Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations

Charline Miot, Kohsuke Imai, Chihaya Imai, Anthony J. Mancini, Zeynep Yesim Kucuk, Tokomki Kawai, Ryuta Nishikomori, Etsuro Ito, Isabelle Pellier, Sophie Dupuis Girod, Jeremie Rosain, Shinya Sasaki, Shanmuganathan Chandrakasan, Jana Pachlopnik Schmid, Tsubasa Okano, Estelle Colin, Alberto Olaya-Vargas, Marco Yamazaki-Nakashimada, Waseem Qasim, Sara Espinosa Padilla & 26 others Andrea Jones, Alfons Krol, Nyree Cole, Stephen Jolles, Jack Bleesing, Thomas Vraetz, Andrew R. Gennery, Mario Abinun, Tayfun Güngör, Beatriz Costa-Carvalho, Antonio Condino-Neto, Paul Veys, Steven M. Holland, Gulbu Uzel, Despina Moshous, Benedicte Neven, Stéphane Blanche, Stephan Ehl, Rainer Döffinger, Smita Y. Patel, Anne Puel, Jacinta Bustamante, Erwin W. Gelfand, Jean Laurent Casanova, Jordan S. Orange, Capucine Picard

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

Original languageEnglish (US)
Pages (from-to)1456-1467
Number of pages12
JournalBlood
Volume130
Issue number12
DOIs
StatePublished - Sep 21 2017

Fingerprint

Hematopoietic Stem Cell Transplantation
Stem cells
Modulators
Mutation
Unrelated Donors
Colitis
Transplantation
Tissue Donors
Ectodermal Dysplasia
Gene encoding
Graft vs Host Disease
Grafts
Health Status
Survival Rate
Health
Infection
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Miot, C., Imai, K., Imai, C., Mancini, A. J., Kucuk, Z. Y., Kawai, T., ... Picard, C. (2017). Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. Blood, 130(12), 1456-1467. https://doi.org/10.1182/blood-2017-03-771600

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. / Miot, Charline; Imai, Kohsuke; Imai, Chihaya; Mancini, Anthony J.; Kucuk, Zeynep Yesim; Kawai, Tokomki; Nishikomori, Ryuta; Ito, Etsuro; Pellier, Isabelle; Girod, Sophie Dupuis; Rosain, Jeremie; Sasaki, Shinya; Chandrakasan, Shanmuganathan; Schmid, Jana Pachlopnik; Okano, Tsubasa; Colin, Estelle; Olaya-Vargas, Alberto; Yamazaki-Nakashimada, Marco; Qasim, Waseem; Padilla, Sara Espinosa; Jones, Andrea; Krol, Alfons; Cole, Nyree; Jolles, Stephen; Bleesing, Jack; Vraetz, Thomas; Gennery, Andrew R.; Abinun, Mario; Güngör, Tayfun; Costa-Carvalho, Beatriz; Condino-Neto, Antonio; Veys, Paul; Holland, Steven M.; Uzel, Gulbu; Moshous, Despina; Neven, Benedicte; Blanche, Stéphane; Ehl, Stephan; Döffinger, Rainer; Patel, Smita Y.; Puel, Anne; Bustamante, Jacinta; Gelfand, Erwin W.; Casanova, Jean Laurent; Orange, Jordan S.; Picard, Capucine.

In: Blood, Vol. 130, No. 12, 21.09.2017, p. 1456-1467.

