DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

Susanne E. Aydin; Sara Sebnem Kilic; Caner Aytekin; Ashish Kumar; Oscar Porras; Leena Kainulainen; Larysa Kostyuchenko; Ferah Genel; Necil Kutukculer; Neslihan Karaca; Luis Gonzalez-Granado; Jordan Abbott; Daifulah Al-Zahrani; Nima Rezaei; Zeina Baz; Jens Thiel; Stephan Ehl; Laszlo Marodi; Jordan S. Orange; Julie Sawalle-Belohradsky; Sevgi Keles; Steven M. Holland; Ozden Sanal; Deniz C. Ayvaz; Ilhan Tezcan; Hamoud Al-Mousa; Zobaida Alsum; Abbas Hawwari; Ayse Metin; Susanne Matthes-Martin; Manfred Hoenig; Ansgar Schulz; Capucine Picard; Vincent Barlogis; Andrew Gennery; Marianne Ifversen; JM van Montfrans; Taco Kuijpers; Robbert Bredius; Gregor Duckers; Waleed Al-Herz; Sung-Yun Pai; Raif Geha; Gundula Notheis; Carl-Philipp Schwarze; Betul Tavil; Fatih Azik; Kirsten Bienemann; Bodo Grimbacher; Valerie Heinz; H. Bobby Gaspar; Roland Aydin; Beate Hagl; Benjamin Gathmann; Bernd H. Belohradsky; Hans D. Ochs; Talal Chatila; Ellen D. Renner; Helen Su; Alexandra F. Freeman; Karin Engelhardt; Michael H. Albert

doi:10.1007/s10875-014-0126-0

DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

Susanne E. Aydin, Sara Sebnem Kilic, Caner Aytekin, Ashish Kumar, Oscar Porras, Leena Kainulainen, Larysa Kostyuchenko, Ferah Genel, Necil Kutukculer, Neslihan Karaca, Luis Gonzalez-Granado, Jordan Abbott, Daifulah Al-Zahrani, Nima Rezaei, Zeina Baz, Jens Thiel, Stephan Ehl, Laszlo Marodi, Jordan S. Orange, Julie Sawalle-BelohradskySevgi Keles, Steven M. Holland, Ozden Sanal, Deniz C. Ayvaz, Ilhan Tezcan, Hamoud Al-Mousa, Zobaida Alsum, Abbas Hawwari, Ayse Metin, Susanne Matthes-Martin, Manfred Hoenig, Ansgar Schulz, Capucine Picard, Vincent Barlogis, Andrew Gennery, Marianne Ifversen, JM van Montfrans, Taco Kuijpers, Robbert Bredius, Gregor Duckers, Waleed Al-Herz, Sung-Yun Pai, Raif Geha, Gundula Notheis, Carl-Philipp Schwarze, Betul Tavil, Fatih Azik, Kirsten Bienemann, Bodo Grimbacher, Valerie Heinz, H. Bobby Gaspar, Roland Aydin, Beate Hagl, Benjamin Gathmann, Bernd H. Belohradsky, Hans D. Ochs, Talal Chatila, Ellen D. Renner, Helen Su, Alexandra F. Freeman, Karin Engelhardt, Michael H. Albert

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

Abstract

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

Original language	English
Pages (from-to)	189-198
Number of pages	10
Journal	Journal of Clinical Immunology
Volume	35
Issue number	2
DOIs	https://doi.org/10.1007/s10875-014-0126-0
Publication status	Published - Feb 2015

Keywords

DOCK8 deficiency
combined immunodeficiency
hyper-IgE syndrome
natural outcome
HYPER-IGE SYNDROME
STEM-CELL TRANSPLANTATION
CYTOKINESIS 8 DEFICIENCY
WISKOTT-ALDRICH SYNDROME
MUTATIONS
DEDICATOR
STAT3
SURVIVAL
INFECTIONS
THERAPY

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Aydin, S. E., Kilic, S. S., Aytekin, C., Kumar, A., Porras, O., Kainulainen, L., Kostyuchenko, L., Genel, F., Kutukculer, N., Karaca, N., Gonzalez-Granado, L., Abbott, J., Al-Zahrani, D., Rezaei, N., Baz, Z., Thiel, J., Ehl, S., Marodi, L., Orange, J. S., ... Albert, M. H. (2015). DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients. Journal of Clinical Immunology, 35(2), 189-198. https://doi.org/10.1007/s10875-014-0126-0

@article{a882ba809b1641a0826794eb7a86d39c,

title = "DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients",

abstract = "Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.",

keywords = "DOCK8 deficiency, combined immunodeficiency, hyper-IgE syndrome, natural outcome, HYPER-IGE SYNDROME, STEM-CELL TRANSPLANTATION, CYTOKINESIS 8 DEFICIENCY, WISKOTT-ALDRICH SYNDROME, MUTATIONS, DEDICATOR, STAT3, SURVIVAL, INFECTIONS, THERAPY",

