The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

Karin R. Engelhardt, Michael E. Gertz, Sevgi Keles, Alejandro A. Schäffer, Elena C. Sigmund, Cristina Glocker, Shiva Saghafi, Zahra Pourpak, Ruben Ceja, Atfa Sassi, Laura E. Graham, Michel J. Massaad, Fethi Mellouli, Imen Ben-Mustapha, Monia Khemiri, Sara Sebnem Kilic, Amos Etzioni, Alexandra F. Freeman, Jens Thiel, Ilka SchulzeWaleed Al-Herz, Ayse Metin, Özden Sanal, Ilhan Tezcan, Mehdi Yeganeh, Tim Niehues, Gregor Dueckers, Sebastian Weinspach, Turkan Patiroglu, Ekrem Unal, Majed Dasouki, Mustafa Yilmaz, Ferah Genel, Caner Aytekin, Necil Kutukculer, Ayper Somer, Mehmet Kilic, Ismail Reisli, Yildiz Camcioglu, Andrew R. Gennery, Andrew J. Cant, Alison Jones, Bobby H. Gaspar, Peter D. Arkwright, Maria C. Pietrogrande, Zeina Baz, Salem Al-Tamemi, Vassilios Lougaris, Gerard Lefranc, Andre Megarbane, Jeannette Boutros, Nermeen Galal, Mohamed Bejaoui, Mohamed Ridha Barbouche, Raif S. Geha, Talal A. Chatila, Bodo Grimbacher

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

Original languageEnglish
Pages (from-to)402-412
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume136
Issue number2
DOIs
Publication statusPublished - Aug 1 2015

Fingerprint

Cytokinesis
Job Syndrome
Phenotype
STAT3 Transcription Factor
Mutation
Immunoglobulin M
Hypersensitivity
Tooth Eruption
Deciduous Tooth
Mycoses
Bone Fractures
Virus Diseases
Eosinophils
Respiratory Tract Infections
Abscess
Immunoglobulin E
Antibody Formation

Keywords

  • autosomal recessive hyper-IgE syndrome
  • dedicator of cytokinesis 8
  • hyper-IgE syndrome
  • Molluscum contagiosum
  • Primary combined immunodeficiency
  • signal transducer and activator of transcription 3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Engelhardt, K. R., Gertz, M. E., Keles, S., Schäffer, A. A., Sigmund, E. C., Glocker, C., ... Grimbacher, B. (2015). The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. Journal of Allergy and Clinical Immunology, 136(2), 402-412. https://doi.org/10.1016/j.jaci.2014.12.1945

The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. / Engelhardt, Karin R.; Gertz, Michael E.; Keles, Sevgi; Schäffer, Alejandro A.; Sigmund, Elena C.; Glocker, Cristina; Saghafi, Shiva; Pourpak, Zahra; Ceja, Ruben; Sassi, Atfa; Graham, Laura E.; Massaad, Michel J.; Mellouli, Fethi; Ben-Mustapha, Imen; Khemiri, Monia; Kilic, Sara Sebnem; Etzioni, Amos; Freeman, Alexandra F.; Thiel, Jens; Schulze, Ilka; Al-Herz, Waleed; Metin, Ayse; Sanal, Özden; Tezcan, Ilhan; Yeganeh, Mehdi; Niehues, Tim; Dueckers, Gregor; Weinspach, Sebastian; Patiroglu, Turkan; Unal, Ekrem; Dasouki, Majed; Yilmaz, Mustafa; Genel, Ferah; Aytekin, Caner; Kutukculer, Necil; Somer, Ayper; Kilic, Mehmet; Reisli, Ismail; Camcioglu, Yildiz; Gennery, Andrew R.; Cant, Andrew J.; Jones, Alison; Gaspar, Bobby H.; Arkwright, Peter D.; Pietrogrande, Maria C.; Baz, Zeina; Al-Tamemi, Salem; Lougaris, Vassilios; Lefranc, Gerard; Megarbane, Andre; Boutros, Jeannette; Galal, Nermeen; Bejaoui, Mohamed; Barbouche, Mohamed Ridha; Geha, Raif S.; Chatila, Talal A.; Grimbacher, Bodo.

