TY - JOUR
T1 - Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2
T2 - A cohort study
AU - Elkaim, Elodie
AU - Neven, Benedicte
AU - Bruneau, Julie
AU - Mitsui-Sekinaka, Kanako
AU - Stanislas, Aurelie
AU - Heurtier, Lucie
AU - Lucas, Carrie L.
AU - Matthews, Helen
AU - Deau, Marie Céline
AU - Sharapova, Svetlana
AU - Curtis, James
AU - Reichenbach, Janine
AU - Glastre, Catherine
AU - Parry, David A.
AU - Arumugakani, Gururaj
AU - McDermott, Elizabeth
AU - Kilic, Sara Sebnem
AU - Yamashita, Motoi
AU - Moshous, Despina
AU - Lamrini, Hicham
AU - Otremba, Burkhard
AU - Gennery, Andrew
AU - Coulter, Tanya
AU - Quinti, Isabella
AU - Stephan, Jean Louis
AU - Lougaris, Vassilios
AU - Brodszki, Nicholas
AU - Barlogis, Vincent
AU - Asano, Takaki
AU - Galicier, Lionel
AU - Boutboul, David
AU - Nonoyama, Shigeaki
AU - Cant, Andrew
AU - Imai, Kohsuke
AU - Picard, Capucine
AU - Nejentsev, Sergey
AU - Molina, Thierry Jo
AU - Lenardo, Michael
AU - Savic, Sinisa
AU - Cavazzana, Marina
AU - Fischer, Alain
AU - Durandy, Anne
AU - Kracker, Sven
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Background 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. Objectives We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results 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. Conclusion 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.
AB - Background 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. Objectives We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results 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. Conclusion 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.
KW - activated phosphoinositide 3-kinase δ syndrome
KW - adenopathy
KW - and immunodeficiency
KW - antibody deficiency
KW - hyper-IgM
KW - immunodeficiency
KW - lymphadenopathy
KW - p110δ
KW - p110δ-activating mutations causing senescent T cells
KW - p85α
KW - phosphoinositide 3-kinase
KW - Primary immunodeficiency
UR - http://www.scopus.com/inward/record.url?scp=84969583249&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2016.03.022
DO - 10.1016/j.jaci.2016.03.022
M3 - Article
C2 - 27221134
AN - SCOPUS:84969583249
SN - 0091-6749
VL - 138
SP - 210-218.e9
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -