Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

被引：315

作者：

Coulter, Tanya I. ^{[1
,2
]}

Chandra, Anita ^{[3
,4
,5
]}

Bacon, Chris M. ^{[6
,46
]}

Babar, Judith ^{[7
]}

Curtis, James ^{[5
]}

Screaton, Nick ^{[48
]}

Goodlad, John R. ^{[49
]}

Farmer, George ^{[8
]}

Steele, Cathal Laurence ^{[9
]}

Leahy, Timothy Ronan ^{[2
]}

Doffinger, Rainer ^{[3
,10
]}

Baxendale, Helen ^{[47
]}

Bernatoniene, Jolanta ^{[11
]}

Edgar, J. David M. ^{[9
]}

Longhurst, Hilary J. ^{[12
]}

Ehl, Stephan ^{[13
]}

Speckmann, Carsten ^{[13
,14
]}

Grimbacher, Bodo ^{[13
]}

Sediva, Anna ^{[15
]}

Milota, Tomas ^{[15
]}

Faust, Saul N. ^{[16
,17
,18
]}

Williams, Anthony P. ^{[16
,17
]}

Hayman, Grant ^{[19
,20
]}

Kucuk, Zeynep Yesim ^{[21
]}

Hague, Rosie ^{[50
]}

French, Paul ^{[51
]}

Brooker, Richard D ^{[22
]}

Forsyth, Peter ^{[8
]}

Herriot, Richard ^{[22
]}

Cancrini, Caterina ^{[9
]}

Palma, Paolo ^{[23
,24
]}

Ariganello, Paola ^{[23
,24
]}

Conlon, Niall ^{[1
]}

Feighery, Conleth ^{[1
]}

Gavin, Patrick J. ^{[2
]}

Jones, Alison ^{[25
]}

Imai, Kohsuke ^{[52
]}

Ibrahim, Mohammad A ^{[26
]}

Markelj, Gasper ^{[27
]}

Abinun, Mario ^{[28
,45
]}

Rieux-Laucat, Frederic ^{[30
,31
]}

Latour, Sylvain ^{[30
,31
]}

Pellier, Isabelle ^{[33
,34
,35
,36
]}

Fischer, Alain ^{[30
,31
,32
,37
]}

Touzot, Fabien ^{[29
,30
,31
]}

Casanova, Jean-Laurent ^{[30
,32
,38
,39
,40
]}

Durandy, Anne ^{[30
,31
]}

Burns, Siobhan O ^{[41
]}

Savic, Sinisa ^{[13
,42
]}

Kumararatne, D. S. ^{[3
]}

机构：

[1] Trinity Coll Dublin, Sch Med, Dept Immunol, Dublin, Ireland

[2] Our Ladys Childrens Hosp Crumlin, Dept Paediat Immunol & Infect Dis, Dublin, Ireland

[3] Addenbrookes Hosp, Dept Clin Biochem & Immunol, Cambridge, England

[4] Babraham Inst, Lymphocyte Signalling & Dev, Cambridge, England

[5] Univ Cambridge, Dept Med, Cambridge, England

[6] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England

[7] Cambridge Univ Hosp NHS Fdn Trust, Dept Radiol, Cambridge, England

[8] Raigmore Hosp, Inverness, Scotland

[9] Royal Hosp, Reg Immunol Serv, Belfast, Antrim, North Ireland

[10] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England

[11] Bristol Royal Hosp Children, Univ Hosp Bristol NHS Fdn Trust, Dept Infect Dis & Immunol, London, England

[12] Barts Hlth NHS Trust, London, England

[13] Univ Hosp Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany

[14] Univ Med Ctr, Dept Pediat & Adolescent Med, Freiburg, Germany

[15] Univ Hosp Motol, Inst Immunol, Prague, Czech Republic

[16] Univ Southampton, Fac Med, Southampton, Hants, England

[17] Univ Southampton, Inst Life Sci, Southampton, Hants, England

[18] Univ Hosp Southampton NHS Fdn Trust, NIHR Wellcome Trust Clin Res Facil, Southampton, Hants, England

[19] Epsom, Dept Immunol, Surrey, England

[20] St Helier Univ Hosp NHS Trust, Surrey, England

[21] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA

[22] Royal Aberdeen Childrens Hosp, Aberdeen, Scotland

[23] Osped Pediat Bambino Gesu, Dept Pediat, Rome, Italy

[24] Univ Roma Tor Vergata, Rome, Italy

[25] Great Ormond St Hosp NHS Fdn Trust, Dept Immunol, London, England

[26] Kings Coll Hosp NHS Fdn Trust, Kings Hlth Partners, Kings Coll London, Sch Med,Div Asthma Allergy & Lung Biol,Dept Immun, London, England

[27] Univ Childrens Hosp, Univ Med Ctr, Dept Allergol Rheumatol & Clin Immunol, Ljubljana, Slovenia

[28] Newcastle Upon Tyne Hosp NHS Fdn Trust, Dept Paediat Immunol, Newcastle Upon Tyne, Tyne & Wear, England

[29] Necker Childrens Hosp, AP HP, Ctr Invest Clin Integre Biotherapies, Dept Biotherapie, Paris, France

[30] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, Paris, France

[31] INSERM UMR1163, Paris, France

[32] Necker Childrens Hosp, AP HP, Dept Pediat Immunol Hematol & Rheumatol, Paris, France

[33] CHU Angers, Unite Oncohematoimmunol Pediat, Angers, France

[34] AP HP, Ctr Reference Deficits Immunitaires Hereditaires, Paris, France

[35] Inserm UMR 892, Angers, France

[36] CNRS UMR 6299, Angers, France

[37] Coll France, Paris, France

[38] Necker Childrens Hosp, Imagine Inst, INSERM UMR1163, Lab Human Genet Infect Dis,Necker Branch, Paris, France

