XPC gene variation in an individual with generalized eruptive keratoacanthomas of grzybowski

Summary: Generalized eruptive keratoacanthomas of Grzybowski (GEKA) is a rare variant of keratoacanthoma (KA) that is characterized by development of hundreds of KAs and has no known germline genetic cause. A 64-year-old white male was referred to our dermatology department in 2023. He had developed frequent keratoacanthoma type squamous cell carcinomas since 2016 and was diagnosed with GEKA in 2018. His physical exam was notable for several widely distributed, solitary, dome-shaped, skin-colored nodules with a central keratinous plug, which were confirmed as KAs on biopsy. Treatments included topical 5-fluorouracil, 5-fluorouracil + calcipotriene cream, imiquimod, triamcinolone cream, and clobetasol ointment; injected 5-fluorouracil and triamcinolone; and oral nicotinamide, acitretin, methotrexate, and cyclophosphamide. These treatments were variably effective in reducing but not eliminating additional KAs. To investigate the genetic cause of his predisposition to KAs, library preparation and next-generation sequencing (NGS) of coding regions of approximately 4800 medically relevant genes was conducted with targeted gene analysis planned. Initial referral for sequencing targeted the <i>TGFBR1</i> gene which was negative. Expanded analysis identified two variants of uncertain significance in <i>XPC</i>. <i>TGFBR1</i> has been shown to play a role in KA development and Multiple Self-Healing Squamous Epithelioma and Loeys-Dietz Syndrome. Prior studies have shown an association between <i>XPC</i> germline mutations and KA development as well as decreased <i>XPC</i> expression levels in KAs, but no studies have linked it directly to GEKA. Similarly, GEKA has been linked to HPV 39 infection, and sporadic keratoacanthomas have shown positivity with multiple HPV subtypes, but this testing is not currently available at our institution. Further testing is indicated to determine the significance of these genetic findings and to explore the role of HPV in GEKA. Jordan Gillespie¹, Afsoon Ghafari-Saravi¹, Amiee Potter¹, Alaa Koleilat¹, Timothy D. O’Brien¹, Arpita Kulkarni¹, Sue Richards¹, Sarah McCabe¹, Sancy Leachman¹ 1. Oregon Health & Science University, Portland, OR, United States. UV Biology/Injury and Non-melanoma Cancers