Ehren Dancy ¹ Pamela Stratton ^2,3* Dominique Pichard ⁴ Beatriz E. Marciano ⁵ Edward Cowen ⁶ Alison A. Mcbride ⁷ Koenraad M. Van Doorslaer ^7,8 Melissa A. Merideth ⁹ Noemi Salmeri ^10,11 Marybeth S. Hughes ¹² Theo Heller ¹³ Mark Parta ¹⁴ Dennis HIckstein ¹⁵ Heidi H. Kong ⁶ Steven M. Holland ⁵ Christa Zerbe ⁵

• ¹ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Phialdelphia, Pennsylvania, United States
• ² National Institutes of Health (NIH), Bethesda, United States
• ³ National Institute of Neurological Disorders and Stroke (NIH), Bethesda, Maryland, United States
• ⁴ National Center for Advancing Translational Sciences (NIH), Bethesda, Maryland, United States
• ⁵ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIH), Bethesda, Maryland, United States
• ⁶ Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH), Bethesda, Maryland, United States
• ⁷ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases (NIH), Bethesda, Maryland, United States
• ⁸ Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, United States
• ⁹ Division of Intramural Research, National Human Genome Research Institute (NIH), Bethesda, Maryland, United States
• ¹⁰ San Raffaele Scientific Institute (IRCCS), Milan, Lombardy, Italy
• ¹¹ Department of Rehabilitation Medicine, Clinical Center (NIH), Bethesda, Maryland, United States
• ¹² Eastern Virginia Medical School, Norfolk, Virginia, United States
• ¹³ National Institute of Diabetes and Digestive and Kidney Diseases (NIH), Bethesda, Maryland, United States
• ¹⁴ Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick (NIH), Frederick, Maryland, United States
• ¹⁵ Center for Cancer Research, National Cancer Institute (NIH), Bethesda, Maryland, United States

Objective: Patients with pathogenic variants in the GATA Binding Protein 2 (GATA2), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with GATA2 haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males.Methods: A 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with GATA2 haploinsufficiency followed at the National Institutes of Health. Student's t-test and Mann-Whitney U test or Fisher's exact test were used to compare differences in continuous or categorical variables, respectively. Spearman's rho coefficient was employed for correlations.Results: Of 68 patients with GATA2 haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males.Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from GATA2 haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males.Females with GATA2 haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. GATA2 haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.