Polymorphic mimicry - When Herpes Isn’t Just Herpes: Genital Herpes Mimicking Secondary Syphilis: A Case Report

Polymorphic mimicry - When Herpes Isn’t Just Herpes: Genital Herpes Mimicking Secondary Syphilis: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Polymorphic mimicry - When Herpes Isn’t Just Herpes: Genital Herpes Mimicking Secondary Syphilis: A Case Report Andrew Vierra, Leena Jamal, Adam Makki, Abdullah Bokhari DO, Abdullah Bokhari This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7090616/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Herpes simplex virus (HSV) infections can present atypically, mimicking a variety of other dermatologic and sexually transmitted diseases. This clinical variability can lead to misdiagnosis and delayed treatment. Case Presentation: We present the case of a 47-year-old male with a history of recurrent genital sores who presented with uncomplicated genital and anal ulcers along with a new targetoid rash on his palms and soles. The clinical picture, particularly the acral rash, strongly suggested secondary syphilis, for which he was empirically treated. Diagnosis and Outcome: Subsequent laboratory testing was negative for syphilis but polymerase chain reaction (PCR) testing of the lesions returned positive for HSV type 2. The acral rash was clinically diagnosed as erythema multiforme (EM) secondary to the HSV infection. The patient’s symptoms and lesions resolved completely following treatment with high-dose valacyclovir. Conclusion: This case highlights that HSV-triggered erythema multiforme can create a clinical presentation that strongly mimics secondary syphilis. Clinicians should maintain a high index of suspicion for HSV and its polymorphic manifestations in the differential diagnosis of patients presenting with genital ulcers and associated acral rashes. Herpes Simplex Virus-2 (HSV-2) Erythema Multiforme Secondary Syphilis Atypical Presentation Genital Ulcers Case Report HSV Proctitis Anal Lesions Anal Fissures Sexually transmitted diseases Figures Figure 1 Figure 2 Figure 3 Introduction Herpes simplex virus type 2 (HSV-2) is a prevalent sexually transmitted infection. While its classic presentation involves painful clusters of vesicles or ulcers on the genitals, its clinical manifestations can vary significantly. These atypical presentations can cause diagnostic confusion, leading to HSV-2 masquerading as other conditions, from anal fissures to dermatophytosis. (1,4) Syphilis, known as "the great imitator," is a primary consideration in patients with genital ulcers and rashes, particularly when the palms and soles are involved. The potential for clinical overlap between secondary syphilis and an atypical HSV-2 infection can mislead clinicians, especially in high-risk patients. (2) Furthermore, HSV is a well-known trigger for erythema multiforme (EM), an acute, immune-mediated condition characterized by targetoid lesions often appearing on the extremities. When an HSV outbreak is accompanied by secondary EM, the resulting polymorphic rash can create a highly deceptive clinical picture. We present a case of a 47-year-old male whose HSV-2 infection, complicated by erythema multiforme, was misdiagnosed as secondary syphilis. This report aims to highlight the diagnostic challenges of this presentation and underscore the importance of including HSV in the differential diagnosis of atypical rashes. Case Report Patient Presentation A 47-year-old male with no significant past medical history presented to the emergency department with uncomplicated genital lesions and a rash on his extremities. The patient had a several-month history of recurrent, genital sores with and without pain, for which he had been seen multiple times in an emergency department. Previous treatments included doxycycline and, two months prior to this visit, intramuscular penicillin for presumed syphilis. His current presentation was prompted by a four-day history of irritated blisters on his penis , followed by the new onset of a spreading, painful rash on the palms of his hands and soles of his feet. He also reported new-onset soreness in the perianal area with bowel movements. The patient was sexually active with multiple partners and used condoms inconsistently. Physical Examination On examination, the patient was afebrile and hemodynamically stable. The genital exam revealed multiple irritated, vesiculopustular lesions and shallow ulcers on the glans and penile shaft. Bilateral tender inguinal lymphadenopathy was present. The groin and base of the penis had annular plaques with raised edges, some of which fluoresced under a black light. (See Figure 1). The hands and feet showed numerous erythematous macules and papules, some with the classic targetoid appearance of EM (central dusky zones with peripheral erythema). (See Figure 2). Anal inspection revealed two superficial longitudinal ulcers at the anal verge, clinically resembling anal fissures, with mild perianal erythema. (See Figure 3). Initial Management and Diagnosis Given the combination of genital ulcers and an acral rash in a high-risk patient, secondary syphilis was the leading presumptive diagnosis. The differential diagnosis also included HSV with erythema multiforme, disseminated gonococcal infection, reactive arthritis, and tinea infection. (See Table 1). A syndromic management approach was initiated in the emergency department. Laboratory panels for CBC, CMP, HIV, and STIs were sent. The patient received empiric treatment with benzathine penicillin and doxycycline. Follow-Up and Definitive Diagnosis The patient returned for follow-up one week later with only marginal improvement. Laboratory results were unremarkable except for the HSV testing, which was positive. A polymerase chain reaction (PCR) test from the lesions confirmed an active HSV-2 infection. The hand and foot rash was clinically diagnosed as EM secondary to the acute HSV infection. The anal lesions were attributed to HSV proctitis mimicking anal fissures. The patient was started on high-dose valacyclovir. Outcome At a two-week follow-up, the patient’s genital and anal lesions had nearly healed, and the palmoplantar rash had resolved. He was counseled on HSV transmission and recurrence. Given the severity of this polymorphic presentation, he was placed on suppressive antiviral therapy to prevent future episodes. Discussion This case illustrates a significant diagnostic challenge where an atypical HSV-2 infection presented with polymorphic features that resulted in a misdiagnosis of secondary syphilis. The initial diagnosis was guided by the classic combination of genital lesions and a palmoplantar rash, a hallmark of syphilis. However, the irritated, vesicular nature of the genital ulcers was more characteristic of herpes. The critical confounding factor was the rash on the hands and feet. While secondary syphilis can cause a papular acral rash, the targetoid appearance of this patient's lesions was highly suggestive of erythema multiforme. HSV is the most common infectious trigger for EM, which is an immune-mediated reaction to the virus rather than a sign of dissemination. The co-occurrence of the HSV outbreak and the EM rash created a convincing but misleading picture of secondary syphilis.(3) This highlights the importance of closely examining lesion morphology, as detailed in Table 1. Furthermore, the patient’s perianal pain and ulcers were initially thought to be anal fissures or anal abrasions, a common anorectal condition thought to be from constipation. However, HSV is a known cause of proctitis and perianal ulceration, which can directly mimic the appearance of fissures. This anorectal manifestation added another layer of complexity to the diagnosis that was missed. The initial syndromic treatment approach, while covering multiple pathogens, did not lead to significant improvement until the correct diagnosis was made and targeted high-dose antiviral therapy was initiated. This case underscores the limitation of purely syndromic management in atypical cases and emphasizes the utility of definitive diagnostic tools like PCR, which confirmed HSV-2 and clarified the entire clinical picture. Conclusion Atypical presentations of HSV-2 can present with polymorphic lesions that mimic other diseases. When an HSV-2 outbreak is complicated by secondary erythema multiforme, the resulting clinical syndrome of genital ulcers and an acral rash can be easily mistaken for secondary syphilis. This case emphasizes that clinicians should consider HSV and its immune-mediated sequelae in their differential diagnosis to avoid diagnostic errors and ensure patients receive timely and appropriate antiviral treatment. Declarations Funding: None. Conflict of interest: None. 1. Ethics Declaration This case report was conducted in accordance with the ethical principles of the Declaration of Helsinki. Patient privacy has been protected, and all identifying information has been anonymized. 2. Consent to Participate Written informed consent to participate in this case report was obtained from the patient while in the emergency department. The consent was witnessed by three physicians at the time of signing and has been retained by the authors. 3. Consent to Publish The patient provided written informed consent for the publication of this case report and any accompanying images. All images were viewed by the patient and found appropriate for inclusion in the publication. 4. Patient Consent: This was obtained while the patient was in the emergency department. All images obtained were viewed by the patient and found appropriate for inclusion by the patient. Written consent was witnessed by three physicians at the time of signing and has been retained by the authors listed herein. References Srinivasan, D., Kaul, C. M., Buttar, A. B., Nottingham, F. I., & Greene, J. B. (2021). Disseminated Herpes Simplex Virus-2 (HSV-2) as a Cause of Viral Hepatitis in an Immunocompetent Host. The American journal of case reports, 22, e932474. https://doi.org/10.12659/AJCR.932474 Larsen, C. N., & Larsen, H. K. (2020). Herpetiform Manifestation of Primary Syphilis: A Case Series. Acta dermato-venereologica, 100(6), adv00072. https://doi.org/10.2340/00015555-3414 Brom A, Goren I, Carmel NN, Segal G. The "Great Masquerader" Strikes Again: Secondary Syphilis Presentation with Erythema Multiforme (EM)-Like Lesions . EJCRIM. 