Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
Authors: Geier Christoph B. , Ellison Maryssa , Cruz Rachel , Pawar Sumit , Leiss-Piller Alexander , Zmajkovicova Katarina , McNulty Shannon M , Yilmaz Melis , Evans Martin Oman , 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 , Förster-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 , Kojić Marina , Kołtan 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. 
Published: August 2022

Abstract
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.