In: Journal of Allergy and Clinical Immunology, Vol. 136, No. 2, 01.08.2015, p. 402-412.

Research output: Contribution to journalArticle

Engelhardt, KR, Gertz, ME, Keles, S, Schäffer, AA, Sigmund, EC, Glocker, C, Saghafi, S, Pourpak, Z, Ceja, R, Sassi, A, Graham, LE, Massaad, MJ, Mellouli, F, Ben-Mustapha, I, Khemiri, M, Kilic, SS, Etzioni, A, Freeman, AF, Thiel, J, Schulze, I, Al-Herz, W, Metin, A, Sanal, Ö, Tezcan, I, Yeganeh, M, Niehues, T, Dueckers, G, Weinspach, S, Patiroglu, T, Unal, E, Dasouki, M, Yilmaz, M, Genel, F, Aytekin, C, Kutukculer, N, Somer, A, Kilic, M, Reisli, I, Camcioglu, Y, Gennery, AR, Cant, AJ, Jones, A, Gaspar, BH, Arkwright, PD, Pietrogrande, MC, Baz, Z, Al-Tamemi, S, Lougaris, V, Lefranc, G, Megarbane, A, Boutros, J, Galal, N, Bejaoui, M, Barbouche, MR, Geha, RS, Chatila, TA & Grimbacher, B 2015, 'The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency', Journal of Allergy and Clinical Immunology, vol. 136, no. 2, pp. 402-412. https://doi.org/10.1016/j.jaci.2014.12.1945
Engelhardt, Karin R. ; Gertz, Michael E. ; Keles, Sevgi ; Schäffer, Alejandro A. ; Sigmund, Elena C. ; Glocker, Cristina ; Saghafi, Shiva ; Pourpak, Zahra ; Ceja, Ruben ; Sassi, Atfa ; Graham, Laura E. ; Massaad, Michel J. ; Mellouli, Fethi ; Ben-Mustapha, Imen ; Khemiri, Monia ; Kilic, Sara Sebnem ; Etzioni, Amos ; Freeman, Alexandra F. ; Thiel, Jens ; Schulze, Ilka ; Al-Herz, Waleed ; Metin, Ayse ; Sanal, Özden ; Tezcan, Ilhan ; Yeganeh, Mehdi ; Niehues, Tim ; Dueckers, Gregor ; Weinspach, Sebastian ; Patiroglu, Turkan ; Unal, Ekrem ; Dasouki, Majed ; Yilmaz, Mustafa ; Genel, Ferah ; Aytekin, Caner ; Kutukculer, Necil ; Somer, Ayper ; Kilic, Mehmet ; Reisli, Ismail ; Camcioglu, Yildiz ; Gennery, Andrew R. ; Cant, Andrew J. ; Jones, Alison ; Gaspar, Bobby H. ; Arkwright, Peter D. ; Pietrogrande, Maria C. ; Baz, Zeina ; Al-Tamemi, Salem ; Lougaris, Vassilios ; Lefranc, Gerard ; Megarbane, Andre ; Boutros, Jeannette ; Galal, Nermeen ; Bejaoui, Mohamed ; Barbouche, Mohamed Ridha ; Geha, Raif S. ; Chatila, Talal A. ; Grimbacher, Bodo. / The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 136, No. 2. pp. 402-412.
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title = "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency",
abstract = "Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92{\%} of patients), and low IgM levels (62{\%}). About 20{\%} of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84{\%}), viral (78{\%}), and fungal (70{\%}) infections were frequently observed. Skin abscesses (60{\%}) and allergies (73{\%}) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34{\%}). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.",
keywords = "autosomal recessive hyper-IgE syndrome, dedicator of cytokinesis 8, hyper-IgE syndrome, Molluscum contagiosum, Primary combined immunodeficiency, signal transducer and activator of transcription 3",
author = "Engelhardt, {Karin R.} and Gertz, {Michael E.} and Sevgi Keles and Sch{\"a}ffer, {Alejandro A.} and Sigmund, {Elena C.} and Cristina Glocker and Shiva Saghafi and Zahra Pourpak and Ruben Ceja and Atfa Sassi and Graham, {Laura E.} and Massaad, {Michel J.} and Fethi Mellouli and Imen Ben-Mustapha and Monia Khemiri and Kilic, {Sara Sebnem} and Amos Etzioni and Freeman, {Alexandra F.} and Jens Thiel and Ilka Schulze and Waleed Al-Herz and Ayse Metin and {\"O}zden Sanal and Ilhan Tezcan and Mehdi Yeganeh and Tim Niehues and Gregor Dueckers and Sebastian Weinspach and Turkan Patiroglu and Ekrem Unal and Majed Dasouki and Mustafa Yilmaz and Ferah Genel and Caner Aytekin and Necil Kutukculer and Ayper Somer and Mehmet Kilic and Ismail Reisli and Yildiz Camcioglu and Gennery, {Andrew R.} and Cant, {Andrew J.} and Alison Jones and Gaspar, {Bobby H.} and Arkwright, {Peter D.} and Pietrogrande, {Maria C.} and Zeina Baz and Salem Al-Tamemi and Vassilios Lougaris and Gerard Lefranc and Andre Megarbane and Jeannette Boutros and Nermeen Galal and Mohamed Bejaoui and Barbouche, {Mohamed Ridha} and Geha, {Raif S.} and Chatila, {Talal A.} and Bodo Grimbacher",
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doi = "10.1016/j.jaci.2014.12.1945",
language = "English",
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TY - JOUR

