178 results on '"Speckmann, C."'
Search Results
2. Neugeborenenscreening auf schwere kombinierte Immundefekte: Wichtigste Fakten für Pädiater
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Schütz, C., Hauck, F., Albert, M. H., Hönig, M., Borte, S., Wahn, V., Schulz, A., Nennstiel, U., and Speckmann, C.
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- 2019
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3. Neugeborenenscreening 2020: Perspektiven der Krankheitsfrüherkennung
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Gramer, G., Hauck, F., Lobitz, S., Sommerburg, O., Speckmann, C., and Hoffmann, G. F.
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- 2017
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4. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study
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Albert MH, Sirait T, Eikema DJ, Bakunina K, Wehr C, Suarez F, Fox ML, Mahlaoui N, Gennery AR, Lankester AJ, Beier R, Bernardo ME, Bigley V, Lindemans CA, OBurns S, Carpenter B, Dybko J, Gungor T, Hauck F, Lum SH, Balashov D, Meisel R, Moshous D, Schulz A, Speckmann C, Slatter MA, Strahm B, Uckan-Cetinkaya D, Meyts I, Vallee TC, Wynn R, Neven B, Morris EC, EBMT IEWP, ESID
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- 2022
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5. Ion-Induced Surface Charge Dynamics in Freestanding Monolayers of Graphene and MoS2 Probed by the Emission of Electrons
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Niggas, A., Schwestka, J., Balzer, K., Weichselbaum, D., Schlünzen, N., Heller, R., Sascha, C., Inani, H., Tripathi, M., Speckmann, C., McEvoy, N., Susi, T., Kotakoski, J., Gan, Z., George, A., Turchanin, A., Bonitz, M., Aumayr, F., and Wilhelm, R. A.
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Highly charged ions ,Graphene ,Electron Emission ,2D materials ,MoS2 ,Surface Charge ,Ion induced surface modifications - Abstract
We compare the ion-induced electron emission from freestanding monolayers of graphene and MoS2 to find a sixfold higher number of emitted electrons for graphene even though both materials have similar work functions. An effective single-band Hubbard model explains this finding by a charge-up in MoS2 that prevents low energy electrons from escaping the surface within a period of a few femtoseconds after ion impact. We support these results by measuring the electron energy distribution for correlated pairs of electrons and transmitted ions. The majority of emitted primary electrons have an energy below 10 eVand are therefore subject to the dynamic charge-up effects at surfaces.
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- 2022
6. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency
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Elgizouli, M., Lowe, D. M., Speckmann, C., Schubert, D., Hülsdünker, J., Eskandarian, Z., Dudek, A., Schmitt-Graeff, A., Wanders, J., Jrgensen, S. F., Fevang, B., Salzer, U., Nieters, A., Burns, S., and Grimbacher, B.
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- 2016
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7. Immunologische Diagnostik bei Kindern und Jugendlichen
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Speckmann, C., primary and Ehl, S., additional
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- 2015
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8. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency
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Rensing-Ehl, A., Warnatz, K., Fuchs, S., Schlesier, M., Salzer, U., Draeger, R., Bondzio, I., Joos, Y., Janda, A., Gomes, M., Abinun, M., Hambleton, S., Cant, A., Shackley, F., Flood, T., Waruiru, C., Beutel, K., Siepermann, K., Dueckers, G., Niehues, T., Wiesel, T., Schuster, V., Seidel, M.G., Minkov, M., Sirkiä, K., Kopp, M.V., Korhonen, M., Schwarz, K., Ehl, S., and Speckmann, C.
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- 2010
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9. Zytomegalievirusinfektionen im ersten Lebensjahr
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Schuster, K., Henneke, P., Huzly, D., and Speckmann, C.
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- 2013
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10. A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency
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Ammann, S., Elling, R., Gyrd-Hansen, M., Dückers, G., Bredius, R., Burns, S. O., Edgar, J. D. M., Worth, A., Brandau, H., Warnatz, K., zur Stadt, U., Hasselblatt, P., Schwarz, K., Ehl, S., and Speckmann, C.
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- 2014
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11. Angeborene Störungen der Immunregulation
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Schulze, I., Rohr, J., and Speckmann, C.
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- 2009
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12. Hematopoietic stem cell transplantation for CD40 ligand deficiency : Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study
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Ferrua, F., Galimberti, S., Courteille, V., Slatter, M.A., Booth, C., Moshous, D., Neven, B., Blanche, S., Cavazzana, M., Laberko, A., Shcherbina, A., Balashov, D., Soncini, E., Porta, F., Al-Mousa, H., Al-Saud, B., Al-Dhekri, H., Arnaout, R., Formankova, R., Bertrand, Y., Lange, A., Smart, J., Wolska-Kusnierz, B., Aquino, V.M., Dvorak, C.C., Fasth, A., Fouyssac, F., Heilmann, C., Hoenig, M., Schuetz, C., Kelecic, J., Bredius, R.G.M., Lankester, A.C., Lindemans, C.A., Suarez, F., Sullivan, K.E., Albert, M.H., Kalwak, K., Barlogis, V., Bhatia, M., Bordon, V., Czogala, W., Alonso, L., Dogu, F., Gozdzik, J., Ikinciogullari, A., Krivan, G., Ljungman, P., Meyts, I., Mustillo, P., Smith, A.R., Speckmann, C., Sundin, M., Keogh, S.J., Shaw, P.J., Boelens, J.J., Schulz, A.S., Sedlacek, P., Veys, P., Mahlaoui, N., Janda, A., Davies, E.G., Fischer, A., Cowan, M.J., Gennery, A.R., SCETIDE, PIDTC, EBMT, ESID IEWP, Ferrua, F, Galimberti, S, Courteille, V, Slatter, M, Booth, C, Moshous, D, Neven, B, Blanche, S, Laberko, A, Shcherbina, A, Balashov, D, Soncini, E, Porta, F, Al-Mousa, H, Al-Saud, B, Al-Dhekri, H, Arnaout, R, Formankova, R, Bertrand, Y, Lange, A, Smart, J, Wolska-Kusnierz, B, Aquino, V, Dvorak, C, Fasth, A, Fouyssac, F, Heilmann, C, Hoenig, M, Schuetz, C, Kelečić, J, Bredius, R, Lankester, A, Lindemans, C, Suarez, F, Sullivan, K, Albert, M, Kałwak, K, Barlogis, V, Bhatia, M, Bordon, V, Czogala, W, Alonso, L, Dogu, F, Gozdzik, J, Ikinciogullari, A, Kriván, G, Ljungman, P, Meyts, I, Mustillo, P, Smith, A, Speckmann, C, Sundin, M, Keogh, S, Shaw, P, Boelens, J, Schulz, A, Sedlacek, P, Veys, P, Mahlaoui, N, Janda, A, Davies, E, Fischer, A, Cowan, M, and Gennery, A
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,X-Linked Combined Immunodeficiency Diseases ,primary immunodeficiency ,Donor lymphocyte infusion ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,X-linked hyper-IgM syndrome ,Humans ,Medicine ,Immunology and Allergy ,Risk factor ,Child ,Prospective cohort study ,business.industry ,Infant, Newborn ,Infant ,medicine.disease ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Graft-versus-host disease ,surgical procedures, operative ,Supportive psychotherapy ,Child, Preschool ,hematopoietic stem cell transplantation ,Primary immunodeficiency ,Bone marrow ,CD40 ligand ,business ,030215 immunology - Abstract
BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:143 issue:6 pages:2238-2253 ispartof: location:United States status: published
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- 2019
13. Elevated Serum BAFF Levels in Patients with Autoimmunity and Lymphoproliferation
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Janda, A., Rensing-Ehl, A., Eibel, H., Ehl, S., and Speckmann, C.
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- 2011
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14. Ulceration in Prolidase Deficiency: Successful Treatment with Anticoagulants
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Süßmuth, K, primary, Metze, D, additional, Muresan, A, additional, Lehmberg, K, additional, Stadt, U, additional, Speckmann, C, additional, Park, J, additional, Marquardt, T, additional, Oji, V, additional, and Goerge, T, additional
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- 2020
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15. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency
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Lawless, D, Geier, CB, Farmer, JR, Lango Allen, H, Thwaites, D, Atschekzei, F, Brown, M, Buchbinder, D, Burns, SO, Butte, MJ, Csomos, K, Deevi, SVV, Egner, W, Ehl, S, Eibl, MM, Fadugba, O, Foldvari, Z, Green, DM, Henrickson, SE, Holland, SM, John, T, Klemann, C, Kuijpers, TW, Moreira, F, Piller, A, Rayner-Matthews, P, Romberg, ND, Sargur, R, Schmidt, RE, Schröder, C, Schuetz, C, Sharapova, SO, Smith, KGC, Sogkas, G, Speckmann, C, Stirrups, K, Thrasher, AJ, Wolf, HM, Notarangelo, LD, Anwar, R, Boyes, J, Ujhazi, B, NIHR BioResource - Rare Diseases Consortium, Thaventhiran, J, Walter, JE, Savic, S, Lango Allen, Hana [0000-0002-7803-8688], Smith, Kenneth [0000-0003-3829-4326], Johnson, Kathleen [0000-0002-6823-3252], Thaventhiran, James [0000-0001-8616-074X], and Apollo - University of Cambridge Repository
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Adult ,DNA-Binding Proteins ,Homeodomain Proteins ,Immunologic Deficiency Syndromes ,Prevalence ,Humans ,Nuclear Proteins - Published
- 2018
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16. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study
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Barzaghi, F., Hernandez, L.C.A., Neven, B., Ricci, S., Kucuk, Z.Y., Bleesing, J.J., Nademi, Z., Slatter, M.A., Ulloa, E.R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J.F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L.D., Gambineri, E., Lionetti, P., Shearer, W.T., Forbes, L.R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F.M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M.H., Kobayashi, I., Alonso, L., Heredia, C.D. de, Kanegane, H., Lawitschka, A., Seo, J.J., Gonzalez-Vicent, M., Diaz, M.A., Goyal, R.K., Sauer, M.G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Padilla, E.J.R., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M.L., Bredius, R.G., Kawak, K., Haddad, E., Seidel, M.G., Duckers, G., Pai, S.Y., Dvorak, C.C., Ehl, S., Locatelli, F., Goldman, F., Gennery, A.R., Cowan, M.J., Roncarolo, M.G., Bacchetta, R., PIDTC, IEWP, European Soc Blood Marrow, Barzaghi, Federica, Hernandez, Laura Cristina Amaya, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J., Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R., Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M., Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frederic, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H., Kobayashi, Ichiro, Alonso, Laura, De Heredia, Cristina Diaz, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G., Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Padilla, Erick J. Richmond, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G., Kalwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C., Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J., Roncarolo, Maria-Grazia, Bacchetta, Rosa, Amaya Hernandez, Laura Cristina, Murguia-Favela, Lui, Shearer, William Thoma, Rieux-Laucat, Frédéric, Diaz De Heredia, Cristina, Richmond Padilla, Erick J., and Kałwak, Krzysztof
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0301 basic medicine ,Male ,Allergy ,medicine.medical_treatment ,Medizin ,Disease ,Hematopoietic stem cell transplantation ,SIROLIMUS ,Regenerative Medicine ,primary immune deficiency ,Medicine and Health Sciences ,IPEX ,Immunology and Allergy ,2.1 Biological and endogenous factors ,Enteropathy ,Aetiology ,POLYENDOCRINOPATHY ,Child ,Pediatric ,CÉLULAS-TRONCO ,immunosuppression ,Hematopoietic Stem Cell Transplantation ,Genetic Diseases, X-Linked ,Immunosuppression ,Forkhead Transcription Factors ,X-LINKED SYNDROME ,Allografts ,Survival Rate ,surgical procedures, operative ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Immune System Diseases ,Genetic Diseases ,Child, Preschool ,hematopoietic stem cell transplantation ,Female ,hematopoietic stem ,neonatal diabetes ,FOXP3 ,Primary Immune Deficiency ,Treg cells ,enteropathy ,genetic autoimmunity ,rapamycin ,Type 1 ,Diarrhea ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,Neonatal onset ,Article ,Disease-Free Survival ,03 medical and health sciences ,Neonatal diabete ,Clinical Research ,Internal medicine ,IMMUNODYSREGULATION ,medicine ,Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation ,Diabetes Mellitus ,Genetics ,Humans ,REGULATORY T-CELLS ,cell transplantation ,Preschool ,Retrospective Studies ,Immunosuppression Therapy ,Transplantation ,IMMUNE DYSREGULATION ,business.industry ,MUTATIONS ,Infant ,Retrospective cohort study ,STEM-CELL TRANSPLANTATION ,IPEX syndrome ,X-Linked ,medicine.disease ,Stem Cell Research ,BONE-MARROW-TRANSPLANTATION ,Treg cell ,FOXP3 MUTATIONS ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,ENGRAFTMENT ,Mutation ,business ,Follow-Up Studies - Abstract
Background Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., GRAPHICAL ABSTRACT
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- 2018
17. Infektionsanfälligkeit bei Immundefizienz
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Speckmann, C, Ehl, S, Liese, J, Trück, Johannes, University of Zurich, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, Berner, Reinhard, Bialek, Ralf, Forster, Johannes, Härtel, Christoph, Heininger, Ulrich, Huppertz, Hans-Iko, Liese, Johannes G, Nadal, David, and Simon, Arne
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10036 Medical Clinic ,610 Medicine & health - Published
- 2018
18. Erratum zu: Zytomegalievirusinfektionen im ersten Lebensjahr
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Schuster, K., Henneke, P., Huzly, D., and Speckmann, C.
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- 2013
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19. Neugeborenenscreening 2020
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Gramer, G., primary, Hauck, F., additional, Lobitz, S., additional, Sommerburg, O., additional, Speckmann, C., additional, and Hoffmann, G. F., additional
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- 2017
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20. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency
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Hassan, A., Booth, C., Brightwell, A., Allwood, Z., Veys, P., Rao, K., Honig, M., Friedrich, W., Gennery, A., Slatter, M., Bredius, R., Finocchi, A., Cancrini, C., Aiuti, A., Porta, F., Lanfranchi, A., Ridella, M., Steward, C., Filipovich, A., Marsh, R., Bordon, V., Al-Muhsen, S., Al-Mousa, H., Alsum, Z., Al-Dhekri, H., Ghonaium, A. al, Speckmann, C., Fischer, A., Mahlaoui, N., Nichols, K.E., Grunebaum, E., Zahrani, D. al, Roifman, C.M., Boelens, J., Davies, E.G., Cavazzana-Calvo, M., Notarangelo, L., Gaspar, H.B., European Grp Blood Marrow Transpla, European Soc Immunodeficiency, Hassan, A, Booth, C, Brightwell, A, Allwood, Z, Veys, P, Rao, K, Hönig, M, Friedrich, W, Gennery, A, Slatter, M, Bredius, R, Finocchi, A, Cancrini, C, Aiuti, Alessandro, Porta, F, Lanfranchi, A, Ridella, M, Steward, C, Filipovich, A, Marsh, R, Bordon, V, AL MUHSEN, S, AL MOUSA, H, Alsum, Z, AL DHEKRI, H, AL GHONAIUM, A, Speckmann, C, Fischer, A, Mahlaoui, N, Nichols, Ke, Grunebaum, E, AL ZAHRANI, D, Roifman, Cm, Boelens, J, Davies, Eg, CAVAZZANA CALVO, M, Notarangelo, L, and Gaspar, Hb
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Oncology ,Male ,Transplantation Conditioning ,Adenosine Deaminase ,Genetic enhancement ,medicine.medical_treatment ,T-Lymphocytes ,Hematopoietic stem cell transplantation ,Kaplan-Meier Estimate ,Biochemistry ,humoral ,Adenosine deaminase ,newborn ,immune system diseases ,Agammaglobulinemia ,hemic and lymphatic diseases ,Child ,Immunity, Cellular ,Hematology ,biology ,Histocompatibility Testing ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,surgical procedures, operative ,Treatment Outcome ,Child, Preschool ,Female ,Unrelated Donors ,medicine.medical_specialty ,Immunology ,preschool ,Internal medicine ,medicine ,Humans ,Lymphocyte Count ,Retrospective Studies ,Settore MED/38 - Pediatria Generale e Specialistica ,Severe combined immunodeficiency ,agammaglobulinemia ,transplantation conditioning ,severe combined immunodeficiency ,humans ,retrospective studies ,infant, newborn ,child ,child, preschool ,kaplan-meier estimate ,infant ,lymphocyte count ,histocompatibility testing ,immunity, cellular ,unrelated donors ,graft survival ,treatment outcome ,myeloablative agonists ,hematopoietic stem cell transplantation ,siblings ,adenosine deaminase ,male ,female ,t-lymphocytes ,immunity, humoral ,business.industry ,Siblings ,Infant, Newborn ,Infant ,Cell Biology ,Myeloablative Agonists ,medicine.disease ,immunity ,Adenosine deaminase deficiency ,Immunity, Humoral ,Transplantation ,biology.protein ,Severe Combined Immunodeficiency ,business ,cellular - Abstract
Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.
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- 2012
21. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study
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Coulter, TI, Chandra, A, Bacon, CM, Babar, J, Curtis, J, Screaton, N, Goodlad, JR, Farmer, G, Steele, CL, Leahy, TR, Doffinger, R, Baxendale, H, Bernatoniene, J, Edgar, JD, Longhurst, HJ, Ehl, S, Speckmann, C, Grimbacher, B, Sediva, A, Milota, T, Faust, SN, Williams, AP, Hayman, G, Kucuk, ZY, Hague, R, French, P, Brooker, R, Forsyth, P, Herriot, R, Cancrini, C, Palma, P, Ariganello, P, Conlon, N, Feighery, C, Gavin, PJ, Jones, A, Imai, K, Ibrahim, MA, Markelj, G, Abinun, M, Rieux-Laucat, F, Latour, S, Pellier, I, Fischer, A, Touzot, F, Casanova, JL, Durandy, A, Burns, SO, Savic, S, Kumararatne, DS, Moshous, D, Kracker, S, Vanhaesebroeck, B, Okkenhaug, K, Picard, C, Nejentsev, S, Condliffe, AM, Cant, AJ, Chandra, Anita [0000-0002-9061-879X], Okkenhaug, Klaus [0000-0002-9432-4051], Nezhentsev, Sergey [0000-0002-7528-4461], and Apollo - University of Cambridge Repository
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Adult ,Male ,Adolescent ,bronchiectasis ,Class I Phosphatidylinositol 3-Kinases ,International Cooperation ,Immunology ,PPV, Pneumococcal polysaccharide vaccine ,HSCT, Hematopoietic stem cell transplantation ,Cohort Studies ,Mice ,Young Adult ,APDS, Activated phosphoinositide-3 kinase δ syndrome ,phosphoinositide 3-kinase inhibitor ,Immune Deficiencies, Infection, and Systemic Immune Disorders ,Recurrence ,PI3K, Phosphoinositide 3-kinase ,Surveys and Questionnaires ,BALF, Bronchoalveolar lavage fluid ,Activated phosphoinositide 3-kinase δ syndrome ,Animals ,Humans ,Immunology and Allergy ,Enzyme Inhibitors ,CMV, Cytomegalovirus ,Child ,HSV, Herpes simplex virus ,Respiratory Tract Infections ,CNS, Central nervous system ,Hematopoietic Stem Cell Transplantation ,Immunologic Deficiency Syndromes ,Immunoglobulins, Intravenous ,Infant ,GOF, Gain of function ,Herpesviridae Infections ,Antibiotic Prophylaxis ,Middle Aged ,PIK3CD gene ,Survival Analysis ,Lymphoproliferative Disorders ,Child, Preschool ,Mutation ,CT, Computed tomography ,p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency ,Female ,immunodeficiency ,phosphoinositide 3-kinase δ ,OR, Odds ratio - Abstract
Background: Activated PI3-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 δ (PI3Kδ).\ud Objective: To review the clinical, immunological, histopathological and radiological features of APDS in a large genetically-defined international cohort.\ud Methods: Clinical questionnaire, and review of medical notes, radiology histopathology and laboratory investigations of 53 APDS patients.\ud Results: Recurrent sino-pulmonary infections (96%) and non-neoplastic 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 (CNS); consistent with this PI3Kδ is broadly expressed in the developing murine CNS. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60% in cohort); the incidence of bronchiectasis was greater than in common variable immunodeficiency (CVID). Elevated IgM (78%), IgG deficiency (43%) and CD4 lymphopenia (84%) were significant immunological features. No immunological 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 five patients underwent haematopoietic stem cell transplant (HSCT). Five patients died from complications of APDS.\ud 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 HSCT for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
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- 2017
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22. From autoinflammatory disease to primary immunodeficiency
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Dückers, G, Ehl, S, Speckmann, C, and Niehues, T
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XIAP ,ddc: 610 ,Fever ,Autoinflammation ,610 Medical sciences ,Medicine ,SoJIA - Abstract
Case: A 3 year old boy of German non consanguineous family with relapsing episodes of severe autoinflammation (spiking fever, transient exanthema, hepatosplenomegaly, hyperferritinemia > 27.500µg/l, LDH >3.500 U/ml, S100 > 8.700 ng/ml) was initially suspected for systemic[for full text, please go to the a.m. URL], 42. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 28. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 24. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)
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- 2014
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23. Immundefekte als Ursache von chronisch-entzündlichen Erkrankungen des Darmes
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Gerner, P., primary, Speckmann, C., primary, Klemann, C., additional, Tegtmeyer, D., additional, and Baumann, U., additional
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- 2016
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24. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency
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Elgizouli, M, primary, Lowe, D M, additional, Speckmann, C, additional, Schubert, D, additional, Hülsdünker, J, additional, Eskandarian, Z, additional, Dudek, A, additional, Schmitt-Graeff, A, additional, Wanders, J, additional, Jørgensen, S F, additional, Fevang, B, additional, Salzer, U, additional, Nieters, A, additional, Burns, S, additional, and Grimbacher, B, additional
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- 2015
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25. Delayed-onset adenosine deaminase deficiency: Strategies for an early diagnosis
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Speckmann, C., Neumann, C., Borte, S., giancarlo la marca, Sass, Jo, Wiech, E., Fisch, P., Schwarz, K., Buchholz, B., Schlesier, M., Felgentreff, K., Grimbacher, B., Santisteban, I., Bali, P., Hershfield, Ms, and Ehl, S.
- Published
- 2012
26. Immunomodulatory Treatment of a Patient with Cross-Reactive Immunologic Material Negative Infantile Pompe Disease and Hypertrophic Cardiomyopathy
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Borell, S., primary, Fleck, T., additional, Speckmann, C., additional, Ehl, S., additional, Franck, P., additional, Fuchs, H., additional, Korinthenberg, R., additional, and Kirschner, J., additional
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- 2015
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27. Reduced memory B cells in patients with hyper IgE syndrome
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Speckmann, C, Enders, A, Woellner, C, Thiel, D, RENSING EHL, A, Schlesier, M, Rohr, J, Jakob, T, Oswald, E, Kopp, M, Sanal, O, Litzman, J, Plebani, Alessandro, Pietrogrande, Mc, Franco, Jl, Espanol, T, Grimbacher, B, and Ehl, S.
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Hyper IgE syndrome ,memory B cells - Published
- 2008
28. X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis
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Speckmann, C., primary, Lehmberg, K., additional, Albert, M.H., additional, Damgaard, R.B., additional, Fritsch, M., additional, Gyrd-Hansen, M., additional, Rensing-Ehl, A., additional, Vraetz, T., additional, Grimbacher, B., additional, Salzer, U., additional, Fuchs, I., additional, Ufheil, H., additional, Belohradsky, B.H., additional, Hassan, A., additional, Cale, C.M., additional, Elawad, M., additional, Strahm, B., additional, Schibli, S., additional, Lauten, M., additional, Kohl, M., additional, Meerpohl, J.J., additional, Rodeck, B., additional, Kolb, R., additional, Eberl, W., additional, Soerensen, J., additional, von Bernuth, H., additional, Lorenz, M., additional, Schwarz, K., additional, zur Stadt, U., additional, and Ehl, S., additional
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- 2013
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29. Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia
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Rensing-Ehl, A., primary, Janda, A., additional, Lorenz, M. R., additional, Gladstone, B. P., additional, Fuchs, I., additional, Abinun, M., additional, Albert, M., additional, Butler, K., additional, Cant, A., additional, Cseh, A.-M., additional, Ebinger, M., additional, Goldacker, S., additional, Hambleton, S., additional, Hebart, H., additional, Houet, L., additional, Kentouche, K., additional, Kuhnle, I., additional, Lehmberg, K., additional, Mejstrikova, E., additional, Niemeyer, C., additional, Minkov, M., additional, Neth, O., additional, Duckers, G., additional, Owens, S., additional, Rosler, J., additional, Schilling, F. H., additional, Schuster, V., additional, Seidel, M. G., additional, Smisek, P., additional, Sukova, M., additional, Svec, P., additional, Wiesel, T., additional, Gathmann, B., additional, Schwarz, K., additional, Vach, W., additional, Ehl, S., additional, and Speckmann, C., additional
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- 2013
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30. Cytomegalovirus infections in the first year of life
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Schuster, K., primary, Henneke, P., additional, Huzly, D., additional, and Speckmann, C., additional
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- 2013
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31. Mowat-Wilson Syndrome, a rare genetic condition with intestinal and cerebral symptoms
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Tacke, U, primary, Speckmann, C, additional, Rieger-Fackeldey, E, additional, Hentschel, R, additional, Rückauer, K, additional, Arnold, R, additional, and Lausch, E, additional
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- 2012
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32. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases
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Rohr, J., primary, Beutel, K., additional, Maul-Pavicic, A., additional, Vraetz, T., additional, Thiel, J., additional, Warnatz, K., additional, Bondzio, I., additional, Gross-Wieltsch, U., additional, Schundeln, M., additional, Schutz, B., additional, Woessmann, W., additional, Groll, A. H., additional, Strahm, B., additional, Pagel, J., additional, Speckmann, C., additional, Janka, G., additional, Griffiths, G., additional, Schwarz, K., additional, zur Stadt, U., additional, and Ehl, S., additional
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- 2010
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33. Reduced memory B cells in patients with hyper IgE syndrome
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Speckmann, C., primary, Enders, A., additional, Woellner, C., additional, Thiel, D., additional, Rensing-Ehl, A., additional, Schlesier, M., additional, Rohr, J., additional, Jakob, T., additional, Oswald, E., additional, Kopp, M.V., additional, Sanal, O., additional, Litzman, J., additional, Plebani, A., additional, Pietrogrande, M.C., additional, Franco, J.L., additional, Espanol, T., additional, Grimbacher, B., additional, and Ehl, S., additional
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- 2008
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34. Adenosindesaminase (ADA)- und Purinnukleosidphosphorylase (PNP)- Defizienz
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Speckmann, C., primary, Wintergerst, U., additional, Rohr, J., additional, Hönig, M., additional, and Ehl, S., additional
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- 2007
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35. Immundefekte als Ursache von chronisch-entzündlichen Erkrankungen des Darmes
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Klemann, C., Tegtmeyer, D., Gerner, P., Speckmann, C., and Baumann, U.
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- 2016
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36. Long-term robustness of a T-cell system emerging from somatic rescue of a genetic block in T-cell development
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Kury, P, primary, Fuhrer, M, additional, Fuchs, S, additional, Lorenz, MR, additional, Giorgetti, OB, additional, Bakhtiar, S, additional, Frei, AP, additional, Fisch, P, additional, Boehm, T, additional, Schwarz, K, additional, Speckmann, C, additional, and Ehl, S, additional
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37. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations
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Tim Niehues, Catherine Waruiru, Conleth Feighery, Uwe Schauer, Virginie Courteille, Kai Lehmberg, Ingo Müller, I. Esteves, Henner Morbach, Michael Borte, Patrick Hundsdoerfer, Klaus Schwarz, Ewelina Gowin, Alessandro Aiuti, Andreas Holbro, Federica Barzaghi, João Farela Neves, Dagmar Graf, Hannah Tamary, Veneta Milenova, Benedikt Boetticher, Eleonora Gambineri, Vera Goda, Alia Eldash, Jan-Christian Wasmuth, Fabio Candotti, Svetlana O. Sharapova, Markus Metzler, Juergen Brunner, Anna Hilfanova, Brindusa Ruxandra Capilna, Pere Soler-Palacín, Arnau Antolí, Horst von Bernuth, Vassilios Lougaris, Maria Carrabba, Bernd H. Belohradsky, Julian Thalhammer, Nathalie de Vergnes, Peter Olbrich, Peter Kopač, Leif G. Hanitsch, Alexandra Nieters, Filomeen Haerynck, Juliana Gabzdilova, Sezin Aydemir, Rabab El Hawary, Patrick F.K. Yong, Maria Giovanna Danieli, Alberto Tommasini, Sandra Steinmann, Ulrich Baumann, Figen Dogu, Elisabeth Förster-Waldl, Carolina Marasco, Donato