author = "Aydin, {Susanne E.} and Kilic, {Sara Sebnem} and Caner Aytekin and Ashish Kumar and Oscar Porras and Leena Kainulainen and Larysa Kostyuchenko and Ferah Genel and Necil Kutukculer and Neslihan Karaca and Luis Gonzalez-Granado and Jordan Abbott and Daifulah Al-Zahrani and Nima Rezaei and Zeina Baz and Jens Thiel and Stephan Ehl and Laszlo Marodi and Orange, {Jordan S.} and Julie Sawalle-Belohradsky and Sevgi Keles and Holland, {Steven M.} and Ozden Sanal and Ayvaz, {Deniz C.} and Ilhan Tezcan and Hamoud Al-Mousa and Zobaida Alsum and Abbas Hawwari and Ayse Metin and Susanne Matthes-Martin and Manfred Hoenig and Ansgar Schulz and Capucine Picard and Vincent Barlogis and Andrew Gennery and Marianne Ifversen and {van Montfrans}, JM and Taco Kuijpers and Robbert Bredius and Gregor Duckers and Waleed Al-Herz and Sung-Yun Pai and Raif Geha and Gundula Notheis and Carl-Philipp Schwarze and Betul Tavil and Fatih Azik and Kirsten Bienemann and Bodo Grimbacher and Valerie Heinz and Gaspar, {H. Bobby} and Roland Aydin and Beate Hagl and Benjamin Gathmann and Belohradsky, {Bernd H.} and Ochs, {Hans D.} and Talal Chatila and Renner, {Ellen D.} and Helen Su and Freeman, {Alexandra F.} and Karin Engelhardt and Albert, {Michael H.}",

year = "2015",

month = feb,

doi = "10.1007/s10875-014-0126-0",

language = "English",

volume = "35",

pages = "189--198",

journal = "Journal of Clinical Immunology",

issn = "0271-9142",

publisher = "Springer New York",

number = "2",

}

Aydin, SE, Kilic, SS, Aytekin, C, Kumar, A, Porras, O, Kainulainen, L, Kostyuchenko, L, Genel, F, Kutukculer, N, Karaca, N, Gonzalez-Granado, L, Abbott, J, Al-Zahrani, D, Rezaei, N, Baz, Z, Thiel, J, Ehl, S, Marodi, L, Orange, JS, Sawalle-Belohradsky, J, Keles, S, Holland, SM, Sanal, O, Ayvaz, DC, Tezcan, I, Al-Mousa, H, Alsum, Z, Hawwari, A, Metin, A, Matthes-Martin, S, Hoenig, M, Schulz, A, Picard, C, Barlogis, V, Gennery, A, Ifversen, M, van Montfrans, JM, Kuijpers, T, Bredius, R, Duckers, G, Al-Herz, W, Pai, S-Y, Geha, R, Notheis, G, Schwarze, C-P, Tavil, B, Azik, F, Bienemann, K, Grimbacher, B, Heinz, V, Gaspar, HB, Aydin, R, Hagl, B, Gathmann, B, Belohradsky, BH, Ochs, HD, Chatila, T, Renner, ED, Su, H, Freeman, AF, Engelhardt, K & Albert, MH 2015, 'DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients', Journal of Clinical Immunology, vol. 35, no. 2, pp. 189-198. https://doi.org/10.1007/s10875-014-0126-0

TY - JOUR

T1 - DOCK8 Deficiency

T2 - Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

AU - Aydin, Susanne E.

AU - Kilic, Sara Sebnem

AU - Aytekin, Caner

AU - Kumar, Ashish

AU - Porras, Oscar

AU - Kainulainen, Leena

AU - Kostyuchenko, Larysa

AU - Genel, Ferah

AU - Kutukculer, Necil

AU - Karaca, Neslihan

AU - Gonzalez-Granado, Luis

AU - Abbott, Jordan

AU - Al-Zahrani, Daifulah

AU - Rezaei, Nima

AU - Baz, Zeina

AU - Thiel, Jens

AU - Ehl, Stephan

AU - Marodi, Laszlo

AU - Orange, Jordan S.

AU - Sawalle-Belohradsky, Julie

AU - Keles, Sevgi

AU - Holland, Steven M.

AU - Sanal, Ozden

AU - Ayvaz, Deniz C.

AU - Tezcan, Ilhan

AU - Al-Mousa, Hamoud

AU - Alsum, Zobaida

AU - Hawwari, Abbas

AU - Metin, Ayse

AU - Matthes-Martin, Susanne

AU - Hoenig, Manfred

AU - Schulz, Ansgar

AU - Picard, Capucine

AU - Barlogis, Vincent

AU - Gennery, Andrew

AU - Ifversen, Marianne

AU - van Montfrans, JM

AU - Kuijpers, Taco

AU - Bredius, Robbert

AU - Duckers, Gregor

AU - Al-Herz, Waleed

AU - Pai, Sung-Yun

AU - Geha, Raif

AU - Notheis, Gundula

AU - Schwarze, Carl-Philipp

AU - Tavil, Betul

AU - Azik, Fatih

AU - Bienemann, Kirsten

AU - Grimbacher, Bodo

AU - Heinz, Valerie

AU - Gaspar, H. Bobby

AU - Aydin, Roland

AU - Hagl, Beate

AU - Gathmann, Benjamin

AU - Belohradsky, Bernd H.

AU - Ochs, Hans D.

AU - Chatila, Talal

AU - Renner, Ellen D.

AU - Su, Helen

AU - Freeman, Alexandra F.

AU - Engelhardt, Karin

AU - Albert, Michael H.

PY - 2015/2

Y1 - 2015/2

N2 - Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

AB - Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

KW - DOCK8 deficiency

KW - combined immunodeficiency

KW - hyper-IgE syndrome

KW - natural outcome

KW - HYPER-IGE SYNDROME

KW - STEM-CELL TRANSPLANTATION

KW - CYTOKINESIS 8 DEFICIENCY

KW - WISKOTT-ALDRICH SYNDROME

KW - MUTATIONS

KW - DEDICATOR

KW - STAT3

KW - SURVIVAL

KW - INFECTIONS

KW - THERAPY

U2 - 10.1007/s10875-014-0126-0

DO - 10.1007/s10875-014-0126-0

M3 - Article

C2 - 25627830

SN - 0271-9142

VL - 35

SP - 189

EP - 198

JO - Journal of Clinical Immunology

JF - Journal of Clinical Immunology

IS - 2

ER -

DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

Abstract

Keywords

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