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Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

2016; Elsevier BV; Volume: 138; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2016.03.022

1097-6825

Élodie Elkaim, Bénédicte Neven, Julie Bruneau, Kanako Mitsui-Sekinaka, Aurélie Stanislas, Lucie Heurtier, C. Lucas, Helen Matthews, Marie‐Céline Deau, Svetlana O. Sharapova, James Curtis, Janine Reichenbach, Catherine Glastre, David Parry, Gururaj Arumugakani, Elizabeth McDermott, Sara Şebnem Kılıç, Motoi Yamashita, Despina Moshous, Hicham Lamrini, Burkhard Otremba, Andrew R. Gennery, Tanya Coulter, Isabella Quinti, Jean‐Louis Stéphan, Vassilios Lougaris, Nicholas Brodszki, Vincent Barlogis, Takaki Asano, Lionel Galicier, David Boutboul, Shigeaki Nonoyama, Andrew J. Cant, Kohsuke Imai, Capucine Pïcard, Sergey Nejentsev, Thierry Jo Molina, Michael J. Lenardo, Sinisa Savic, Marina Cavazzana, Alain Fischer, Anne Durandy, Sven Kracker,

Blood disorders and treatments

Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases.We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort.The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed.Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications.APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.