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    DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients
    (Springer New York LLC, 2015) Aydin S.E.; Kilic S.S.; Aytekin C.; Kumar A.; Porras O.; Kainulainen L.; Kostyuchenko L.; Genel F.; Kütükcüler N.; Karaca N.; Gonzalez-Granado L.; Abbott J.; Al-Zahrani D.; Rezaei N.; Baz Z.; Thiel J.; Ehl S.; Marodi L.; Orange J.S.; Sawalle-Belohradsky J.; Keles S.; Holland S.M.; Sanal Ö.; Ayvaz D.C.; Tezcan I.; Al-Mousa H.; Alsum Z.; Hawwari A.; Metin A.; Matthes-Martin S.; Hönig M.; Schulz A.; Picard C.; Barlogis V.; Gennery A.; Ifversen M.; van Montfrans J.; Kuijpers T.; Bredius R.; Dückers 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 H.B.; Aydin R.; Hagl B.; Gathmann B.; Belohradsky B.H.; Ochs H.D.; Chatila T.; Renner E.D.; Su H.; Freeman A.F.; Engelhardt K.; Albert M.H.
    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. © 2015, Springer Science+Business Media New York.
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    The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency
    (Mosby Inc., 2015) Engelhardt K.R.; Gertz M.E.; Keles S.; Schäffer A.A.; Sigmund E.C.; Glocker C.; Saghafi S.; Pourpak Z.; Ceja R.; Sassi A.; Graham L.E.; Massaad M.J.; Mellouli F.; Ben-Mustapha I.; Khemiri M.; Kilic S.S.; Etzioni A.; Freeman A.F.; 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 A.R.; Cant A.J.; Jones A.; Gaspar B.H.; Arkwright P.D.; Pietrogrande M.C.; Baz Z.; Al-Tamemi S.; Lougaris V.; Lefranc G.; Megarbane A.; Boutros J.; Galal N.; Bejaoui M.; Barbouche M.-R.; Geha R.S.; Chatila T.A.; Grimbacher B.
    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. © 2015 American Academy of Allergy, Asthma & Immunology.