Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

NIHR BioResource; Tiziana Lorenzini; Manfred Fliegauf; Nils Klammer; Natalie Frede; Michele Proietti; Alla Bulashevska; Nadezhda Camacho-Ordonez; Markku Varjosalo; Matias Kinnunen; Esther de Vries; Jos W M van der Meer; Rohan Ameratunga; Chaim M Roifman; Yael D Schejter; Robin Kobbe; Timo Hautala; Faranaz Atschekzei; Reinhold E Schmidt; Claudia Schröder; Polina Stepensky; Bella Shadur; Luis A Pedroza; Michiel van der Flier; Mónica Martínez-Gallo; Luis Ignacio Gonzalez-Granado; Luis M Allende; Anna Shcherbina; Natalia Kuzmenko; Victoria Zakharova; João Farela Neves; Peter Svec; Ute Fischer; Winnie Ip; Oliver Bartsch; Safa Barış; Christoph Klein; Raif Geha; Janet Chou; Mohammed Alosaimi; Lauren Weintraub; Kaan Boztug; Tatjana Hirschmugl; Maria Marluce Dos Santos Vilela; Dirk Holzinger; Maximilian Seidl; Vassilios Lougaris; Alessandro Plebani; Laia Alsina; Merja Helminen; Jaana Syrjänen

doi:10.1016/j.jaci.2019.11.051

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

NIHR BioResource, Tiziana Lorenzini, Manfred Fliegauf, Nils Klammer, Natalie Frede, Michele Proietti, Alla Bulashevska, Nadezhda Camacho-Ordonez, Markku Varjosalo, Matias Kinnunen, Esther de Vries, Jos W M van der Meer, Rohan Ameratunga, Chaim M Roifman, Yael D Schejter, Robin Kobbe, Timo Hautala, Faranaz Atschekzei, Reinhold E Schmidt, Claudia SchröderPolina Stepensky, Bella Shadur, Luis A Pedroza, Michiel van der Flier, Mónica Martínez-Gallo, Luis Ignacio Gonzalez-Granado, Luis M Allende, Anna Shcherbina, Natalia Kuzmenko, Victoria Zakharova, João Farela Neves, Peter Svec, Ute Fischer, Winnie Ip, Oliver Bartsch, Safa Barış, Christoph Klein, Raif Geha, Janet Chou, Mohammed Alosaimi, Lauren Weintraub, Kaan Boztug, Tatjana Hirschmugl, Maria Marluce Dos Santos Vilela, Dirk Holzinger, Maximilian Seidl, Vassilios Lougaris, Alessandro Plebani, Laia Alsina, Merja Helminen, Jaana Syrjänen

Research output: Contribution to journal › Article › Scientific › peer-review

85 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	901-911
Number of pages	11
Journal	JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume	146
Issue number	4
DOIs	https://doi.org/10.1016/j.jaci.2019.11.051
Publication status	Published - 2020
Publication type	A1 Journal article-refereed

Keywords

NF-?B1-related phenotype
NFKB1 mutation
NFKB1 variant
autosomal dominant
common variable immunodeficiency
reduced penetrance

Publication forum classification

Publication forum level 3

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jaci.2019.11.051

Cite this

NIHR BioResource, 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, J. W. M., Ameratunga, R., Roifman, C. M., Schejter, Y. D., Kobbe, R., Hautala, T., Atschekzei, F., Schmidt, R. E., ... Syrjänen, J. (2020). Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 146(4), 901-911. https://doi.org/10.1016/j.jaci.2019.11.051

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title = "Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations",

abstract = "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.",

keywords = "NF-?B1-related phenotype, NFKB1 mutation, NFKB1 variant, autosomal dominant, common variable immunodeficiency, reduced penetrance, NF-?B1-related phenotype, NFKB1 mutation, NFKB1 variant, autosomal dominant, common variable immunodeficiency, reduced penetrance",

