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

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...

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Published in:Journal of clinical immunology 2015-02, Vol.35 (2), p.189-198
Main Authors: Aydin, Susanne E., Kilic, Sara Sebnem, Aytekin, Caner, Kumar, Ashish, Porras, Oscar, Kainulainen, Leena, Kostyuchenko, Larysa, Genel, Ferah, Kütükcüler, Necil, Karaca, Neslihan, Gonzalez-Granado, Luis, Abbott, Jordan, Al-Zahrani, Daifulah, Rezaei, Nima, Baz, Zeina, Thiel, Jens, Ehl, Stephan, Marodi, László, Orange, Jordan S., Sawalle-Belohradsky, Julie, Keles, Sevgi, Holland, Steven M., Sanal, Özden, Ayvaz, Deniz C., Tezcan, Ilhan, Al-Mousa, Hamoud, Alsum, Zobaida, Hawwari, Abbas, Metin, Ayse, Matthes-Martin, Susanne, Hönig, Manfred, Schulz, Ansgar, Picard, Capucine, Barlogis, Vincent, Gennery, Andrew, Ifversen, Marianne, van Montfrans, Joris, Kuijpers, Taco, Bredius, Robbert, Dückers, Gregor, Al-Herz, Waleed, Pai, Sung-Yun, Geha, Raif, Notheis, Gundula, Schwarze, Carl-Philipp, Tavil, Betül, Azik, Fatih, Bienemann, Kirsten, Grimbacher, Bodo, Heinz, Valerie, Gaspar, H. Bobby, Aydin, Roland, Hagl, Beate, Gathmann, Benjamin, Belohradsky, Bernd H., Ochs, Hans D., Chatila, Talal, Renner, Ellen D., Su, Helen, Freeman, Alexandra F., Engelhardt, Karin, Albert, Michael H.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Biomedical and Life Sciences
Biomedicine
Child
Child, Preschool
Cohort Studies
Female
Follow-Up Studies
Genetic Association Studies
Guanine Nucleotide Exchange Factors - deficiency
Guanine Nucleotide Exchange Factors - genetics
Humans
Immunoglobulin E - blood
Immunoglobulin E - immunology
Immunology
Incidence
Infant
Infection - diagnosis
Infection - epidemiology
Infection - etiology
Infectious Diseases
Internal Medicine
Job Syndrome - complications
Job Syndrome - diagnosis
Job Syndrome - genetics
Job Syndrome - immunology
Job Syndrome - mortality
Job Syndrome - therapy
Lymphocyte Count
Lymphocyte Subsets - immunology
Lymphocyte Subsets - metabolism
Male
Medical Microbiology
Middle Aged
Mutation
Neoplasms - epidemiology
Neoplasms - etiology
Original Research
Phenotype
Young Adult
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Summary: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.
ISSN:0271-9142
1573-2592
DOI:10.1007/s10875-014-0126-0