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 Kütükcüler, Neslihan Karaca, Luis Gonzalez-Granado, Jordan Abbott, Daifulah Al-Zahrani, Nima Rezaei, Zeina Baz, Jens Thiel, Stephan Ehl, László Marodi, Jordan S. Orange, Julie Sawalle-Belohradsky, Sevgi Keles, Steven M. Holland, Özden Sanal, Deniz C. Ayvaz, Ilhan Tezcan, Hamoud Al-Mousa, Zobaida Alsum, Abbas Hawwari, Ayse Metin, Susanne Matthes-Martin, Manfred Hönig, Ansgar Schulz, Capucine Picard, Vincent Barlogis, Andrew Gennery, Marianne Ifversen, Joris van Montfrans, Taco Kuijpers, Robbert Bredius, Gregor Dückers, Waleed Al-Herz, Sung-Yun Pai, Raif Geha, Gundula Notheis, Carl-Philipp Schwarze, Betül 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, On behalf of the inborn errors working party of EBMT

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.