Amodio, Lorenzo Lodi, Xavier Solanich, Caterina Cancrini, Brigita Sitkauskiene, Torsten Witte, Clementina Vanessa, Nima Rezaei, Jean-Christophe Goffard, Kirsten Wittke, Emmanouil Liatsis, Helen Baxendale, Susana L. Silva, Bodo Grimbacher, Henrike Ritterbusch, Evangelia Farmaki, Safa Meshaal, Sujal Ghosh, Larysa Kostyuchenko, David Edgar, Simone Cesaro, R Zeuner, Nerea Salmón Rodríguez, Isabella Quinti, Stephan Ehl, Pauline Brosselin, Joerg C. Henes, Pilar Llobet Agulló, Rosa Maria Dellepiane, Andrea Meinhardt, Marina Kojić, Georgios Sogkas, Stephan Borte, Catharina Schuetz, Suheyla Ocak, Karin Marschall, Lukas M. Gasteiger, Stefan Raffac, Sofia Tantou, Sadia Noorani, Matthaios Speletas, Philippe Randrianomenjanahary, Ursula Holzer, Ayca Kiykim, Johannes G. Liese, Angelo Vacca, Gisela Fecker, Ekrem Unal, Koen J. van Aerde, Alba Parra-Martínez, Kaan Boztug, Sophie Stiehler, Sybille Landwehr-Kenzel, Claudio Pignata, Jennifer Neubert, Janine Reichenbach, Shahnaz Parvin, Sarah Goddard, Andrea Schroll, Dirk Holzinger, Asghar Aghamohammadi, Hassan Abolhassani, Johannes Trück, Estela Paz-Artal, Shereen M. Reda, Anna Shcherbina, Maria Raptaki, Jaroslava Orosova, Beata Wolska-Kuśnierz, Tessa Kerre, Gerrit Ahrenstorf, Ben Zion Garty, Dirk Foell, Benjamin Becker, Ulrike F. Demel, Androniki Kapousouzi, Abraham Rutgers, Klaus Warnatz, Gemma Rocamora Blanch, Stephan Rusch, Luis M. Allende, Dalia Abd Elaziz, Safa Baris, Jorisvan Montfrans, Dominik T. Schneider, Raphael Scheible, Juana Gil-Herrera, Gerhard Kindle, Annarosa Soresina, Giovanna Fabio, Uwe Wintergerst, Emilia Faria, Maria Fasshauer, Silvia Ricci, Aisha Elmarsafy, Barbara Pietrucha, Carsten Speckmann, Nizar Mahlaoui, Ulrich Heininger, Isabelle Meyts, Matthew Buckland, Efimia Papadopoulou-Alataki, Robin Kobbe, A Herwadkar, Sebastian F. N. Bode, Ali Sobh, László Maródi, Baldassarre Martire, Chiara Azzari, Maximilian Heeg, Katja Masjosthusmann, Michael H. Albert, Matteo Chinello, Juan Luis Santos-Pérez, Aarnoud Huissoon, Tanya I. Coulter, Hendrik Schulze-Koops, Norbert Graf, Radwa Alkady, Jolanta Bernatoniene, Seraina Prader, Alenka Gagro, Joachim Roesler, Taco W. Kuijpers, Ewa Więsik-Szewczyk, Maria Elena Maccari, Conrad Ferdinand Lippert, Miriam González-Amores, Johannes Dirks, Daniel E Pleguezuelo, Christof M. Kramm, Anders Fasth, Volker Schuster, Olov Ekwall, Nikolaus Rieber, Javier Carbone, Petra Kaiser-Labusch, Diana Ernst, Lucia Augusta Baselli, Luis Ignacio Gonzalez-Granado, Maria Kanariou, Stefanie S. V. Henriet, Sigune Goldacker, Kerstin Felgentreff, Oana Joean, Fine Roosens, Fabian Hauck, Eva C. Schwaneck, Milos Jesenak, Manfred Hoenig, Lenka Kapustova, Christoph Boesecke, Alain Fischer, Sara Pereira da Silva, Julia Körholz, Ansgar Schulz, Carolynne Schwarze-Zander, Mikko Seppänen, Nermeen Galal, Nora Naumann-Bartsch, Tomaz Garcez, Peter Ciznar, Klara M. Posfay-Barbe, Zelimir Pavle Eric, Reinhold E. Schmidt, Hermann J. Girschick, Sabine Heine, Anika-Kerstin Biegner, Annick A. J. M. van de Ven, Stefan Schreiber, J. Merlijn van den Berg, Nurit Assia Batzir, Alexandra Jablonka, Kim Stol, Gregor Dückers, Antonios G.A. Kolios, Ioannis Kakkas, Christian Klemann, Marina N. Guseva, Sofia Grigoriadou, Elif Karakoc-Aydiner, Antonio Marzollo, Peter D. Arkwright, Urs C. Steiner, Sara Sebnem Kilic, Romina Dieli-Crimi, Gergely Kriván, Monika Sparber-Sauer, Marco Cazzaniga, Fulvio Porta, Paraskevi Maggina, Tomas Milota, Robbert G. M. Bredius, Martine Pergent, Klaus Tenbrock, Jana Pachlopnik Schmid, Florentia Dimitriou, Cathal Laurence Steele, Helen Bourne, Anna Bobcakova, Gerd Horneff, Judith Potjewijd, Marc Schmalzing, Tobias Ankermann, Paul Ryan, Oksana Boyarchuk, Necil Kutukculer, Carl Friedrich Classen, Zita Chovancová, Moira Thomas, Cinzia Milito, Michaela Bitzenhofer-Grüber, Faranaz Atschekzei, Eva Hlaváčková, Viviana Moschese, Julie Smet, Hans-Hartmut Peter, Carla Teixeira, Sabine M El-Helou, Suzanne de Kruijf Bazen, Helmut Wittkowski, Donate Jakoby, Marina Garcia-Prat, Esther de Vries, Richard Herriot, Sven Kracker, Alessandro Plebani, Lisa Göschl, Laura Hora Marques, Anna Sediva, Jiri Litzman, Mark M. Gompels, Renate Krüger, Şefika İlknur Kökçü Karadağ, Nadine Binder, Anna Szaflarska, Peter Jandus, Lisa Ibberson, Johann Greil, Ulf Schulze-Sturm, Mehtap Sirin, Aydan Ikinciogullari, Edyta Heropolitańska-Pliszka, Michael E. Weiss, Alla Skapenko, Lukas Wisgrill, Hana Alachkar, Uta Behrends, Silvia Sánchez-Ramón, Maria N. Hatzistilianou, Otilia Petrovicova, Darko Richter, Zoreh Nademi, Jürgen K. Rockstroh, Sohilla Lotfy, Markus G. Seidel, Timothy Ronan Leahy, Audra Blažienė, Translational Immunology Groningen (TRIGR), Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Zurich, Ehl, Stephan, Thalhammer, J., Kindle, G., Nieters, A., Rusch, S., Seppanen, M. R. J., Fischer, A., Grimbacher, B., Edgar, D., Buckland, M., Mahlaoui, N., Ehl, S., Boztug, K., Brunner, J., Demel, U. F., Forster-Waldl, E., Gasteiger, L. M., Goschl, L., Kojic, M., Schroll, A., Seidel, M. G., Wintergerst, U., Wisgrill, L., Sharapova, S. O., Goffard, J. -C., Kerre, T., Meyts, I., Roosens, F., Smet, J., Haerynck, F., Eric, Z. P., Milenova, V., Gagro, A., Richter, D., Chovancova, Z., Hlavackova, E., Litzman, J., Milota, T., Sediva, A., Elaziz, D. A., Alkady, R. S., El Sayed El Hawary, R., Eldash, A. S., Galal, N., Lotfy, S., Meshaal, S. S., Reda, S. M., Sobh, A., Elmarsafy, A., Brosselin, P., Courteille, V., De Vergnes, N., Kracker, S., Pergent, M., Randrianomenjanahary, P., Ahrenstorf, G., Albert, M. H., Ankermann, T., Atschekzei, F., Baumann, U., Becker, B. C., Behrends, U., Belohradsky, B. H., Biegner, A. -K., Binder, N., Bode, S. F. N., Boesecke, C., Boetticher, B., Borte, M., Borte, S., Classen, C. F., Dirks, J., Duckers, G., El-Helou, S., Ernst, D., Fasshauer, M., Fecker, G., Felgentreff, K., Foell, D., Ghosh, S., Girschick, H. J., Goldacker, S., Graf, N., Graf, D., Greil, J., Hanitsch, L. G., Hauck, F., Heeg, M., Heine, S. I., Henes, J. C., Hoenig, M., Holzer, U., Holzinger, D., Horneff, G., Hundsdoerfer, P., Jablonka, A., Jakoby, D., Joean, O., Kaiser-Labusch, P., Klemann, C., Kobbe, R., Korholz, J., Kramm, C. M., Kruger, R., Landwehr-Kenzel, S., Lehmberg, K., Liese, J. G., Lippert, C. F., Maccari, M. E., Masjosthusmann, K., Meinhardt, A., Metzler, M., Morbach, H., Muller, I., Naumann-Bartsch, N., Neubert, J., Niehues, T., Peter, H. -H., Rieber, N., Ritterbusch, H., Rockstroh, J. K., Roesler, J., Schauer, U., Scheible, R., Schmalzing, M., Schmidt, R. E., Schneider, D. T., Schreiber, S., Schuetz, C., Schulz, A., Schulze-Koops, H., Schulze-Sturm, U., Schuster, V., Schwaneck, E. C., Schwarz, K., Schwarze-Zander, C., Sirin, M., Skapenko, A., Sogkas, G., Sparber-Sauer, M., Speckmann, C., Steinmann, S., Stiehler, S., Tenbrock, K., von