Persistent High Risk HPV Infection in the Presence of a Pathogenic FAS Mutation

Abstract

IntroductionAutoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to aberrant lymphocyte homeostasis. It mainly results from mutations in the Fas-mediated apoptotic pathway, with deleterious heterozygous mutations in the FAS gene being most common. While patients with pathogenic FAS mutations often demonstrate defective apoptosis in vitro, this is not sufficient to diagnose clinical disease and disease penetrance is less than 60%. Although lymphomas have been reported in FAS mutation positive, disease negative patients, to our knowledge persistent HPV infection has not previously been reported in this context. Case DescriptionA 58-year-old lady was evaluated for persistent human papillomavirus (HPV) infection. HPV 16 positive dysplasia of the cervical, vulvar, vaginal, and anal canal was identified at age 30. Despite treatment, subsequent smears and anoscopy examinations were without dysplasia but with persistent HPV 16 infection. Past medical history was notable for Bechet’s disease and Sjogren’s Syndrome. Family history was noncontributory. Complete blood count and lymphocyte enumeration were normal. Immunoglobulin levels (IgG and IgM) were normal with elevated IgA (397 mg/dL). Vitamin B12 level was increased (1,569 pg/mL). Double negative T cells (DNTs) were normal (28 cells/mcL). There was a mild increase in double negative T cells expressing B220 (15 cells/mcL; reference < 6 cells/ mcL). Fas-mediated apoptosis was decreased at 40% (reference >/ = 56%). Cytokine panel demonstrated normal IL-10 level. Prior imaging was without lymphadenopathy or hepatosplenomegaly. Whole exome sequencing was normal. Whole genome sequencing demonstrated a pathogenic variant in FAS [c.429dup (p.Asp144*)]. DiscussionChronic nonmalignant noninfectious lymphadenopathy and/or splenomegaly and elevated DNTs are required for the diagnosis of ALPS. Our patient does not meet the definition of clinical ALPS but has a confirmed pathogenic mutation, defective Fas-mediated apoptosis, and elevated serum B12 level. While ALPS is associated with an increased risk for both Hodgkin’s lymphoma and a non-Hodgkin’s lymphoma, the presence of a pathogenic FAS mutation has not been reported in association with persistent HPV infection previously to our knowledge. This case highlights the expanded clinical phenotype possible in the presence of pathogenic FAS mutations and highlights the need for close cancer surveillance in mutation positive, disease negative patients.