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 Lamrini; Burkhard 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

doi:10.1016/j.jaci.2016.03.022

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 journal › Article › Academic › peer-review

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 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 language	English
Pages (from-to)	210-218.e9
Journal	Journal of Allergy and Clinical Immunology
Volume	138
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2016.03.022
Publication status	Published - Jul 2016
Externally published	Yes

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10.1016/j.jaci.2016.03.022

Cite this

Elkaim, E., Neven, B., Bruneau, J., Mitsui-Sekinaka, K., Stanislas, A., Heurtier, L., Lucas, C. L., Matthews, H., Deau, M-C., Sharapova, S., Curtis, J., Reichenbach, J., Glastre, C., Parry, D. A., Arumugakani, G., McDermott, E., Kilic, S. S., Yamashita, M., Moshous, D., ... Kracker, S. (2016). Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study. Journal of Allergy and Clinical Immunology, 138(1), 210-218.e9. https://doi.org/10.1016/j.jaci.2016.03.022

@article{e06cb96e967b484a80b0303960007f1d,

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

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 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.",

keywords = "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",

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

year = "2016",

month = jul,

doi = "10.1016/j.jaci.2016.03.022",

language = "English",

volume = "138",

pages = "210--218.e9",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "1",

}

Elkaim, E, Neven, B, Bruneau, J, Mitsui-Sekinaka, K, Stanislas, A, Heurtier, L, Lucas, CL, Matthews, H, Deau, M-C, Sharapova, S, Curtis, J, Reichenbach, J, Glastre, C, Parry, DA, Arumugakani, G, McDermott, E, Kilic, SS, Yamashita, M, Moshous, D, Lamrini, H, Otremba, B, Gennery, A, Coulter, T, Quinti, I, Stephan, J-L, Lougaris, V, Brodszki, N, Barlogis, V, Asano, T, Galicier, L, Boutboul, D, Nonoyama, S, Cant, A, Imai, K, Picard, C, Nejentsev, S, Molina, TJ, Lenardo, M, Savic, S, Cavazzana, M, Fischer, A, Durandy, A & Kracker, S 2016, 'Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study', Journal of Allergy and Clinical Immunology, vol. 138, no. 1, pp. 210-218.e9. https://doi.org/10.1016/j.jaci.2016.03.022

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

Y1 - 2016/7

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 - Adolescent

KW - Adult

KW - Alleles

KW - Biopsy

KW - CD8-Positive T-Lymphocytes/immunology

KW - Child

KW - Child, Preschool

KW - Class I Phosphatidylinositol 3-Kinases/genetics

KW - Cohort Studies

KW - Female

KW - Gene Frequency

KW - Genotype

KW - Humans

KW - Immunologic Deficiency Syndromes/diagnosis

KW - Male

KW - Middle Aged

KW - Mutation

KW - Phenotype

KW - RNA Splice Sites

KW - T-Lymphocyte Subsets/immunology

KW - Young Adult

U2 - 10.1016/j.jaci.2016.03.022

DO - 10.1016/j.jaci.2016.03.022

M3 - Article

C2 - 27221134

VL - 138

SP - 210-218.e9

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 1

ER -