoungPing YuEliska Zlamalova

subject

0301 basic medicineMaleNF-KAPPA-BMedizinlnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]Fluorescent Antibody TechniqueAutoimmunityDiseaseNUCLEAR-FACTORKaplan-Meier Estimatemedicine.disease_causeHypogammaglobulinemia0302 clinical medicineNFKB1 variants and mutations; autosomal dominant inheritance; common variable immunodeficiency; reduced penetrance; variable expressivityHDE PEDImmunology and Allergyvariants and mutationsNF-κB1-related phenotypeImmunodeficiencyIMMUNODEFICIENCY*NF-?B1-related phenotypeNFKB1 variants and mutations1184 Genetics developmental biology physiologycommon variable immunodeficiencyDisease ManagementMiddle AgedNF-kappa B1-related phenotypereduced penetrancePrognosisPenetranceImmunohistochemistryMagnetic Resonance Imaging3. Good healthPhenotypeNFKB1 variant*NFKB1 variant*common variable immunodeficiencyFemaleHaploinsufficiency*reduced penetranceNFKB1 mutationAdultHeterozygote*NFKB1 mutationImmunologyHAPLOINSUFFICIENCYArticle03 medical and health sciencesvariable expressivityautosomal dominantmedicineHumansGenetic Predisposition to DiseaseGenetic Association StudiesAgedbusiness.industryCommon variable immunodeficiencyNF-kappa B p50 SubunitNF-KAPPA-B1Immune dysregulationmedicine.diseaseautosomal dominant inheritance030104 developmental biologyBiological Variation PopulationImmunologyCELLSMutation*autosomal dominantPrimary immunodeficiency3111 BiomedicinebusinessTomography X-Ray ComputedBiomarkers030215 immunology

description

Contains fulltext : 229571.pdf (Publisher’s version ) (Closed access) 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.

yearjournalcountryeditionlanguage
2020-10-01
10.1016/j.jaci.2019.11.051