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
Y1 - 2016
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 -
