Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations

Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations Publisher

Lorenzini T^{1, 2} ; Fliegauf M^{1, 3} ; Klammer N¹ ; Frede N¹ ; Proietti M¹ ; Bulashevska A¹ ; Camachoordonez N¹ ; Varjosalo M⁴ ; Kinnunen M⁴ ; De Vries E⁵ ; Van Der Meer JWM⁶ ; Ameratunga R⁷ ; Roifman CM⁸ ; Schejter YD⁸ Show All Authors

Lorenzini T^{1, 2}
Fliegauf M^{1, 3}
Klammer N¹
Frede N¹
Proietti M¹
Bulashevska A¹
Camachoordonez N¹
Varjosalo M⁴
Kinnunen M⁴
De Vries E⁵
Van Der Meer JWM⁶
Ameratunga R⁷
Roifman CM⁸
Schejter YD⁸
Kobbe R⁹
Hautala T¹⁰
Atschekzei F^{11, 12}
Schmidt RE^{11, 12}
Schroder C¹¹
Stepensky P¹³
Shadur B^{13, 14}
Pedroza LA^{15, 16}
Van Der Flier M¹⁷
Martinezgallo M^{18, 19}
Gonzalezgranado LI²⁰
Allende LM²¹
Shcherbina A²²
Kuzmenko N²²
Zakharova V²³
Neves JF²⁴
Svec P²⁵
Fischer U²⁶
Ip W²⁷
Bartsch O²⁸
Baris S²⁹
Klein C³⁰
Geha R³¹
Chou J³¹
Alosaimi M³¹
Weintraub L³²
Boztug K³³
Hirschmugl T³³
Dos Santos Vilela MM³⁴
Holzinger D³⁵
Seidl M³⁶
Lougaris V²
Plebani A²
Alsina L³⁷
Piquergibert M³⁷
Deyamartinez A³⁷
Slade CA³⁸
Aghamohammadi A³⁹
Abolhassani H^{39, 40}
Hammarstrom L⁴⁰
Kuismin O⁴¹
Helminen M⁴²
Allen HL^{43, 44}
Thaventhiran JE⁴⁵
Freeman AF⁴⁶
Cook M^{47, 48}
Bakhtiar S⁴⁹
Christiansen M⁵⁰
Cunninghamrundles C⁵¹
Patel NC⁵²
Rae W⁵³
Niehues T⁵⁴
Brauer N⁵⁴
Syrjanen J⁵⁵
Seppanen MRJ⁵⁶
Burns SO⁵⁷
Tuijnenburg P⁵⁸
Kuijpers TW⁵⁸
Warnatz K^{1, 61}
Grimbacher B^{1, 3, 12, 59, 60, 61}

Source: Journal of Allergy and Clinical Immunology Published:2020

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. © 2020

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Style	Citing Format
MLA	Lorenzini T, et al.. "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, 2020, pp. 901-911.
APA	Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, Camachoordonez 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, Schroder C, ... Grimbacher B (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.
Chicago	Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, Camachoordonez N, et al.. "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, no. 4 (2020): 901-911.
Harvard	Lorenzini T et al. (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), pp. 901-911.
Vancouver	Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, et al.. Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations. Journal of Allergy and Clinical Immunology. 2020;146(4):901-911.
BibTex	@article{ author = {Lorenzini T and Fliegauf M and Klammer N and Frede N and Proietti M and Bulashevska A and Camachoordonez N and Varjosalo M and Kinnunen M and De Vries E and Van Der Meer JWM and Ameratunga R and Roifman CM and Schejter YD and Kobbe R and Hautala T and Atschekzei F and Schmidt RE and Schroder C and Stepensky P and Shadur B and Pedroza LA and Van Der Flier M and Martinezgallo M and Gonzalezgranado LI and Allende LM and Shcherbina A and Kuzmenko N and Zakharova V and Neves JF and Svec P and Fischer U and Ip W and Bartsch O and Baris S and Klein C and Geha R and Chou J and Alosaimi M and Weintraub L and Boztug K and Hirschmugl T and Dos Santos Vilela MM and Holzinger D and Seidl M and Lougaris V and Plebani A and Alsina L and Piquergibert M and Deyamartinez A and Slade CA and Aghamohammadi A and Abolhassani H and Hammarstrom L and Kuismin O and Helminen M and Allen HL and Thaventhiran JE and Freeman AF and Cook M and Bakhtiar S and Christiansen M and Cunninghamrundles C and Patel NC and Rae W and Niehues T and Brauer N and Syrjanen J and Seppanen MRJ and Burns SO and Tuijnenburg P and Kuijpers TW and Warnatz K and Grimbacher B}, title = {Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations}, journal = {Journal of Allergy and Clinical Immunology}, volume = {146}, number = {4}, pages = {901-911}, year = {2020} }
RIS	TY - JOUR AU - Lorenzini T AU - Fliegauf M AU - Klammer N AU - Frede N AU - Proietti M AU - Bulashevska A AU - Camachoordonez N AU - Varjosalo M AU - Kinnunen M AU - De Vries E AU - Van Der Meer JWM AU - Ameratunga R AU - Roifman CM AU - Schejter YD AU - Kobbe R AU - Hautala T AU - Atschekzei F AU - Schmidt RE AU - Schroder C AU - Stepensky P AU - Shadur B AU - Pedroza LA AU - Van Der Flier M AU - Martinezgallo M AU - Gonzalezgranado LI AU - Allende LM AU - Shcherbina A AU - Kuzmenko N AU - Zakharova V AU - Neves JF AU - Svec P AU - Fischer U AU - Ip W AU - Bartsch O AU - Baris 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 MM AU - Holzinger D AU - Seidl M AU - Lougaris V AU - Plebani A AU - Alsina L AU - Piquergibert M AU - Deyamartinez A AU - Slade CA AU - Aghamohammadi A AU - Abolhassani H AU - Hammarstrom L AU - Kuismin O AU - Helminen M AU - Allen HL AU - Thaventhiran JE AU - Freeman AF AU - Cook M AU - Bakhtiar S AU - Christiansen M AU - Cunninghamrundles C AU - Patel NC AU - Rae W AU - Niehues T AU - Brauer N AU - Syrjanen J AU - Seppanen MRJ AU - Burns SO AU - Tuijnenburg P AU - Kuijpers TW AU - Warnatz K AU - Grimbacher B TI - Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations JO - Journal of Allergy and Clinical Immunology VL - 146 IS - 4 SP - 901 EP - 911 PY - 2020 ER -