Bernuth, H., Warnatz, K., Wasmuth, J. -C., Weiss, M., Witte, T., Wittke, K., Wittkowski, H., Zeuner, R. A., Farmaki, E., Hatzistilianou, M. N., Kakkas, I., Kanariou, M. G., Kapousouzi, A., Liatsis, E., Maggina, P., Papadopoulou-Alataki, E., Raptaki, M., Speletas, M., Tantou, S., Goda, V., Krivan, G., Marodi, L., Abolhassani, H., Aghamohammadi, A., Rezaei, N., Feighery, C., Leahy, T. R., Ryan, P., Batzir, N. A., Garty, B. Z., Tamary, H., Aiuti, A., Amodio, D., Azzari, C., Barzaghi, F., Baselli, L. A., Cancrini, C., Carrabba, M., Cazzaniga, M., Cesaro, S., Chinello, M., Danieli, M. G., Dellepiane, R. M., Fabio, G., Gambineri, E., Lodi, L., Lougaris, V., Marasco, C., Martire, B., Marzollo, A., Milito, C., Moschese, V., Pignata, C., Plebani, A., Porta, F., Quinti, I., Ricci, S., Soresina, A., Tommasini, A., Vacca, A., Vanessa, C., Blaziene, A., Sitkauskiene, B., Gowin, E., Heropolitanska-Pliszka, E., Pietrucha, B., Szaflarska, A., Wiesik-Szewczyk, E., Wolska-Kusnierz, B., Esteves, I., Faria, E., Marques, L. H., Neves, J. F., Silva, S. L., Teixeira, C., Pereira da Silva, S., Capilna, B. R., Guseva, M. N., Shcherbina, A., Bobcakova, A., Ciznar, P., Gabzdilova, J., Jesenak, M., Kapustova, L., Orosova, J., Petrovicova, O., Raffac, S., Kopac, P., Allende, L. M., Antoli, A., Blanch, G. R., Carbone, J., Dieli-Crimi, R., Garcia-Prat, M., Gil-Herrera, J., Gonzalez-Granado, L. I., Agullo, P. L., Olbrich, P., Parra-Martinez, A., Paz-Artal, E., Pleguezuelo, D. E., Rodriguez, N. S., Sanchez-Ramon, S., Santos-Perez, J. L., Solanich, X., Soler-Palacin, P., Gonzalez-Amores, M., Ekwall, O., Fasth, A., Bitzenhofer-Gruber, M., Candotti, F., Dimitriou, F., Heininger, U., Holbro, A., Jandus, P., Kolios, A. G. A., Marschall, K., Schmid, J. P., Posfay-Barbe, K. M., Prader, S., Reichenbach, J., Steiner, U. C., Truck, J., Bredius, R. G., de Kruijf- Bazen, S., de Vries, E., Henriet, S. S. V., Kuijpers, T. W., Potjewijd, J., Rutgers, A., Stol, K., van Aerde, K. J., Van den Berg, J. M., van de Ven, A. A. J. M., Montfrans, J., Aydemir, S., Baris, S., Dogu, F., Ikinciogullari, A., Karakoc-Aydiner, E., Kilic, S. S., Kiykim, A., Kokcu Karadag, S. I., Kutukculer, N., Ocak, S., Unal, E., Boyarchuk, O., Hilfanova, A., Kostyuchenko, L. V., Alachkar, H., Arkwright, P. D., Baxendale, H. E., Bernatoniene, J., Coulter, T. I., Garcez, T., Goddard, S., Gompels, M. M., Grigoriadou, S., Herriot, R., Herwadkar, A., Huissoon, A., Ibberson, L., Nademi, Z., Noorani, S., Parvin, S., Steele, C. L., Thomas, M., Waruiru, C., Yong, P. F. K., and Bourne, H.
- Subjects
0301 basic medicine ,Male ,Pediatrics ,syndromic ,Sex Factor ,Disease ,registry ,medicine.disease_cause ,Cohort Studies ,0302 clinical medicine ,Primary Immunodeficiency Disease ,inborn error of immunity ,Immunology and Allergy ,warning signs ,Age Factor ,Registries ,Family history ,presenting symptom ,Child ,Primary immunodeficiency ,Granuloma ,autoimmune ,immune dysregulation ,inflammatory ,Adult ,Autoimmune Diseases ,Female ,Humans ,Infections ,Lymphoproliferative Disorders ,Middle Aged ,Primary Immunodeficiency Diseases ,Sex Factors ,Age Factors ,10177 Dermatology Clinic ,Infections/epidemiology ,3. Good health ,Settore MED/02 ,Warning signs ,Lymphoproliferative Disorder ,2723 Immunology and Allergy ,Infection ,Human ,medicine.medical_specialty ,Immunology ,610 Medicine & health ,Malignancy ,primary immunodeficiency ,Autoimmune Disease ,03 medical and health sciences ,Immunity ,Autoimmune Diseases/epidemiology ,medicine ,2403 Immunology ,business.industry ,warning sign ,Common variable immunodeficiency ,Granuloma/epidemiology ,Immune dysregulation ,medicine.disease ,Primary Immunodeficiency Diseases/epidemiology ,030104 developmental biology ,Lymphoproliferative Disorders/epidemiology ,Cohort Studie ,business ,030215 immunology - Abstract
BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.
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- 2021
38. Successful Long-Term Enzyme Replacement Therapy in a Patient with Delayed-Onset ADA Deficiency.
- Author
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Toskov V, Bali P, Hershfield MS, Ehl S, and Speckmann C
- Subjects
- Humans, Treatment Outcome, Male, Female, Mutation genetics, Severe Combined Immunodeficiency, Enzyme Replacement Therapy methods, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Agammaglobulinemia drug therapy, Agammaglobulinemia therapy, Agammaglobulinemia genetics
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- 2024
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39. Haematopoietic stem cell transplantation for CTLA-4 insufficiency across Europe: an EBMT Inborn Errors Working Party study.
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Tsilifis C, Speckmann C, Lum SH, Fox TA, Soler AM, Mozo Y, Corral D, Ewins AM, Hague R, Oikonomopoulou C, Kałwak K, Drabko K, Wynn R, Morris EC, Elcombe S, Bigley V, Lougaris V, Malagola M, Hauck F, Sedlacek P, Laberko A, Tjon JML, Buddingh EP, Wehr C, Grimbacher B, Gennery AR, Lankester AC, Albert MH, Neven B, and Slatter MA
- Abstract
Background: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterised by lymphoproliferation, dysgammaglobulinaemia, and multi-organ autoimmunity including cytopenias and colitis., Objective: To examine the outcome of HSCT for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4-Ig therapy and pre-HSCT immune dysregulation on survival and immunological outcome., Methods: Retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the Inborn Errors Working Party of EBMT. Primary endpoints were overall survival (OS) and disease- and chronic GvHD-free survival (DFS). Secondary endpoint was immunological outcome assessed by Immune Dysregulation Disease Activity (IDDA) score., Results: Forty patients were included over a 25-year period. Pre-HSCT, 60% received CTLA-4-Ig and IDDA was 23.3 (3.9-84.0). Median age at HSCT was 14.2 (1.3-56.0) years. Patients received PBSC (58%) or marrow (43%) from MUD (75%), MMUD (12.5%) or MFD (12.5%). Median follow-up was 3 years (0.6-15 years) and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, 28/30 surviving patients are in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity pre-HSCT (IDDA<23, p=0.002 and p=0.006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant-related in 7/8 patients., Conclusion: This is the largest retrospective study of HSCT for CTLA-4 insufficiency to date. HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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40. The different faces of GATA2 deficiency: implications for therapy and surveillance.
