Christoph B. Geier, Maryssa Ellison, Rachel Cruz, Sumit Pawar, Alexander Leiss-Piller, Katarina Zmajkovicova, Shannon M McNulty, Melis Yilmaz, Martin Oman Evans, Sumai Gordon, Boglarka Ujhazi, Ivana Wiest, Hassan Abolhassani, Asghar Aghamohammadi, Sara Barmettler, Saleh Bhar, Anastasia Bondarenko, Audrey Anna Bolyard, David Buchbinder, Michaela Cada, Mirta Cavieres, James A. Connelly, David C. Dale, Ekaterina Deordieva, Morna J. Dorsey, Simon B. Drysdale, Stephan Ehl, Reem Elfeky, Francesca Fioredda, Frank Firkin, Elizabeth Förster-Waldl, Bob Geng, Vera Goda, Luis Gonzalez-Granado, Eyal Grunebaum, Elzbieta Grzesk, Sarah E. Henrickson, Anna Hilfanova, Mitsuteru Hiwatari, Chihaya Imai, Winnie Ip, Soma Jyonouchi, Hirokazu Kanegane, Yuta Kawahara, Amer M. Khojah, Vy Hong-Diep Kim, Marina Kojić, Sylwia Kołtan, Gergely Krivan, Daman Langguth, Yu-Lung Lau, Daniel Leung, Maurizio Miano, Irina Mersyanova, Talal Mousallem, Mica Muskat, Flavio A. Naoum, Suzie A. Noronha, Monia Ouederni, Shuichi Ozono, G. Wendell Richmond, Inga Sakovich, Ulrich Salzer, Catharina Schuetz, Filiz Odabasi Seeborg, Svetlana O. Sharapova, Katja Sockel, Alla Volokha, Malte von Bonin, Klaus Warnatz, Oliver Wegehaupt, Geoffrey A. Weinberg, Ke-Juin Wong, Austen Worth, Huang Yu, Yulia Zharankova, Xiaodong Zhao, Lisa Devlin, Adriana Badarau, Krisztian Csomos, Marton Keszei, Joao Pereira, Arthur G Taveras, Sarah L. Beaussant-Cohen, Mei-Sing Ong, Anna Shcherbina, and Jolan E. Walter
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.