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

Elkaim, Elodie; Neven, Benedicte; Bruneau, Julie; Mitsui-Sekinaka, Kanako; Stanislas, Aurelie; Heurtier, Lucie; Lucas, Carrie L.; Matthews, Helen; Deau, Marie Céline and Sharapova, Svetlana, et al. (2015) In Journal of Allergy and Clinical Immunology
Abstract

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... (More)

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.

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Activated phosphoinositide 3-kinase δ syndrome, Adenopathy, And immunodeficiency, Antibody deficiency, Hyper-IgM, Immunodeficiency, Lymphadenopathy, P110δ, P110δ-activating mutations causing senescent T cells, P85α, Phosphoinositide 3-kinase, Primary immunodeficiency
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Journal of Allergy and Clinical Immunology
publisher
Elsevier
external identifiers
  • Scopus:84969583249
ISSN
0091-6749
DOI
10.1016/j.jaci.2016.03.022
language
English
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no
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ce0fb429-6301-437e-a33a-3481f5fdf0c5
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2016-07-04 14:21:51
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2016-11-20 04:34:37
@misc{ce0fb429-6301-437e-a33a-3481f5fdf0c5,
  abstract     = {<p>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.</p>},
  author       = {Elkaim, Elodie and Neven, Benedicte and Bruneau, Julie and Mitsui-Sekinaka, Kanako and Stanislas, Aurelie and Heurtier, Lucie and Lucas, Carrie L. and Matthews, Helen and Deau, Marie Céline and Sharapova, Svetlana and Curtis, James and Reichenbach, Janine and Glastre, Catherine and Parry, David A. and Arumugakani, Gururaj and McDermott, Elizabeth and Kilic, Sara Sebnem and Yamashita, Motoi and Moshous, Despina and Lamrini, Hicham and Otremba, Burkhard and Gennery, Andrew and Coulter, Tanya and Quinti, Isabella and Stephan, Jean Louis and Lougaris, Vassilios and Brodszki, Nicholas and Barlogis, Vincent and Asano, Takaki and Galicier, Lionel and Boutboul, David and Nonoyama, Shigeaki and Cant, Andrew and Imai, Kohsuke and Picard, Capucine and Nejentsev, Sergey and Molina, Thierry Jo and Lenardo, Michael and Savic, Sinisa and Cavazzana, Marina and Fischer, Alain and Durandy, Anne and Kracker, Sven},
  issn         = {0091-6749},
  keyword      = {Activated phosphoinositide 3-kinase δ syndrome,Adenopathy,And immunodeficiency,Antibody deficiency,Hyper-IgM,Immunodeficiency,Lymphadenopathy,P110δ,P110δ-activating mutations causing senescent T cells,P85α,Phosphoinositide 3-kinase,Primary immunodeficiency},
  language     = {eng},
  month        = {10},
  publisher    = {ARRAY(0xbc7a8a0)},
  series       = {Journal of Allergy and Clinical Immunology},
  title        = {Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2 : A cohort study},
  url          = {http://dx.doi.org/10.1016/j.jaci.2016.03.022},
  year         = {2015},
}