author = "{NIHR BioResource} and Tiziana Lorenzini and Manfred Fliegauf and Nils Klammer and Natalie Frede and Michele Proietti and Alla Bulashevska and Nadezhda Camacho-Ordonez and Markku Varjosalo and Matias Kinnunen and {de Vries}, Esther and {van der Meer}, {Jos W M} and Rohan Ameratunga and Roifman, {Chaim M} and Schejter, {Yael D} and Robin Kobbe and Timo Hautala and Faranaz Atschekzei and Schmidt, {Reinhold E} and Claudia Schr{\"o}der and Polina Stepensky and Bella Shadur and Pedroza, {Luis A} and {van der Flier}, Michiel and M{\'o}nica Mart{\'i}nez-Gallo and Gonzalez-Granado, {Luis Ignacio} and Allende, {Luis M} and Anna Shcherbina and Natalia Kuzmenko and Victoria Zakharova and Neves, {Jo{\~a}o Farela} and Peter Svec and Ute Fischer and Winnie Ip and Oliver Bartsch and Safa Barı{\c s} and Christoph Klein and Raif Geha and Janet Chou and Mohammed Alosaimi and Lauren Weintraub and Kaan Boztug and Tatjana Hirschmugl and {Dos Santos Vilela}, {Maria Marluce} and Dirk Holzinger and Maximilian Seidl and Vassilios Lougaris and Alessandro Plebani and Laia Alsina and Merja Helminen and Jaana Syrj{\"a}nen",

note = "Copyright {\textcopyright} 2020. Published by Elsevier Inc.",

year = "2020",

doi = "10.1016/j.jaci.2019.11.051",

language = "English",

volume = "146",

pages = "901--911",

journal = "JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY",

issn = "0091-6749",

publisher = "Elsevier",

number = "4",

}

NIHR BioResource, 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, JWM, 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, Helminen, M & Syrjänen, J 2020, 'Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 146, no. 4, pp. 901-911. https://doi.org/10.1016/j.jaci.2019.11.051

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. / NIHR BioResource; Lorenzini, Tiziana; Fliegauf, Manfred et al.
In: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol. 146, No. 4, 2020, p. 901-911.

Research output: Contribution to journal › Article › Scientific › peer-review

TY - JOUR

T1 - Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

AU - NIHR BioResource

AU - Lorenzini, Tiziana

AU - Fliegauf, Manfred

AU - Klammer, Nils

AU - Frede, Natalie

AU - Proietti, Michele

AU - Bulashevska, Alla

AU - Camacho-Ordonez, Nadezhda

AU - Varjosalo, Markku

AU - Kinnunen, Matias

AU - de Vries, Esther

AU - van der Meer, Jos W M

AU - Ameratunga, Rohan

AU - Roifman, Chaim M

AU - Schejter, Yael D

AU - Kobbe, Robin

AU - Hautala, Timo

AU - Atschekzei, Faranaz

AU - Schmidt, Reinhold E

AU - Schröder, Claudia

AU - Stepensky, Polina

AU - Shadur, Bella

AU - Pedroza, Luis A

AU - van der Flier, Michiel

AU - Martínez-Gallo, Mónica

AU - Gonzalez-Granado, Luis Ignacio

AU - Allende, Luis M

AU - Shcherbina, Anna

AU - Kuzmenko, Natalia

AU - Zakharova, Victoria

AU - Neves, João Farela

AU - Svec, Peter

AU - Fischer, Ute

AU - Ip, Winnie

AU - Bartsch, Oliver

AU - Barış, Safa

AU - Klein, Christoph

AU - Geha, Raif

AU - Chou, Janet

AU - Alosaimi, Mohammed

AU - Weintraub, Lauren

AU - Boztug, Kaan

AU - Hirschmugl, Tatjana

AU - Dos Santos Vilela, Maria Marluce

AU - Holzinger, Dirk

AU - Seidl, Maximilian

AU - Lougaris, Vassilios

AU - Plebani, Alessandro

AU - Alsina, Laia

AU - Helminen, Merja

AU - Syrjänen, Jaana

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - NF-?B1-related phenotype

KW - NFKB1 mutation

KW - NFKB1 variant

KW - autosomal dominant

KW - common variable immunodeficiency

KW - reduced penetrance

KW - NF-?B1-related phenotype

KW - NFKB1 mutation

KW - NFKB1 variant

KW - autosomal dominant

KW - common variable immunodeficiency

KW - reduced penetrance

U2 - 10.1016/j.jaci.2019.11.051

DO - 10.1016/j.jaci.2019.11.051

M3 - Article

C2 - 32278790

SN - 0091-6749

VL - 146

SP - 901

EP - 911

JO - JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

JF - JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

IS - 4

ER -

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

Abstract

Keywords

Publication forum classification

UN SDGs

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