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

BACKGROUND: Activated phosphoinositide 3-kinase δ 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 δ (PI3Kδ). 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 PI3Kδ in the central nervous system; consistent with this, PI3Kδ 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 PI3Kδ inhibitors offer new prospects for APDS treatment.T.C. is supported by National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland. A.C. has a Wellcome Trust Postdoctoral Training Fellowship for Clinicians (103413/Z/13/Z). K.O. is supported by funding from BBSRC, MRC, Wellcome Trust and GSK. R.D. and D.S.K are funded by National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. C.S. and S.E. are supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803 grant to the Center of Chronic immunodeficiency and BMBF 01GM1111B grant to the PID-NET initiative). S.N.F is supported in part by the Southampton UK National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility and NIHR Respiratory Biomedical Research Unit. M.A.A.I. is funded by NHS Innovation London and King’s College Hospital Charitable Trust. A.F., S.L., A.D., F.R-L and S.K. are supported by the European Union’s 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE contract 249816) and a government grant managed by the French Agence Nationale de la Recherche as part of the "Investments for the Future" program (ANR-10-IAHU-01). S.L. is supported by the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0028-01), the Foundation ARC pour la Recherche sur le Cancer (France), the Rare Diseases Foundation (France) and François Aupetit Association (France). S.L. is a senior scientist and S.K is a researcher at the Centre National de la Recherche Scientifique-CNRS (France). A.D. and S.K. are supported by the “Institut National de la Santé et de la Recherche Médicale". S.K. also supported by the Fondation pour la Recherche Médicale (grant number: ING20130526624), la Ligue Contre le Cancer (Comité de Paris) and the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH). S.O.B is supported by the Higher Education Funding Council for England. B.V. is supported by the UK Biotechnology and Biological Sciences Research Council [BB/I007806/1], Cancer Research UK [C23338/A15965) and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. B.V. is consultant to Karus Therapeutics (Oxford, UK). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z). S.N. is also supported by the European Research Council Starting grant 260477, the EU FP7 collaborative grant 261441 (PEVNET project) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, UK. A.M.C. is funded by the Medical Research Council, British Lung Foundation, University of Sheffield and Cambridge NIHR-BRC. Research in A.M.C. laboratory has received non-commercial grant support from GSK, Novartis, and MedImmune.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jaci.2016.06.02

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Causes, devenir et thérapeutiques des malades avec hypogammaglobulinémie

L hypogammaglobulinémie est un déficit de l immunité humorale qui est caractérisée par une altération de la production d anticorps aussi appelés immunoglobulines. On classe les étiologies des hypogammaglobulinémies suivant la pathologie ou le trouble qui occasionne une diminution des Immunoglobulines de type G en particulier. Si le Déficit Immunitaire Commun Variable (DICV) est le plus fréquent des déficits primitifs, il faut savoir que de nombreux déficits secondaires ont une origine médicamenteuse. La problématique infectieuse est très importante chez ces patients, notamment au niveau pulmonaire, ORL et digestif. La prise en charge de ce type de déficit immunitaire passe par deux thérapeutiques phares, l antibioprophylaxie et la substitution en immunoglobulines injectables. Le diagnostic précoce d hypogammaglobulinémie permet d améliorer le pronostic des patients et de proposer une prise en charge adaptée. Notre étude porte sur les caractéristiques étiologiques des hypogammaglobulinémies, les devenirs et thérapeutiques des patients suivis au CHU d Angers entre 2005 et 2010, pour lesquels le dosage d IgG en 2005 était inférieur à la normale.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Evaluation de la thymopoïèse des enfants et adultes traités pour un lymphome de Hodgkin à distance d'un traitement par radiothérapie médiastinale

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Le syndrome de Wiskott-Aldrich

