Novel PI3Kc Mutation in a 44-Year-Old Man with Chronic Infections and Chronic Pelvic Pain

A 44-year-old man is presented here with 14 years of chronic purulent sinusitis, a chronic fungal rash of the scrotum, and chronic pelvic pain. Treatment with antifungal therapy resulted in symptom improvement, however he was unable to establish an effective long-term treatment regimen, resulting in debilitating symptoms. He had undergone extensive workup without identifying a clear underlying etiology, although Candida species were cultured from the prostatic fluid. 100 genes involved in the cellular immune response were sequenced and a missense mutation was identified in the Ras-binding domain of PI3Kc. PI3Kc is a crucial signaling element in leukotaxis and other leukocyte functions. We hypothesize that his mutation led to his chronic infections and pelvic pain. Citation: Bojarski EF, Strauss AC, Fagin AP, Plantinga TS, Hoischen A, et al. (2013) Novel PI3Kc Mutation in a 44-Year-Old Man with Chronic Infections and Chronic Pelvic Pain. PLoS ONE 8(7): e68118. doi:10.1371/journal.pone.0068118 Editor: Joy Sturtevant, Louisiana State University, United States of America Received March 13, 2013; Accepted May 24, 2013; Published July 8, 2013 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work was supported by a Vici Grant of the Netherlands Organization for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work. Introduction and Materials and Methods Case Report A 44 year-old male presented with 14 years of chronic infections and pelvic pain. Although subject to frequent respiratory and gastrointestinal infections since childhood, his pelvic pain began at age 30. Following initiation of antibiotic and corticosteroid treatment for acute sinusitis, he developed a painful erythematous scrotal rash. His core symptoms are presented in Table S1. He initially attempted treatment with antifungals with mild improvement, but his rash gradually worsened over time. After another course of antibiotics for acute sinusitis, his rash spread to the glans penis and he subsequently developed severe urethral, testicular, and pelvic pain. He also began having chronic purulent sinusitis, and since that time he has struggled to control his upper respiratory symptoms, pelvic pain, and scrotal rash. The dynamics of his symptoms over time is presented in Figure 1. He has undergone treatment with numerous immunologic and antifungal therapies including G-CSF, IFN-gamma, GM-CSF, IVIG, IL-2, fluconazole, amphotericin B, micafungin, itraconazole, caspofungin, voriconazole, with varying levels of success (Figures 2–8). He experienced substantial improvement of his pelvic pain and skin lesions and mild improvement of his upper respiratory symptoms with micafungin but had to forego therapy for financial reasons (Figure 1 and Figure 5). Other regimens including GM-CSF (Figure 3) with fluconazole and amphotericin (Figure 2) with caspofungin (Figure 4) have also helped control symptoms, but to a lesser degree. He has consistently noted worsening of his pelvic pain, rash, and upper respiratory symptoms with antibiotic treatments. Unfortunately, medication costs and side effects have prohibited the establishment of a successful longterm regimen. His pelvic pain and the fatigue associated with his symptoms have significantly impacted his quality of life. His pelvic pain limits his ability to sit for long periods of time, and his sinusitis is associated with pharyngitis, headaches, fatigue, and malaise. These symptoms have limited his ability to work, exercise, maintain a social life, and enjoy dating or sexual activity. He has undergone extensive work-up, which has failed to identify a unifying underlying diagnosis (Tables 1, 2, and 3 and Tables S2, S3, S4). Prostatic fluid and ejaculate cultures, however, have grown multiple Candida species (Table 4), and immunologic testing has demonstrated anergy to Candida antigen (Table S3). We hypothesized that defects in the cellular immune response may underlie his clinical condition, as we have demonstrated previously in other chronic fungal infections. [1,2] The current study was approved by the Institutional Review Boards of Children’s Hospital Boston, Beth Israel Deaconess Medical Center in Boston and Radboud University in Nijmegen, the Netherlands. PLOS ONE | www.plosone.org 1 July 2013 | Volume 8 | Issue 7 | e68118 The individual in this manuscript has given written informed consent to publish these case details, as outlined in the PLoS consent form available at: http://www.plosone.org/static/ plos_consent_form.pdf.’’