Style

Citing Format

MLA

Lorenzini T, et al.. "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, 2020, pp. 901-911.

APA

Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, Camachoordonez 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, Schroder C, ... Grimbacher B (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.

Chicago

Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, Camachoordonez N, et al.. "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, no. 4 (2020): 901-911.

Harvard

Lorenzini T et al. (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), pp. 901-911.

Vancouver

Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, et al.. Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations. Journal of Allergy and Clinical Immunology. 2020;146(4):901-911.

BibTex

@article{ author = {Lorenzini T and Fliegauf M and Klammer N and Frede N and Proietti M and Bulashevska A and Camachoordonez N and Varjosalo M and Kinnunen M and De Vries E and Van Der Meer JWM and Ameratunga R and Roifman CM and Schejter YD and Kobbe R and Hautala T and Atschekzei F and Schmidt RE and Schroder C and Stepensky P and Shadur B and Pedroza LA and Van Der Flier M and Martinezgallo M and Gonzalezgranado LI and Allende LM and Shcherbina A and Kuzmenko N and Zakharova V and Neves JF and Svec P and Fischer U and Ip W and Bartsch O and Baris S and Klein C and Geha R and Chou J and Alosaimi M and Weintraub L and Boztug K and Hirschmugl T and Dos Santos Vilela MM and Holzinger D and Seidl M and Lougaris V and Plebani A and Alsina L and Piquergibert M and Deyamartinez A and Slade CA and Aghamohammadi A and Abolhassani H and Hammarstrom L and Kuismin O and Helminen M and Allen HL and Thaventhiran JE and Freeman AF and Cook M and Bakhtiar S and Christiansen M and Cunninghamrundles C and Patel NC and Rae W and Niehues T and Brauer N and Syrjanen J and Seppanen MRJ and Burns SO and Tuijnenburg P and Kuijpers TW and Warnatz K and Grimbacher B}, title = {Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations}, journal = {Journal of Allergy and Clinical Immunology}, volume = {146}, number = {4}, pages = {901-911}, year = {2020} }

RIS

TY - JOUR
AU - Lorenzini T
AU - Fliegauf M
AU - Klammer N
AU - Frede N
AU - Proietti M
AU - Bulashevska A
AU - Camachoordonez N
AU - Varjosalo M
AU - Kinnunen M
AU - De Vries E
AU - Van Der Meer JWM
AU - Ameratunga R
AU - Roifman CM
AU - Schejter YD
AU - Kobbe R
AU - Hautala T
AU - Atschekzei F
AU - Schmidt RE
AU - Schroder C
AU - Stepensky P
AU - Shadur B
AU - Pedroza LA
AU - Van Der Flier M
AU - Martinezgallo M
AU - Gonzalezgranado LI
AU - Allende LM
AU - Shcherbina A
AU - Kuzmenko N
AU - Zakharova V
AU - Neves JF
AU - Svec P
AU - Fischer U
AU - Ip W
AU - Bartsch O
AU - Baris 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 MM
AU - Holzinger D
AU - Seidl M
AU - Lougaris V
AU - Plebani A
AU - Alsina L
AU - Piquergibert M
AU - Deyamartinez A
AU - Slade CA
AU - Aghamohammadi A
AU - Abolhassani H
AU - Hammarstrom L
AU - Kuismin O
AU - Helminen M
AU - Allen HL
AU - Thaventhiran JE
AU - Freeman AF
AU - Cook M
AU - Bakhtiar S
AU - Christiansen M
AU - Cunninghamrundles C
AU - Patel NC
AU - Rae W
AU - Niehues T
AU - Brauer N
AU - Syrjanen J
AU - Seppanen MRJ
AU - Burns SO
AU - Tuijnenburg P
AU - Kuijpers TW
AU - Warnatz K
AU - Grimbacher B
TI - Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations
JO - Journal of Allergy and Clinical Immunology
VL - 146
IS - 4
SP - 901
EP - 911
PY - 2020
ER -

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