International audienceW iskott-Aldrich syndrome (WAS) is a primary immunode- ficiency disorder, characterized by a classic triad of microthrombocytopenia, eczema and infections. It is a monogenic X-linked recessive disorder. X-linked thrombocy- topenia (XLT) is now part of this syndrome with clinical forms initially described as less severe, but whose non-serious evolution is now questioned. WAS/XLT usually occurs during childhood, but a neonatal onset is possible. This pathology is associated with an increased risk of autoimmune manifesta- tions and onco-hematological complications which can occur regardless of the initial severity. The first manifestations are hemorrhagic (petechiae, bruising, purpura, epistaxis, oral or intracranial bleeding, bloody diarrhea). The second characte- ristic is acute or chronic eczema. Due to the immune deficiency, there are infectious manifestations (airways, digestive tract, skin) due to conventional or opportunistic bacteria. The severity of the disease, in addition to severe infectious complications, is linked to autoimmune manifestations in more than 40% of cases (hemolytic anemia and/or autoimmune neutropenia, vasculitis, inflammatory colitis, glomerulopathy, inflammatory joint pathologies). Patients with WAS also have an increased risk of developing tumors (especially lymphomas) at any age. Therapeutic progress in recent years are based on better management of complications, better results of bone marrow transplantation and development of gene therapy

Diagnostic biologique des déficits immunitaires primitifs

International audienceLe diagnostic précoce des déficits immuni-taires primitifs (DIP) est un élément clé pour une prise en charge adéquate des patients, afin de limiter la survenue de complications. Les manifestations cliniques et biologiques des DIP sont variées, incluant les infections récurrentes, mais aussi des manifestations oncologiques ou auto immunes. Des exa-mens biologiques simples, tels que l'hémo-gramme, le dosage pondéral des immuno-globulines et les sérologies post-vaccinales, peuvent permettre d'orienter le diagnostic étiologique. Des analyses plus spécialisées, comme le phénotypage lymphocytaire ou le dosage des sous classes d'IgG peuvent être réalisées en seconde intention. L'ensemble de ces examens nécessitent une interpré-tation rigoureuse en tenant notamment compte de l'âge du patient et du spectre infectieux

CD21 deficiency in two siblings with recurrent respiratory infections and hypogammaglobulinemia

International audienceno abstrac

CD21 deficiency in two siblings with recurrent respiratory infections and hypogammaglobulinemia

International audienceno abstrac

Long-term visual acuity in patients with optic pathway glioma treated during childhood with up-front BB-SFOP chemotherapy-Analysis of a French pediatric historical cohort.

BackgroundVisual outcome is one of the main issues in the treatment of optic pathway glioma in childhood. Although the prognostic factors of low vision have been discussed extensively, no reliable indicators for visual loss exist. Therefore, we aimed to define initial and evolving factors associated with long-term vision loss.MethodsWe conducted a multicenter historical cohort study of children treated in France with up-front BB-SFOP chemotherapy between 1990 and 2004. Visual acuity performed at the long-term follow-up visit or within 6 months prior was analyzed. Logistic regression analysis was used to estimate the effects of clinical and radiological factors on long-term visual outcome.FindingsOf the 180 patients in the cohort, long-term visual acuity data were available for 132 (73.3%) patients (median follow-up: 14.2 years; range: 6.1-25.6). At the last follow-up, 61/132 patients (46.2%) had impaired vision, and 35 of these patients (57.3%) were partially sighted or blind. Multivariate analysis showed that factors associated with a worse prognosis for long-term visual acuity were an age at diagnosis of InterpretationOur study confirms that a large proportion of children with optic pathway glioma have poor long-term outcomes of visual acuity. These data suggest new prognostic factors for visual acuity, but these results need to be confirmed further by large- and international-scale studies

Skeletal Muscle Cells Derived from Induced Pluripotent Stem Cells: A Platform for Limb Girdle Muscular Dystrophies

International audienceLimb girdle muscular dystrophies (LGMD), caused by mutations in 29 different genes, are the fourth most prevalent group of genetic muscle diseases. Although the link between LGMD and its genetic origins has been determined, LGMD still represent an unmet medical need. Here, we describe a platform for modeling LGMD based on the use of human induced pluripotent stem cells (hiPSC). Thanks to the self-renewing and pluripotency properties of hiPSC, this platform provides a renewable and an alternative source of skeletal muscle cells (skMC) to primary, immortalized, or overexpressing cells. We report that skMC derived from hiPSC express the majority of the genes and proteins that cause LGMD. As a proof of concept, we demonstrate the importance of this cellular model for studying LGMDR9 by evaluating disease-specific phenotypes in skMC derived from hiPSC obtained from four patients