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

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...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Journal of allergy and clinical immunology 2015-08, Vol.136 (2), p.402-412
Hauptverfasser:	Engelhardt, Karin R., PhD, Gertz, Michael E., PhD, Keles, Sevgi, MD, Schäffer, Alejandro A., PhD, Sigmund, Elena C., BSc, Glocker, Cristina, PhD, Saghafi, Shiva, MSc, Pourpak, Zahra, MD, PhD, Ceja, Ruben, MSc, Sassi, Atfa, PhD, Graham, Laura E., BSc, MBChB, Massaad, Michel J., PhD, Mellouli, Fethi, MD, Ben-Mustapha, Imen, MD, Khemiri, Monia, MD, Kilic, Sara Sebnem, MD, Etzioni, Amos, MD, Freeman, Alexandra F., MD, Thiel, Jens, MD, Schulze, Ilka, MD, Al-Herz, Waleed, MD, Metin, Ayse, MD, PhD, Sanal, Özden, MD, Tezcan, Ilhan, MD, Yeganeh, Mehdi, MD, Niehues, Tim, MD, Dueckers, Gregor, MD, Weinspach, Sebastian, MD, Patiroglu, Turkan, MD, Unal, Ekrem, MD, Dasouki, Majed, MD, Yilmaz, Mustafa, MD, Genel, Ferah, MD, Aytekin, Caner, MD, Kutukculer, Necil, MD, Somer, Ayper, MD, Kilic, Mehmet, MD, Reisli, Ismail, MD, Camcioglu, Yildiz, MD, Gennery, Andrew R., MD, Cant, Andrew J., MD, Jones, Alison, MD, Gaspar, Bobby H., MD, Arkwright, Peter D., MD, DPhil, Pietrogrande, Maria C., MD, Baz, Zeina, MD, Al-Tamemi, Salem, MD, Lougaris, Vassilios, MD, Lefranc, Gerard, PhD, Megarbane, Andre, MD, PhD, Boutros, Jeannette, MD, Galal, Nermeen, MD, Bejaoui, Mohamed, MD, Barbouche, Mohamed-Ridha, MD, PhD, Geha, Raif S., MD, Chatila, Talal A., MD, MSc, Grimbacher, Bodo, MD
Format:	Artikel
Sprache:	eng
Schlagworte:	Adolescent Adult Allergy and Immunology Antigens, Bacterial Antigens, Bacterial - blood Antigens, Bacterial - immunology Antigens, Viral Antigens, Viral - blood Antigens, Viral - immunology autosomal recessive hyper-IgE syndrome Bacterial Infections Bacterial Infections - complications Bacterial Infections - genetics Bacterial Infections - immunology Bacterial Infections - mortality CD4-Positive T-Lymphocytes CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - pathology CD8-Positive T-Lymphocytes CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - pathology Child Child, Preschool dedicator of cytokinesis 8 Deoxyribonucleic acid DNA Eosinophils Eosinophils - immunology Eosinophils - pathology Families & family life Female Genotype & phenotype Guanine Nucleotide Exchange Factors Guanine Nucleotide Exchange Factors - deficiency Guanine Nucleotide Exchange Factors - genetics Guanine Nucleotide Exchange Factors - immunology Humans hyper-IgE syndrome Immunoglobulin E Immunoglobulin E - blood Immunoglobulin E - genetics Immunoglobulin M Immunoglobulin M - blood Immunoglobulin M - genetics Immunoglobulins Infant Job Syndrome Job Syndrome - complications Job Syndrome - genetics Job Syndrome - immunology Job Syndrome - mortality Laboratories Life Sciences Lymphocyte Count Lymphocytes Lymphoma Male Middle Aged Molluscum contagiosum Mutation Phenotype Primary combined immunodeficiency signal transducer and activator of transcription 3 Skin Diseases Skin Diseases - complications Skin Diseases - genetics Skin Diseases - immunology Skin Diseases - mortality STAT3 Transcription Factor STAT3 Transcription Factor - genetics STAT3 Transcription Factor - immunology Support Vector Machine Survival Analysis Viral infections Virus Diseases Virus Diseases - complications Virus Diseases - genetics Virus Diseases - immunology Virus Diseases - mortality
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
ISSN:	0091-6749 1097-6825
DOI:	10.1016/j.jaci.2014.12.1945