[39] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA

[40] Howard Hughes Med Inst, Chevy Chase, MD USA

[41] UCL, Inst Immun & Transplantat, London, England

[42] St James Univ Hosp, Dept Clin Immunol & Allergy, Leeds, W Yorkshire, England

[43] UCL, UCL Canc Inst, London, England

[44] Univ Sheffield, Dept Infect Immun & Cardiovasc Dis, Sheffield S10 2RX, S Yorkshire, England

[45] Newcastle Univ, Newcastle Upon Tyne Hosp NHS Trust, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[46] Newcastle Upon Tyne NHS Fdn Trust, Northern England Haematooncol Diagnost Serv, Newcastle Upon Tyne, Tyne & Wear, England

[47] Papworth Everard, Papworth Hosp NHS Trust, Cambridge, England

[48] Papworth Everard Hosp, Papworth Hosp NHS Fdn Trust, Dept Radiol, Cambridge, England

[49] Western Gen Hosp, Dept Pathol, Edinburgh, Midlothian, Scotland

[50] Dept Royal Hosp Children, Glasgow, Lanark, Scotland

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2017年 / 139卷 / 02期

基金：

欧洲研究理事会; 英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

Activated phosphoinositide 3-kinase delta syndrome; p110 delta-activating mutation causing senescent T cells; lymphadenopathy; immunodeficiency; phosphoinositide 3-kinase delta; PIK3CD gene; bronchiectasis; hematopoietic stem cell; transplantation; phosphoinositide 3-kinase inhibitor; COMMON VARIABLE IMMUNODEFICIENCY; HYPER-IGM SYNDROME; B-CELL; REFERENCE VALUES; IMMUNOLOGICAL FEATURES; P110; DELTA; P110-DELTA; MUTATIONS; PIK3CD; CT;

D O I：

10.1016/j.jaci.2016.06.021

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase delta (PI3K delta). Objective: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. Methods: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Results: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3K delta in the central nervous system; consistent with this, PI3K delta is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3K delta inhibitors offer new prospects for APDS treatment.

引用

页码：597 / +

页数：14

共 41 条

[31] Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization [J].

Peng, Juan ;

Awad, Aline ;

Sar, Sokhavuth ;

Komaiha, Ola Hamze ;

Moyano, Romina ;

Rayal, Amel ;

Samuel, Didier ;

Shewan, Annette ;

Vanhaesebroeck, Bart ;

Mostov, Keith ;

Gassama-Diagne, Ama .

NATURE COMMUNICATIONS, 2015, 6

[32] B Cell Subsets in Healthy Children: Reference Values for Evaluation of B Cell Maturation Process in Peripheral Blood [J].

Piatosa, Barbara ;

Wolska-Kusnierz, Beata ;

Pac, Malgorzata ;

Siewiera, Katarzyna ;

Galkowska, Ewa ;

Bernatowska, Ewa .

CYTOMETRY PART B-CLINICAL CYTOMETRY, 2010, 78B (06) :372-381

[33] Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency [J].

Quinti, Isabella ;

Soresina, Annarosa ;

Spadaro, Giuseppe ;

Martino, Silvana ;

Donnanno, Simona ;

Agostini, Carlo ;

Claudio, Pignata ;

Franco, Dammacco ;

Pesce, Anna Maria ;

Borghese, Federica ;

Guerra, Andrea ;

Rondelli, Roberto ;

Plebani, Alessandro .

JOURNAL OF CLINICAL IMMUNOLOGY, 2007, 27 (03) :308-316

[34]

Sawyer C, 2003, CANCER RES, V63, P1667

[35] Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes [J].

Spinelli, Laura ;

Black, Fiona M. ;

Berg, Jonathan N. ;

Eickholt, Britta J. ;

Leslie, Nicholas R. .

JOURNAL OF MEDICAL GENETICS, 2015, 52 (02) :128-134

[36] Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death [J].

Suarez-Fueyo, Abel ;

Barber, Domingo F. ;

Martinez-Ara, Jorge ;

Zea-Mendoza, Antonio C. ;

Carrera, Ana C. .

JOURNAL OF IMMUNOLOGY, 2011, 187 (05) :2376-2385

[37] Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings [J].

Thickett, KM ;

Kumararatne, DS ;

Banerjee, AK ;

Dudley, R ;

Stableforth, DE .

QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, 2002, 95 (10) :655-662

[38] p110 delta, a novel phosphoinositide 3-kinase in leukocytes [J].

Vanhaesebroeck, B ;

Welham, MJ ;

Kotani, K ;

Stein, R ;

Warne, PH ;

Zvelebil, MJ ;

Higashi, K ;

Volinia, S ;

Downward, J ;

Waterfield, MD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (09) :4330-4335

[39] Isoform-selective induction of human p110δ PI3K expression by TNFα: identification of a new and inducible PIK3CD promoter [J].

Whitehead, Maria A. ;

Bombardieri, Michele ;

Pitzalis, Costantino ;

Vanhaesebroeck, Bart .

BIOCHEMICAL JOURNAL, 2012, 443 :857-867

[40] The X-linked hyper-IgM syndrome - Clinical and immunologic features of 79 patients [J].

Winkelstein, JA ;

Marino, MC ;

Ochs, H ;

Fuleihan, R ;

Scholl, PR ;

Geha, R ;

Stiehm, ER ;

Conley, ME .

MEDICINE, 2003, 82 (06) :373-384

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