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

T. Lorenzini; M. Fliegauf; N. Klammer; N. Frede; M. Proietti; A. Bulashevska; N. Camacho-Ordonez; M. Varjosala; M. Kinnunen; E. de Vries; J. W. M. van der Meer; R. Ameratunga; C. M. Roifman; Y. D. Schejter; R. Kobbe; T. Hautala; F. Atschekzei; R. E. Schmidt; C. Schröder; P. Stepensky; B. Shadur; L. A. Pedroza; M.  Van der Flier; M. Martínez-Gallo; L. I. Gonzalez-Granado; L. M. Allende; A. Shcherbina; N. Kuzmenk; V. Zakharova; J. F. Neves; P. Svec; U. Fischer; W. Ip; O. Bartsch; S. Barış; C. Klein; R. Geha; J. Chou; M. Alosaimi; L. Weintraub; K. Boztug; T. Hirschmugl; M. M. Dos Santos Vilela; D. Holzinger; M. Seidl; V. Lougaris; A. Plebani; L. Alsina; M. Piquer-Gibert; A. Deyà-Martínez; C. A. Slade; A. Aghamohammadi; H. Abolhassani; L. Hammarström; O. Kuismin; M. Helminen; H. Lango Allen; J. E. Thaventhiran; A. F. Freeman; M. Cook; S. Bakhtiar; M. Christiansen; C. Cunningham-Rundles; N. C. Patel; W. Rae; T. Niehues; N. Brauer; J. Syrjänen; M. R. J. Seppänen; S. O. Burns; P. Tuijnenburg; T. W. Kuijpers; K. Warnatz; B. Grimbacher; NIHR BioResource

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

T. Lorenzini
, M. Fliegauf
, N. Klammer
, N. Frede
, M. Proietti
, A. Bulashevska
, N. Camacho-Ordonez
, M. Varjosala
, M. Kinnunen
, E. de Vries
, J. W. M. van der Meer
, R. Ameratunga
, C. M. Roifman
, Y. D. Schejter
, R. Kobbe
, T. Hautala
, F. Atschekzei
, R. E. Schmidt
, C. Schröder
, P. Stepensky

B. Shadur, L. A. Pedroza, M. Van der Flier, M. Martínez-Gallo, L. I. Gonzalez-Granado, L. M. Allende, A. Shcherbina, N. Kuzmenk, V. Zakharova, J. F. Neves, P. Svec, U. Fischer, W. Ip, O. Bartsch, S. Barış , C. Klein, R. Geha, J. Chou, M. Alosaimi, L. Weintraub, K. Boztug, T. Hirschmugl, M. M. Dos Santos Vilela, D. Holzinger, M. Seidl, V. Lougaris, A. Plebani, L. Alsina, M. Piquer-Gibert, A. Deyà-Martínez, C. A. Slade, A. Aghamohammadi, H. Abolhassani, L. Hammarström, O. Kuismin, M. Helminen, H. Lango Allen, J. E. Thaventhiran, A. F. Freeman, M. Cook, S. Bakhtiar, M. Christiansen, C. Cunningham-Rundles, N. C. Patel, W. Rae, T. Niehues, N. Brauer, J. Syrjänen, M. R. J. Seppänen, S. O. Burns, P. Tuijnenburg, T. W. Kuijpers, K. Warnatz, B. Grimbacher^*, NIHR BioResource

^*Corresponding author for this work

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
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

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

CELLS
HAPLOINSUFFICIENCY
IMMUNODEFICIENCY
NF-KAPPA-B
NF-KAPPA-B1
NF-kappa B1-related phenotype
NFKB1 mutation
NFKB1 variant
NUCLEAR-FACTOR
autosomal dominant
common variable immunodeficiency
reduced penetrance

Access to Document

10.1016/j.jaci.2019.11.051

Cite this

Lorenzini, T., Fliegauf, M., Klammer, N., Frede, N., Proietti, M., Bulashevska, A., Camacho-Ordonez, N., Varjosala, 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., Schröder, C., ... NIHR BioResource (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

@article{d1443f5a24204ea88404efeface90730,

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 = "CELLS, HAPLOINSUFFICIENCY, IMMUNODEFICIENCY, NF-KAPPA-B, NF-KAPPA-B1, NF-kappa B1-related phenotype, NFKB1 mutation, NFKB1 variant, NUCLEAR-FACTOR, autosomal dominant, common variable immunodeficiency, reduced penetrance",

