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

Elodie Elkaim, Benedicte Neven, Julie Bruneau, Kanako Mitsui-Sekinaka, Aurelie Stanislas, Lucie Heurtier, Carrie L Lucas, Helen Matthews, Marie-Céline Deau, Svetlana Sharapova, James Curtis, Janine Reichenbach, Catherine Glastre, David A Parry, Gururaj Arumugakani, Elizabeth McDermott, Sara Sebnem Kilic, Motoi Yamashita, Despina Moshous, Hicham LamriniBurkhard Otremba, Andrew Gennery, Tanya Coulter, Isabella Quinti, Jean-Louis Stephan, Vassilios Lougaris, Nicholas Brodszki, Vincent Barlogis, Takaki Asano, Lionel Galicier, David Boutboul, Shigeaki Nonoyama, Andrew Cant, Kohsuke Imai, Capucine Picard, Sergey Nejentsev, Thierry Jo Molina, Michael Lenardo, Sinisa Savic, Marina Cavazzana, Alain Fischer, Anne Durandy, Sven Kracker

Research output: Contribution to journalArticleAcademicpeer-review

190 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)210-218.e9
JournalJournal of allergy and clinical immunology
Issue number1
Publication statusPublished - Jul 2016
Externally publishedYes


  • Adolescent
  • Adult
  • Alleles
  • Biopsy
  • CD8-Positive T-Lymphocytes/immunology
  • Child
  • Child, Preschool
  • Class I Phosphatidylinositol 3-Kinases/genetics
  • Cohort Studies
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Immunologic Deficiency Syndromes/diagnosis
  • Male
  • Middle Aged
  • Mutation
  • Phenotype
  • RNA Splice Sites
  • T-Lymphocyte Subsets/immunology
  • Young Adult

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