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

被引：154

作者：

Engelhardt, Karin R. ^{[1
,2
,3
,4
]}

Gertz, Michael E. ^{[5
]}

Keles, Sevgi ^{[6
,7
,8
]}

Schaeffer, Alejandro A. ^{[5
]}

Sigmund, Elena C. ^{[3
]}

Glocker, Cristina ^{[3
]}

Saghafi, Shiva ^{[9
]}

Pourpak, Zahra ^{[9
]}

Ceja, Ruben ^{[6
,8
]}

Sassi, Atfa ^{[11
,12
]}

Graham, Laura E. ^{[1
,2
]}

Massaad, Michel J. ^{[8
]}

Mellouli, Fethi ^{[13
]}

Ben-Mustapha, Imen ^{[11
,12
]}

Khemiri, Monia ^{[14
]}

Kilic, Sara Sebnem ^{[15
]}

Etzioni, Amos ^{[16
,17
]}

Freeman, Alexandra F. ^{[18
]}

Thiel, Jens ^{[3
]}

Schulze, Ilka ^{[3
]}

Al-Herz, Waleed ^{[19
,20
]}

Metin, Ayse ^{[21
]}

Sanal, Oezden ^{[22
]}

Tezcan, Ilhan ^{[22
]}

Yeganeh, Mehdi ^{[10
]}

Niehues, Tim ^{[23
]}

Dueckers, Gregor ^{[23
]}

Weinspach, Sebastian ^{[24
]}

Patiroglu, Turkan ^{[25
]}

Unal, Ekrem ^{[26
]}

Dasouki, Majed ^{[27
]}

Yilmaz, Mustafa ^{[28
]}

Genel, Ferah ^{[29
]}

Aytekin, Caner ^{[30
]}

Kutukculer, Necil ^{[31
]}

Somer, Ayper ^{[32
]}

Kilic, Mehmet ^{[33
]}

Reisli, Ismail ^{[7
]}

Camcioglu, Yildiz ^{[34
]}

Gennery, Andrew R. ^{[4
]}

Cant, Andrew J. ^{[4
]}

Jones, Alison ^{[35
]}

Gaspar, Bobby H. ^{[35
]}

Arkwright, Peter D. ^{[36
]}

Pietrogrande, Maria C. ^{[37
]}

Baz, Zeina ^{[38
]}

Al-Tamemi, Salem ^{[39
]}

Lougaris, Vassilios ^{[40
,41
]}

Lefranc, Gerard ^{[42
,43
]}

Megarbane, Andre ^{[44
]}

机构：

[1] Royal Free Hosp, Dept Immunol & Mol Pathol, London, England

[2] UCL, London WC1E 6BT, England

[3] Univ Med Ctr Freiburg, CCI, Freiburg, Germany

[4] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[5] NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20892 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Div Immunol Allergy & Rheumatol, Los Angeles, CA 90095 USA

[7] Konya Necmettin Erbakan Univ, Div Pediat Allergy & Immunol, Konya, Turkey

[8] Childrens Hosp, Div Immunol, Boston, MA 02115 USA

[9] Univ Tehran Med Sci, Childrens Med Ctr, Immunol Asthma & Allergy Res Inst, Tehran, Iran

[10] Univ Tehran Med Sci, Childrens Med Ctr, Immunol Asthma & Allergy Res Inst, Tehran, Iran

[11] Pasteur Inst Tunis, Lab Immunol Vaccinol & Mol Genet, Tunis, Tunisia

[12] Univ Tunis El Manar, El Manar, Tunisia

[13] Bone Marrow Transplantat Ctr, Dept Pediat, Tunis, Tunisia

[14] Childrens Hosp, Dept Pediat, Tunis, Tunisia

[15] Uludag Univ, Dept Pediat Immunol, Fac Med, Bursa, Turkey

[16] Rambam Hlth Care Campus, Meyers Children Hosp, Haifa, Israel

[17] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel

[18] NIAID, Lab Clin Infect Dis, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA

[19] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait

[20] Al Sabah Hosp, Dept Pediat, Allergy & Clin Immunol Unit, Kuwait, Kuwait

[21] SB Ankara Diskapi Childrens Hosp, Pediat Immunol Unit, Ankara, Turkey

[22] Hacettepe Univ, Childrens Hosp, Div Immunol, Ankara, Turkey

[23] HELIOS Klinikum Krefeld, Zentrum Kinder & Jugendmed, Krefeld, Germany

[24] Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, Ctr Child & Adolescent Med, Dusseldorf, Germany

[25] Erciyes Univ, Fac Med, Div Pediat Hematol & Immunol, Dept Pediat, Kayseri, Turkey

[26] Erciyes Univ, Fac Med, Div Pediat Hematol & Oncol, Dept Pediat, Kayseri, Turkey

[27] Univ Kansas, Med Ctr, Dept Pediat, Kansas City, KS USA

[28] Cukurova Univ, Adana, Turkey

[29] Behcet Uz State Hosp, Div Pediat Immunol, Izmir, Turkey

[30] Dr Sami Ulus Matern & Childrens Hlth & Dis Traini, Dept Pediat Immunol, Ankara, Turkey

[31] Ege Univ, Fac Med, Dept Pediat, Izmir, Turkey

[32] Istanbul Univ, Istanbul Fac Med, Div Infect Dis & Immunol, Istanbul, Turkey

[33] Firat Univ, TR-23169 Elazig, Turkey

[34] Istanbul Univ, Cerrahpasa Med Fac, Div Pediat Allergy Immunol & Infect Dis, Istanbul, Turkey

[35] Great Ormond St Hosp Sick Children, Dept Immunol, London, England

[36] Univ Manchester, Royal Manchester Childrens Hosp, Manchester M13 9PL, Lancs, England

[37] Univ Milan, Dept Pediat, Fdn Policlin IRCCS, Milan, Italy

[38] St George Hosp Univ, Med Ctr, Dept Pediat, Beirut, Lebanon

[39] Sultan Qaboos Univ, Dept Pediat, Muscat, Oman

[40] Univ Brescia, Spedali Civili Brescia, Pediat Clin, I-25121 Brescia, Italy

[41] Univ Brescia, Spedali Civili Brescia, Inst Mol Med A Nocivelli, Dept Clin & Expt Sci, I-25121 Brescia, Italy

[42] Univ Montpellier 2, Montpellier, France

[43] CNRS, Inst Human Genet, Montpellier, France

[44] St Joseph Univ, Med Genet Unit, Beirut, Lebanon

[45] Cairo Univ, Specialized Pediat Hosp, Primary Immunodeficiency Clin, Cairo, Egypt

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2015年 / 136卷 / 02期

基金：

美国国家卫生研究院;

关键词：

Primary combined immunodeficiency; hyper-IgE syndrome; autosomal recessive hyper-IgE syndrome; dedicator of cytokinesis 8; signal transducer and activator of transcription 3; Molluscum contagiosum; HYPER-IGE SYNDROME; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; DOCK8; DEFICIENCY; MUTATIONS; IMMUNODEFICIENCY; STAT3; GLYCOSYLATION; DISORDER; SURVIVAL;

D O I：

10.1016/j.jaci.2014.12.1945

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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/mu L (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.

引用

页码：402 / 412

页数：11

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