Research output: Contribution to journalArticle

Miot, C, Imai, K, Imai, C, Mancini, AJ, Kucuk, ZY, Kawai, T, Nishikomori, R, Ito, E, Pellier, I, Girod, SD, Rosain, J, Sasaki, S, Chandrakasan, S, Schmid, JP, Okano, T, Colin, E, Olaya-Vargas, A, Yamazaki-Nakashimada, M, Qasim, W, Padilla, SE, Jones, A, Krol, A, Cole, N, Jolles, S, Bleesing, J, Vraetz, T, Gennery, AR, Abinun, M, Güngör, T, Costa-Carvalho, B, Condino-Neto, A, Veys, P, Holland, SM, Uzel, G, Moshous, D, Neven, B, Blanche, S, Ehl, S, Döffinger, R, Patel, SY, Puel, A, Bustamante, J, Gelfand, EW, Casanova, JL, Orange, JS & Picard, C 2017, 'Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations', Blood, vol. 130, no. 12, pp. 1456-1467. https://doi.org/10.1182/blood-2017-03-771600
Miot, Charline ; Imai, Kohsuke ; Imai, Chihaya ; Mancini, Anthony J. ; Kucuk, Zeynep Yesim ; Kawai, Tokomki ; Nishikomori, Ryuta ; Ito, Etsuro ; Pellier, Isabelle ; Girod, Sophie Dupuis ; Rosain, Jeremie ; Sasaki, Shinya ; Chandrakasan, Shanmuganathan ; Schmid, Jana Pachlopnik ; Okano, Tsubasa ; Colin, Estelle ; Olaya-Vargas, Alberto ; Yamazaki-Nakashimada, Marco ; Qasim, Waseem ; Padilla, Sara Espinosa ; Jones, Andrea ; Krol, Alfons ; Cole, Nyree ; Jolles, Stephen ; Bleesing, Jack ; Vraetz, Thomas ; Gennery, Andrew R. ; Abinun, Mario ; Güngör, Tayfun ; Costa-Carvalho, Beatriz ; Condino-Neto, Antonio ; Veys, Paul ; Holland, Steven M. ; Uzel, Gulbu ; Moshous, Despina ; Neven, Benedicte ; Blanche, Stéphane ; Ehl, Stephan ; Döffinger, Rainer ; Patel, Smita Y. ; Puel, Anne ; Bustamante, Jacinta ; Gelfand, Erwin W. ; Casanova, Jean Laurent ; Orange, Jordan S. ; Picard, Capucine. / Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. In: Blood. 2017 ; Vol. 130, No. 12. pp. 1456-1467.
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title = "Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations",
abstract = "X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74{\%} at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.",
author = "Charline Miot and Kohsuke Imai and Chihaya Imai and Mancini, {Anthony J.} and Kucuk, {Zeynep Yesim} and Tokomki Kawai and Ryuta Nishikomori and Etsuro Ito and Isabelle Pellier and Girod, {Sophie Dupuis} and Jeremie Rosain and Shinya Sasaki and Shanmuganathan Chandrakasan and Schmid, {Jana Pachlopnik} and Tsubasa Okano and Estelle Colin and Alberto Olaya-Vargas and Marco Yamazaki-Nakashimada and Waseem Qasim and Padilla, {Sara Espinosa} and Andrea Jones and Alfons Krol and Nyree Cole and Stephen Jolles and Jack Bleesing and Thomas Vraetz and Gennery, {Andrew R.} and Mario Abinun and Tayfun G{\"u}ng{\"o}r and Beatriz Costa-Carvalho and Antonio Condino-Neto and Paul Veys and Holland, {Steven M.} and Gulbu Uzel and Despina Moshous and Benedicte Neven and St{\'e}phane Blanche and Stephan Ehl and Rainer D{\"o}ffinger and Patel, {Smita Y.} and Anne Puel and Jacinta Bustamante and Gelfand, {Erwin W.} and Casanova, {Jean Laurent} and Orange, {Jordan S.} and Capucine Picard",
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AU - Miot, Charline

AU - Imai, Kohsuke

AU - Imai, Chihaya

AU - Mancini, Anthony J.

AU - Kucuk, Zeynep Yesim

AU - Kawai, Tokomki

AU - Nishikomori, Ryuta

AU - Ito, Etsuro

AU - Pellier, Isabelle

AU - Girod, Sophie Dupuis

AU - Rosain, Jeremie

AU - Sasaki, Shinya

AU - Chandrakasan, Shanmuganathan

AU - Schmid, Jana Pachlopnik

AU - Okano, Tsubasa

AU - Colin, Estelle

AU - Olaya-Vargas, Alberto

AU - Yamazaki-Nakashimada, Marco

AU - Qasim, Waseem

AU - Padilla, Sara Espinosa

AU - Jones, Andrea

AU - Krol, Alfons

AU - Cole, Nyree

AU - Jolles, Stephen

AU - Bleesing, Jack

AU - Vraetz, Thomas

AU - Gennery, Andrew R.

AU - Abinun, Mario

AU - Güngör, Tayfun

AU - Costa-Carvalho, Beatriz

AU - Condino-Neto, Antonio

AU - Veys, Paul

AU - Holland, Steven M.

AU - Uzel, Gulbu

AU - Moshous, Despina

AU - Neven, Benedicte

AU - Blanche, Stéphane

AU - Ehl, Stephan

AU - Döffinger, Rainer

AU - Patel, Smita Y.

AU - Puel, Anne

AU - Bustamante, Jacinta

AU - Gelfand, Erwin W.

AU - Casanova, Jean Laurent

AU - Orange, Jordan S.

AU - Picard, Capucine

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N2 - X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

AB - X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

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