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Vinci L, Strahm B, Speckmann C, and Erlacher M
- Abstract
GATA2 deficiency is one of the most common genetic predispositions to pediatric myelodysplastic syndrome (MDS) in children and adolescents. The wide spectrum of disease comprises, among others, hematological, immunological and pulmonary manifestations, as well as occasionally distinct organ anomalies. Due to the elevated risk of progression, nearly all individuals with GATA2-related MDS eventually undergo a hematopoietic stem cell transplantation (HSCT) at some point in their lives. Nevertheless, the optimal timing, method, and even the indication for HSCT in certain cases are still matter of debate and warrant further research. In this article, we report five patients with different hematological and immunological manifestations of GATA2 deficiency ranging from immunodeficiency and refractory cytopenia of childhood without chromosomal aberrations to relapsed MDS-related acute myeloid leukemia. We discuss the adopted strategies, including intensity of surveillance, indication and timing of HSCT, based on morphological, clinical and molecular markers, as well as individual patient needs. We conclude that a better characterization of the natural disease course, a better understanding of the prognostic significance of somatic aberrations and a thorough evaluation of patients´ perspectives and preferences are required to achieve a personalized approach aimed at improving the care of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vinci, Strahm, Speckmann and Erlacher.)
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- 2024
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41. Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation.
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Böhm S, Wustrau K, Pachlopnik Schmid J, Prader S, Ahlmann M, Yacobovich J, Beier R, Speckmann C, Behnisch W, Ifversen M, Jordan M, Marsh R, Naumann-Bartsch N, Mauz-Körholz C, Hönig M, Schulz A, Malinowska I, Hines M, Nichols KE, Gil-Herrera J, Talano JA, Crooks B, Formankova R, Jorch N, Bakhtiar S, Kühnle I, Streiter M, Nathrath M, Russo A, Dürken M, Lang P, Lindemans C, Henter JI, Lehmberg K, and Ehl S
- Subjects
- Infant, Newborn, Humans, Etoposide therapeutic use, Treatment Outcome, Lymphohistiocytosis, Hemophagocytic drug therapy, Lymphohistiocytosis, Hemophagocytic diagnosis, Hematopoietic Stem Cell Transplantation methods, Lymphoproliferative Disorders etiology
- Abstract
Abstract: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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42. Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.
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Hägele P, Staus P, Scheible R, Uhlmann A, Heeg M, Klemann C, Maccari ME, Ritterbusch H, Armstrong M, Cutcutache I, Elliott KS, von Bernuth H, Leahy TR, Leyh J, Holzinger D, Lehmberg K, Svec P, Masjosthusmann K, Hambleton S, Jakob M, Sparber-Sauer M, Kager L, Puzik A, Wolkewitz M, Lorenz MR, Schwarz K, Speckmann C, Rensing-Ehl A, and Ehl S
- Subjects
- Male, Female, Child, Humans, Child, Preschool, Adolescent, Prospective Studies, Biomarkers, Adaptor Proteins, Signal Transducing genetics, Autoimmune Lymphoproliferative Syndrome diagnosis, Autoimmune Lymphoproliferative Syndrome genetics, Autoimmune Lymphoproliferative Syndrome therapy, Common Variable Immunodeficiency, Anemia, Hemolytic, Autoimmune, Thrombocytopenia
- Abstract
Background: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification., Methods: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing., Findings: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses., Interpretation: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome., Funding: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SE are members of a data monitoring committee for leniolisib (Pharming). SH and SE received research funding from Pharming. MA and IC are a full-time employees of UCB Pharma and are shareholders of UCB. SE received research support from UCB for this study, including the whole-genome trio analysis of 30 families. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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43. Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.
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Migliavacca M, Barzaghi F, Fossati C, Rancoita PMV, Gabaldo M, Dionisio F, Giannelli S, Salerio FA, Ferrua F, Tucci F, Calbi V, Gallo V, Recupero S, Consiglieri G, Pajno R, Sambuco M, Priolo A, Ferri C, Garella V, Monti I, Silvani P, Darin S, Casiraghi M, Corti A, Zancan S, Levi M, Cesana D, Carlucci F, Pituch-Noworolska A, AbdElaziz D, Baumann U, Finocchi A, Cancrini C, Ladogana S, Meinhardt A, Meyts I, Montin D, Notarangelo LD, Porta F, Pasquet M, Speckmann C, Stepensky P, Tommasini A, Rabusin M, Karakas Z, Galicchio M, Leonardi L, Duse M, Guner SN, Di Serio C, Ciceri F, Bernardo ME, Aiuti A, and Cicalese MP
- Subjects
- Humans, Adenosine Deaminase genetics, Adenosine Deaminase therapeutic use, Busulfan adverse effects, Genetic Therapy, Retroviridae genetics, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy, Hematopoietic Stem Cell Transplantation, Agammaglobulinemia
- Abstract
Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34
+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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44. Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome.
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Pellé O, Moreno S, Lorenz MR, Riller Q, Fuehrer M, Stolzenberg MC, Maccari ME, Lenoir C, Cheminant M, Hinze T, Hebart HF, König C, Schvartz A, Schmitt Y, Vinit A, Henry E, Touzart A, Villarese P, Isnard P, Neveux N, Landman-Parker J, Picard C, Fouyssac F, Neven B, Grimbacher B, Speckmann C, Fischer A, Latour S, Schwarz K, Ehl S, Rieux-Laucat F, Rensing-Ehl A, and Magérus A
- Subjects
- Humans, Apoptosis genetics, Autoimmune Diseases genetics, Comparative Genomic Hybridization, DNA, fas Receptor genetics, Germ Cells pathology, Mutation, Autoimmune Lymphoproliferative Syndrome genetics, Fas-Associated Death Domain Protein genetics, Fas-Associated Death Domain Protein metabolism
- Abstract
Background: The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated., Objective: We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent., Methods: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4
+ or DN T cells., Results: We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations., Conclusions: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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45. Impact of newborn screening for SCID on the management of congenital athymia.
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Howley E, Golwala Z, Buckland M, Barzaghi F, Ghosh S, Hackett S, Hague R, Hauck F, Holzer U, Klocperk A, Koskenvuo M, Marcus N, Marzollo A, Pac M, Sinclair J, Speckmann C, Soomann M, Speirs L, Suresh S, Taque S, van Montfrans J, von Bernuth H, Wainstein BK, Worth A, Davies EG, and Kreins AY
- Subjects
- Infant, Infant, Newborn, Humans, Neonatal Screening, Thymus Gland, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency therapy, Immunologic Deficiency Syndromes
- Abstract
Background: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom)., Objective: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH., Methods: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation., Results: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation., Conclusion: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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46. JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.