T1 - The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

AU - Engelhardt, Karin R.

AU - Gertz, Michael E.

AU - Keles, Sevgi

AU - Schäffer, Alejandro A.

AU - Sigmund, Elena C.

AU - Glocker, Cristina

AU - Saghafi, Shiva

AU - Pourpak, Zahra

AU - Ceja, Ruben

AU - Sassi, Atfa

AU - Graham, Laura E.

AU - Massaad, Michel J.

AU - Mellouli, Fethi

AU - Ben-Mustapha, Imen

AU - Khemiri, Monia

AU - Kilic, Sara Sebnem

AU - Etzioni, Amos

AU - Freeman, Alexandra F.

AU - Thiel, Jens

AU - Schulze, Ilka

AU - Al-Herz, Waleed

AU - Metin, Ayse

AU - Sanal, Özden

AU - Tezcan, Ilhan

AU - Yeganeh, Mehdi

AU - Niehues, Tim

AU - Dueckers, Gregor

AU - Weinspach, Sebastian

AU - Patiroglu, Turkan

AU - Unal, Ekrem

AU - Dasouki, Majed

AU - Yilmaz, Mustafa

AU - Genel, Ferah

AU - Aytekin, Caner

AU - Kutukculer, Necil

AU - Somer, Ayper

AU - Kilic, Mehmet

AU - Reisli, Ismail

AU - Camcioglu, Yildiz

AU - Gennery, Andrew R.

AU - Cant, Andrew J.

AU - Jones, Alison

AU - Gaspar, Bobby H.

AU - Arkwright, Peter D.

AU - Pietrogrande, Maria C.

AU - Baz, Zeina

AU - Al-Tamemi, Salem

AU - Lougaris, Vassilios

AU - Lefranc, Gerard

AU - Megarbane, Andre

AU - Boutros, Jeannette

AU - Galal, Nermeen

AU - Bejaoui, Mohamed

AU - Barbouche, Mohamed Ridha

AU - Geha, Raif S.

AU - Chatila, Talal A.

AU - Grimbacher, Bodo

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

AB - Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

KW - autosomal recessive hyper-IgE syndrome

KW - dedicator of cytokinesis 8

KW - hyper-IgE syndrome

KW - Molluscum contagiosum

KW - Primary combined immunodeficiency

KW - signal transducer and activator of transcription 3

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