author = "T. Lorenzini and M. Fliegauf and N. Klammer and N. Frede and M. Proietti and A. Bulashevska and N. Camacho-Ordonez and M. Varjosala and M. Kinnunen and \{de Vries\}, E. and \{van der Meer\}, \{J. W. M.\} and R. Ameratunga and Roifman, \{C. M.\} and Schejter, \{Y. D.\} and R. Kobbe and T. Hautala and F. Atschekzei and Schmidt, \{R. E.\} and C. Schr{\"o}der and P. Stepensky and B. Shadur and Pedroza, \{L. A.\} and \{Van der Flier\}, M. and M. Mart{\'i}nez-Gallo and Gonzalez-Granado, \{L. I.\} and Allende, \{L. M.\} and A. Shcherbina and N. Kuzmenk and V. Zakharova and Neves, \{J. F.\} and P. Svec and U. Fischer and W. Ip and O. Bartsch and S. Barı{\c s} and C. Klein and R. Geha and J. Chou and M. Alosaimi and L. Weintraub and K. Boztug and T. Hirschmugl and \{Dos Santos Vilela\}, \{M. M.\} and D. Holzinger and M. Seidl and V. Lougaris and A. Plebani and L. Alsina and M. Piquer-Gibert and A. Dey{\`a}-Mart{\'i}nez and Slade, \{C. A.\} and A. Aghamohammadi and H. Abolhassani and L. Hammarstr{\"o}m and O. Kuismin and M. Helminen and \{Lango Allen\}, H. and Thaventhiran, \{J. E.\} and Freeman, \{A. F.\} and M. Cook and S. Bakhtiar and M. Christiansen and C. Cunningham-Rundles and Patel, \{N. C.\} and W. Rae and T. Niehues and N. Brauer and J. Syrj{\"a}nen and Sepp{\"a}nen, \{M. R. J.\} and Burns, \{S. O.\} and P. Tuijnenburg and Kuijpers, \{T. W.\} and K. Warnatz and B. Grimbacher and \{NIHR BioResource\}",

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 Inc.",

number = "4",

}

Lorenzini, T, Fliegauf, M, Klammer, N, Frede, N, Proietti, M, Bulashevska, A, Camacho-Ordonez, N, Varjosala, 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, Kuzmenk, 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, Lango Allen, H, Thaventhiran, JE, Freeman, AF, Cook, M, Bakhtiar, S, Christiansen, M, Cunningham-Rundles, C, Patel, NC, Rae, W, Niehues, T, Brauer, N, Syrjänen, J, Seppänen, MRJ, Burns, SO, Tuijnenburg, P, Kuijpers, TW, Warnatz, K, Grimbacher, B & NIHR BioResource 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

TY - JOUR

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

AU - Lorenzini, T.

AU - Fliegauf, M.

AU - Klammer, N.

AU - Frede, N.

AU - Proietti, M.

AU - Bulashevska, A.

AU - Camacho-Ordonez, N.

AU - Varjosala, M.

AU - Kinnunen, M.

AU - de Vries, E.

AU - van der Meer, J. W. M.

AU - Ameratunga, R.

AU - Roifman, C. M.

AU - Schejter, Y. D.

AU - Kobbe, R.

AU - Hautala, T.

AU - Atschekzei, F.

AU - Schmidt, R. E.

AU - Schröder, C.

AU - Stepensky, P.

AU - Shadur, B.

AU - Pedroza, L. A.

AU - Van der Flier, M.

AU - Martínez-Gallo, M.

AU - Gonzalez-Granado, L. I.

AU - Allende, L. M.

AU - Shcherbina, A.

AU - Kuzmenk, N.

AU - Zakharova, V.

AU - Neves, J. F.

AU - Svec, P.

AU - Fischer, U.

AU - Ip, W.

AU - Bartsch, O.

AU - Barış , S.

AU - Klein, C.

AU - Geha, R.

AU - Chou, J.

AU - Alosaimi, M.

AU - Weintraub, L.

AU - Boztug, K.

AU - Hirschmugl, T.

AU - Dos Santos Vilela, M. M.

AU - Holzinger, D.

AU - Seidl, M.

AU - Lougaris, V.

AU - Plebani, A.

AU - Alsina, L.

AU - Piquer-Gibert, M.

AU - Deyà-Martínez, A.

AU - Slade, C. A.

AU - Aghamohammadi, A.

AU - Abolhassani, H.

AU - Hammarström, L.

AU - Kuismin, O.

AU - Helminen, M.

AU - Lango Allen, H.

AU - Thaventhiran, J. E.

AU - Freeman, A. F.

AU - Cook, M.

AU - Bakhtiar, S.

AU - Christiansen, M.

AU - Cunningham-Rundles, C.

AU - Patel, N. C.

AU - Rae, W.

AU - Niehues, T.

AU - Brauer, N.

AU - Syrjänen, J.

AU - Seppänen, M. R. J.

AU - Burns, S. O.

AU - Tuijnenburg, P.

AU - Kuijpers, T. W.

AU - Warnatz, K.

AU - Grimbacher, B.

AU - NIHR BioResource

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 - CELLS

KW - HAPLOINSUFFICIENCY

KW - IMMUNODEFICIENCY

KW - NF-KAPPA-B

KW - NF-KAPPA-B1

KW - NF-kappa B1-related phenotype

KW - NFKB1 mutation

KW - NFKB1 variant

KW - NUCLEAR-FACTOR

KW - autosomal dominant

KW - common variable immunodeficiency

KW - reduced penetrance

UR - https://www.scopus.com/pages/publications/85084240212

U2 - 10.1016/j.jaci.2019.11.051

DO - 10.1016/j.jaci.2019.11.051

M3 - Article

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

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this