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Fischer M, Olbrich P, Hadjadj J, Aumann V, Bakhtiar S, Barlogis V, von Bismarck P, Bloomfield M, Booth C, Buddingh EP, Cagdas D, Castelle M, Chan AY, Chandrakasan S, Chetty K, Cougoul P, Crickx E, Dara J, Deyà-Martínez A, Farmand S, Formankova R, Gennery AR, Gonzalez-Granado LI, Hagin D, Hanitsch LG, Hanzlikovà J, Hauck F, Ivorra-Cortés J, Kisand K, Kiykim A, Körholz J, Leahy TR, van Montfrans J, Nademi Z, Nelken B, Parikh S, Plado S, Ramakers J, Redlich A, Rieux-Laucat F, Rivière JG, Rodina Y, Júnior PR, Salou S, Schuetz C, Shcherbina A, Slatter MA, Touzot F, Unal E, Lankester AC, Burns S, Seppänen MRJ, Neth O, Albert MH, Ehl S, Neven B, and Speckmann C
- Subjects
- Child, Humans, Retrospective Studies, Prospective Studies, Treatment Outcome, Janus Kinase Inhibitors therapeutic use, Immunologic Deficiency Syndromes therapy
- Abstract
Background: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited., Objective: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers., Methods: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months., Results: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival., Conclusions: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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47. Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing.
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Rensing-Ehl A, Lorenz MR, Führer M, Willenbacher W, Willenbacher E, Sopper S, Abinun M, Maccari ME, König C, Haegele P, Fuchs S, Castro C, Kury P, Pelle O, Klemann C, Heeg M, Thalhammer J, Wegehaupt O, Fischer M, Goldacker S, Schulte B, Biskup S, Chatelain P, Schuster V, Warnatz K, Grimbacher B, Meinhardt A, Holzinger D, Oommen PT, Hinze T, Hebart H, Seeger K, Lehmberg K, Leahy TR, Claviez A, Vieth S, Schilling FH, Fuchs I, Groß M, Rieux-Laucat F, Magerus A, Speckmann C, Schwarz K, and Ehl S
- Subjects
- Humans, Biomarkers, DNA Copy Number Variations, Exome Sequencing, Fas-Associated Death Domain Protein genetics, Mutation, Autoimmune Lymphoproliferative Syndrome diagnosis, Autoimmune Lymphoproliferative Syndrome genetics, fas Receptor genetics
- Abstract
Background: Elevated TCRαβ
+ CD4- CD8- double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U)., Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases., Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57+ DNT, which can predict somatic loss of heterozygosity (sLOH)., Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+ DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH., Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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48. C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib.
- Author
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Kapp FG, Kretschmer S, Beckmann CCA, Wäsch L, Molitor A, Carapito R, Schubert M, Lucas N, Conrad S, Poignant S, Isidor B, Rohlfs M, Kisaarslan AP, Schanze D, Zenker M, Schmitt-Graeff A, Strahm B, Peters A, Yoshimi A, Driever W, Zillinger T, Günther C, Maharana S, Guan K, Klein C, Ehl S, Niemeyer CM, Unal E, Bahram S, Hauck F, Lee-Kirsch MA, and Speckmann C
- Subjects
- Humans, Infant, Newborn, cdc42 GTP-Binding Protein, Inflammasomes genetics, Nitriles, Syndrome, Interferon Type I, Lymphohistiocytosis, Hemophagocytic etiology
- Abstract
C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments. Here, we demonstrate in four NOCARH patients from three families that cell-intrinsic activation of type I interferon (IFN) is a previously unrecognized driver of autoinflammation in NOCARH. Our data show that aberrant innate immune activation is caused by sensing of cytosolic nucleic acids released from mitochondria, which exhibit disturbances in integrity and dynamics due to CDC42 dysfunction. In one of our patients, treatment with the Janus kinase inhibitor ruxolitinib led to complete remission, indicating that inhibition of type I IFN signaling may have an important role in the management of autoinflammation in patients with NOCARH., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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49. [Newborn screening for severe combined immunodeficiencies (SCID) in Germany].
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Ghosh S, Albert MH, Hauck F, Hönig M, Schütz C, Schulz A, and Speckmann C
- Subjects
- Infant, Infant, Newborn, Humans, United States, Neonatal Screening methods, Germany, T-Lymphocytes, Receptors, Antigen, T-Cell genetics, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency therapy, Severe Combined Immunodeficiency epidemiology, Lymphopenia diagnosis
- Abstract
Patients with a severe combined immunodeficiency (SCID) harbor genetic mutations disrupting T cell immunity and hence suffer severe, life-threatening infections or manifestations of immune dysregulation within the first months of their life. The only cure is to correct their immune system, usually by means of hematopoietic stem cell transplantation (HSCT). Pilot studies and national programs in the United States and in European countries have shown that patients can be identified at an early asymptomatic stage through newborn screening. This allows treatment before the occurrence of severe complications, which improves the outcome of curative strategies like HSCT.After assessment by the Federal Joint Committee (G-BA), the SCID screening was implemented into newborn screening in Germany in 2019. The first results of the screening (dry blood spot cards from around 2 million newborns between August 2019 and February 2022) were recently published. As expected, in addition to classic SCID diseases (incidence 1:54,000), infants with syndromic disorders and T cell lymphopenia were also identified. All patients with classic SCID were scheduled for curative treatment. Of the 25 patients with classic SCID, 21 were already transplanted at the time of data analysis. Only one of 21 transplanted patients died due to pre-existing infections. A comparison of the recent screening data with historical data suggests that SCID newborn screening has been successfully implemented in Germany. Patients with SCID are routinely identified very early and scheduled for curative therapy., (© 2023. The Author(s).)
- Published
- 2023
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50. Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
- Author
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Maccari ME, Wolkewitz M, Schwab C, Lorenzini T, Leiding JW, Aladjdi N, Abolhassani H, Abou-Chahla W, Aiuti A, Azarnoush S, Baris S, Barlogis V, Barzaghi F, Baumann U, Bloomfield M, Bohynikova N, Bodet D, Boutboul D, Bucciol G, Buckland MS, Burns SO, Cancrini C, Cathébras P, Cavazzana M, Cheminant M, Chinello M, Ciznar P, Coulter TI, D'Aveni M, Ekwall O, Eric Z, Eren E, Fasth A, Frange P, Fournier B, Garcia-Prat M, Gardembas M, Geier C, Ghosh S, Goda V, Hammarström L, Hauck F, Heeg M, Heropolitanska-Pliszka E, Hilfanova A, Jolles S, Karakoc-Aydiner E, Kindle GR, Kiykim A, Klemann C, Koletsi P, Koltan S, Kondratenko I, Körholz J, Krüger R, Jeziorski E, Levy R, Le Guenno G, Lefevre G, Lougaris V, Marzollo A, Mahlaoui N, Malphettes M, Meinhardt A, Merlin E, Meyts I, Milota T, Moreira F, Moshous D, Mukhina A, Neth O, Neubert J, Neven B, Nieters A, Nove-Josserand R, Oksenhendler E, Ozen A, Olbrich P, Perlat A, Pac M, Schmid JP, Pacillo L, Parra-Martinez A, Paschenko O, Pellier I, Sefer AP, Plebani A, Plantaz D, Prader S, Raffray L, Ritterbusch H, Riviere JG, Rivalta B, Rusch S, Sakovich I, Savic S, Scheible R, Schleinitz N, Schuetz C, Schulz A, Sediva A, Semeraro M, Sharapova SO, Shcherbina A, Slatter MA, Sogkas G, Soler-Palacin P, Speckmann C, Stephan JL, Suarez F, Tommasini A, Trück J, Uhlmann A, van Aerde KJ, van Montfrans J, von Bernuth H, Warnatz K, Williams T, Worth AJJ, Ip W, Picard C, Catherinot E, Nademi Z, Grimbacher B, Forbes Satter LR, Kracker S, Chandra A, Condliffe AM, and Ehl S
- Subjects
- Humans, Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases, CTLA-4 Antigen genetics, Mutation, Registries, Phosphatidylinositol 3-Kinase genetics, Primary Immunodeficiency Diseases genetics
- Abstract
Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking., Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS., Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs., Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS., Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
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