Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
作者全名："Geier, Christoph B.; Ellison, Maryssa; Cruz, Rachel; Pawar, Sumit; Leiss-Piller, Alexander; Zmajkovicova, Katarina; McNulty, Shannon M.; Yilmaz, Melis; Evans, Martin Oman, II; Gordon, Sumai; Ujhazi, Boglarka; Wiest, Ivana; Abolhassani, Hassan; Aghamohammadi, Asghar; Barmettler, Sara; Bhar, Saleh; Bondarenko, Anastasia; Bolyard, Audrey Anna; Buchbinder, David; Cada, Michaela; Cavieres, Mirta; Connelly, James A.; Dale, David C.; Deordieva, Ekaterina; Dorsey, Morna J.; Drysdale, Simon B.; Ehl, Stephan; Elfeky, Reem; Fioredda, Francesca; Firkin, Frank; Forster-Waldl, Elizabeth; Geng, Bob; Goda, Vera; Gonzalez-Granado, Luis; Grunebaum, Eyal; Grzesk, Elzbieta; Henrickson, Sarah E.; Hilfanova, Anna; Hiwatari, Mitsuteru; Imai, Chihaya; Ip, Winnie; Jyonouchi, Soma; Kanegane, Hirokazu; Kawahara, Yuta; Khojah, Amer M.; Kim, Vy Hong-Diep; Kojic, Marina; Koltan, Sylwia; Krivan, Gergely; Langguth, Daman; Lau, Yu-Lung; Leung, Daniel; Miano, Maurizio; Mersyanova, Irina; Mousallem, Talal; Muskat, Mica; Naoum, Flavio A.; Noronha, Suzie A.; Ouederni, Monia; Ozono, Shuichi; Richmond, G. Wendell; Sakovich, Inga; Salzer, Ulrich; Schuetz, Catharina; Seeborg, Filiz Odabasi; Sharapova, Svetlana O.; Sockel, Katja; Volokha, Alla; von Bonin, Malte; Warnatz, Klaus; Wegehaupt, Oliver; Weinberg, Geoffrey A.; Wong, Ke-Juin; Worth, Austen; Yu, Huang; Zharankova, Yulia; Zhao, Xiaodong; Devlin, Lisa; Badarau, Adriana; Csomos, Krisztian; Keszei, Marton; Pereira, Joao; Taveras, Arthur G.; Beaussant-Cohen, Sarah L.; Ong, Mei-Sing; Shcherbina, Anna; Walter, Jolan E."
作者地址："[Geier, Christoph B.; Ehl, Stephan; Warnatz, Klaus; Wegehaupt, Oliver] Univ Freiburg, Med Ctr, Ctr Chron Immunodeficiency, Inst Immunodeficiency,Fac Med, Freiburg, Germany; [Geier, Christoph B.; Salzer, Ulrich; Warnatz, Klaus] Univ Freiburg, Med Ctr, Fac Med,Dept Rheumatol & Clin Immunol, Ctr Chron Immunodeficiency, Freiburg, Germany; [Ellison, Maryssa; Cruz, Rachel; Yilmaz, Melis; Gordon, Sumai; Ujhazi, Boglarka; Csomos, Krisztian; Walter, Jolan E.] Univ S Florida, Dept Pediat, Div Pediat Allergy & Immunol, St Petersburg, FL 33701 USA; [Cruz, Rachel] Univ S Florida, Morsani Coll Med, Tampa, FL USA; [Pawar, Sumit; Zmajkovicova, Katarina; Wiest, Ivana; Badarau, Adriana] X4 Pharmaceut Austria GmbH, Vienna, Austria; [Leiss-Piller, Alexander] Immunol Outpatient Clin, Vienna, Austria; [McNulty, Shannon M.] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA; [Evans, Martin Oman, II] Blanchfield Army Community Hosp, Ft Campbell, KY USA; [Abolhassani, Hassan; Aghamohammadi, Asghar] Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran; [Abolhassani, Hassan] Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol, Karolinska Inst, Stockholm, Sweden; [Barmettler, Sara] Massachusetts Gen Hosp, Allergy & Clin Immunol Unit, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA; [Bhar, Saleh] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat,Bone Marrow Transplantat, Sect Hematol Oncol & Crit Care Med, Houston, TX 77030 USA; [Bondarenko, Anastasia; Hilfanova, Anna; Volokha, Alla] Shupyk Natl Med Acad Postgrad Educ, Kiev, Ukraine; [Bolyard, Audrey Anna] Univ Washington, Severe Chron Neutropenia Int Registry, Seattle, WA 98195 USA; [Buchbinder, David] CHOC Childrens Hosp, Div Hematol, Orange, CA USA; [Cada, Michaela] Hosp Sick Children, Div Hematol & Oncol, Toronto, ON, Canada; [Cada, Michaela; Grunebaum, Eyal; Kim, Vy Hong-Diep] Univ Toronto, Dept Pediat, Toronto, ON, Canada; [Cavieres, Mirta] Dr Luis Calvo Mackenna Childrens Hosp, Hematol Unit, Santiago, Chile; [Connelly, James A.] Vanderbilt Univ Sch Med, Nashville, TN USA; [Dale, David C.] Univ Washington, Dept Med, Seattle, WA USA; [Deordieva, Ekaterina; Mersyanova, Irina; Shcherbina, Anna] Dmitry Rogachev Natl Med Ctr Pediat Hematol Oncol, Immunol, Moscow, Russia; [Dorsey, Morna J.] UCSF Benioff Childrens Hosp, Dept Pediat, Div Allergy Immunol & Blood & Marrow Transplantat, San Francisco, CA USA; [Drysdale, Simon B.] St Georges Univ Hosp NHS Fdn Trust, Paediat Infect Dis Res Grp, London, England; [Elfeky, Reem] Royal Free Hosp, Dept Clin Immunol, London, England; [Fioredda, Francesca; Miano, Maurizio] IRCCS Ist Giannina Gaslini, Haematol Unit, Genoa, Italy; [Firkin, Frank] Univ Melbourne, Dept Med, St Vincents Hosp, Fitzroy, Vic, Australia; [Firkin, Frank] St Vincents Hosp, Dept Clin Haematol, Fitzroy, Vic, Australia; [Forster-Waldl, Elizabeth; Kojic, Marina] Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria; [Forster-Waldl, Elizabeth] Med Univ Vienna, Dept Pediat & Adolescent Med, Div Neonatol Pediat Intens Care & Neuropediat, Vienna, Austria; [Forster-Waldl, Elizabeth] Med Univ Vienna, Ctr Congenital Immunodeficiencies, Vienna, Austria; [Forster-Waldl, Elizabeth] Jeffrey Modell Diagnost & Res Ctr, Vienna, Austria; [Geng, Bob] Univ Calif San Diego, Div Adult & Pediat Allergy, San Diego, CA 92103 USA; [Geng, Bob] Univ Calif San Diego, Div Immunol, San Diego, CA 92103 USA; [Goda, Vera; Krivan, Gergely] Cent Hosp Southern Pest, Dept Pediat Hematol & Hemopoiet Stem Cell Transpl, Natl Inst Hematol & Infect Dis, Budapest, Hungary; [Gonzalez-Granado, Luis] Univ Hosp 12 Octubre, Res Inst Hosp 12 Octubre, Dept Pediat, Immunodeficiencies Unit, Madrid, Spain; [Grunebaum, Eyal; Kim, Vy Hong-Diep] Hosp Sick Children, Div Immunol & Allergy, Toronto, ON, Canada; [Grzesk, Elzbieta; Koltan, Sylwia] Bydgoszcz Nicolaus Copernicus Univ, Hematol & Oncol Coll Med, Dept Pediat, Torun, Poland; [Henrickson, Sarah E.] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA 19104 USA; [Henrickson, Sarah E.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA; [Henrickson, Sarah E.] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA; [Hiwatari, Mitsuteru] Univ Tokyo, Grad Sch Med, Dept Pediat, Tokyo, Japan; [Imai, Chihaya] Niigata Univ, Dept Pediat, Grad Sch Med & Dent Sci, Niigata, Japan; [Imai, Chihaya] Niigata Univ Med & Dent Hosp, Dept Pediat, Niigata, Japan; [Ip, Winnie; Worth, Austen] Great Ormond St Hosp Sick Children, London, England; [Jyonouchi, Soma] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Div Allergy & Immunol,Dept Pediat, Philadelphia, PA 19104 USA; [Kanegane, Hirokazu] Tokyo Med & Dent Univ TMDU, Grad Sch Med & Dent Sci, Dept Child Hlth & Dev, Tokyo, Japan; [Kawahara, Yuta] Jichi Med Univ, Dept Pediat, Sch Med, Shimotsuke, Tochigi, Japan; [Khojah, Amer M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA; [Langguth, Daman] Sullivan & Nicolaides Pathol, Dept Immunol, Brisbane, Qld, Australia; [Lau, Yu-Lung; Leung, Daniel] Univ Hong Kong, Dept Paediat & Adolescent Med, Hong Kong, Peoples R China; [Mousallem, Talal] Duke Univ Med Ctr, Dept Pediat, Div Pediat Allergy & Immunol, Durham, NC USA; [Muskat, Mica] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA USA; [Naoum, Flavio A.] Acad Ciencia & Tecnol, Sao Jose Do Rio Preto, Brazil; [Noronha, Suzie A.] Univ Rochester, Med Ctr, Dept Pediat, Div Hematol Oncol, Rochester, NY 14642 USA; [Ouederni, Monia] Univ Tunis El Manar, Fac Med, Tunis, Tunisia; [Ouederni, Monia] Bone Marrow Transplantat Ctr Tunisia, Dept Pediat Immunohematol & Stem Cell Transplanta, Tunis, Tunisia; [Ozono, Shuichi] Kurume Univ, Dept Pediat, Sch Med, 67 Asahi Machi, Kurume, Fukuoka, Japan; [Richmond, G. Wendell] Rush Univ Med Ctr, Sect Allergy & Immunol, Chicago, IL USA; [Sakovich, Inga; Sharapova, Svetlana O.; Zharankova, Yulia] Belarusian Res Ctr Pediat Oncol Hematol & Immunol, Res Dept, Minsk, BELARUS; [Schuetz, Catharina] Tech Univ Dresden, Dept Pediat, Med Fak Carl Gustav Carus, Dresden, Germany; [Seeborg, Filiz Odabasi] Baylor Coll Med, Sect Immunol Allergy & Rheumatol, Dept Pediat, Houston, TX 77030 USA; [Seeborg, Filiz Odabasi] Texas Childrens Hosp, Houston, TX 77030 USA; [Sockel, Katja] Univ Hosp Carl Gustav Carus, Dept Internal Med 1, Dresden, Germany; [von Bonin, Malte] Univ Klinikum Dresden, Med Klin & Poliklin 1, Dresden, Germany; [Wegehaupt, Oliver] Univ Freiburg, Fac Med, Ctr Pediat & Adolescent Med, Med Ctr, Freiburg, Germany; [Weinberg, Geoffrey A.] Univ Rochester, Sch Med & Dent, Dept Pediat, Golisano Childrens Hosp, Rochester, NY 14642 USA; [Wong, Ke-Juin] Sabah Women & Childrens Hosp, Kota Kinabalu, Sabah, Malaysia; [Yu, Huang; Zhao, Xiaodong] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Children Hosp, Chongqing 400014, Peoples R China; [Devlin, Lisa] Belfast Hlth & Social Care Trust, Belfast, Antrim, North Ireland; [Devlin, Lisa] Belfast Hlth & Social Care Trust, Reg Immunol Serv, Belfast, Antrim, North Ireland; [Keszei, Marton] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden; [Pereira, Joao] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA; [Taveras, Arthur G.; Beaussant-Cohen, Sarah L.] X4 Pharmaceut Inc, Cambridge, MA USA; [Ong, Mei-Sing] Harvard Med Sch, Dept Populat Med, Boston, MA 02115 USA; [Ong, Mei-Sing] Harvard Pilgrim Hlth Care Inst, Boston, MA USA; [Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Allergy & Immunol, Boston, MA 02114 USA"
通信作者："Walter, JE (通讯作者)，Univ S Florida, Dept Pediat, Div Pediat Allergy & Immunol, St Petersburg, FL 33701 USA.; Walter, JE (通讯作者)，Massachusetts Gen Hosp Children, Div Allergy & Immunol, Boston, MA 02114 USA."
来源：JOURNAL OF CLINICAL IMMUNOLOGY
ESI学科分类：IMMUNOLOGY
WOS号：WOS:000838547000002
JCR分区：Q1
影响因子：9.1
年份：2022
卷号：
期号：
开始页：
结束页：
文献类型：Article; Early Access
关键词：CXCR4; myelokathexis; warts; autoimmunity; neutropenia; lymphopenia
摘要："Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts."
基金机构："National Institutes of Health [R01AI100887-05, R24AI 049393]; Robert A. Good Endowment, University of South Florida; Jeffrey Modell Foundation; X4 Pharmaceuticals, Inc.; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [K23AI163350]"
基金资助正文："This work was supported by the National Institutes of Health (sub-R01AI100887-05 to JW, R24AI 049393 to DCD), Robert A. Good Endowment, University of South Florida (to JW), and Jeffrey Modell Foundation (to JW). This study was supported by research funding from X4 Pharmaceuticals, Inc. Sara Barmettler is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number K23AI163350. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health."