2014. https://doi.org/10.12890/2014_000161. Winceslaus J, Jones PA. Genital herpes masquerading as anal fissures . J R Coll Surg Edinb. 1997;42(4):276-277. Table Table 1: Differential Diagnosis of Genital Ulcers with an Acral Rash Legend: This table outlines the key clinical features and distinguishing points for conditions considered in the differential diagnosis. It compares the presentation of secondary syphilis, genital HSV with and without erythema multiforme, and other potential etiologies based on lesion characteristics, systemic symptoms, and diagnostic testing. Differential Diagnosis Key Features Distinguishing Points Secondary syphilis Generalized rash often involving palms and soles; mucous patches; condyloma lata; systemic symptoms (fever, lymphadenopathy). Genital lesions (primary chancre or condyloma lata) may be present but often painless. Palmar/plantar rash can appear coppery or scaly, not typically “target” lesions. Genital ulcer of primary syphilis is classically solitary and painless (though variations occur). Serologic tests (RPR, treponemal antibody) are usually positive in the secondary stage. Genital HSV infection Painful clusters of vesicles or ulcers on genital or anal area; may recur. Often associated with localized pain, burning, with or without fever. Typical lesions heal with crusting. Lesions are usually painful and in crops. HSV can be confirmed by PCR or culture from lesions. Unlike syphilis, HSV does not typically cause a diffuse rash (any widespread eruption suggests coexistent EM or dissemination). HSV with erythema multiforme Target lesions on hands, feet, or elsewhere following an HSV outbreak. Target lesions have concentric rings (dark center, pale intermediate ring, outer red ring). May have some lesions with central blister or crust. EM lesions are immune-mediated and not infectious. Diagnosis is clinical. HSV is a known trigger. Syphilitic rashes can mimic but usually lack classic target appearance. Reactive arthritis (Reiter’s syndrome) Triad: arthritis, urethritis, conjunctivitis. Cutaneous: keratoderma blennorrhagica (hyperkeratotic pustules on palms/soles), circinate balanitis. Often follows Chlamydia infection. Genital lesions usually painless. Associated with joint pain and eye symptoms. Palmar/plantar lesions are wart-like. Chlamydia testing may help. HSV PCR is negative. Disseminated gonococcal infection (DGI) Dermatitis, migratory polyarthralgia, tenosynovitis. Few pustular or vesicular lesions on extremities (including palms). Genital symptoms minimal or absent. Rash is sparse and systemic signs may be present. Confirmed via culture or NAAT from mucosal or blood specimens. Prominent genital ulcers are atypical. Hand-foot-and-mouth disease Coxsackievirus infection, usually pediatric. Fever, oral erosions, and vesicular palm/sole lesions. Genital lesions rare. Epidemiology, age, and exposure history help. PCR from throat or lesions confirms enterovirus. Chancroid ( Haemophilus ducreyi ) Painful genital ulcer(s) with ragged undermined edges, suppurative inguinal nodes. Rare in developed countries. Deep purulent ulcers. Confirmed via culture or PCR. Rash on hands/feet is absent. Others (e.g., Behçet’s, SJS, pemphigus syphiliticus) Rare causes of genital ulcers and palm involvement. Behçet’s: oral/genital ulcers + uveitis. SJS: mucosal erosion + drug trigger. Pemphigus: bullae. Ruled out by mucosal sparing, lack of drug history, and systemic features. Important to consider if refractory. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7090616","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":506076144,"identity":"88031836-9897-43b6-9feb-74eeac28facd","order_by":0,"name":"Andrew Vierra","email":"","orcid":"","institution":"McLaren Oakland Hospital","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Vierra","suffix":""},{"id":506076145,"identity":"4470d599-2e72-4ffd-9900-a8f3b1a448c3","order_by":1,"name":"Leena Jamal","email":"","orcid":"","institution":"Michigan State University College of Osteopathic Medicine","correspondingAuthor":false,"prefix":"","firstName":"Leena","middleName":"","lastName":"Jamal","suffix":""},{"id":506076146,"identity":"9307c8ce-773f-4468-84d8-880ab6fcad49","order_by":2,"name":"Adam Makki","email":"","orcid":"","institution":"McLaren Oakland Hospital","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"","lastName":"Makki","suffix":""},{"id":506076147,"identity":"6f62899d-14b3-4e6b-8762-590a484cc4ef","order_by":3,"name":"Abdullah Bokhari DO","email":"","orcid":"","institution":"McLaren Oakland Hospital","correspondingAuthor":false,"prefix":"","firstName":"Abdullah","middleName":"Bokhari","lastName":"DO","suffix":""},{"id":506076148,"identity":"1678d962-64a1-4604-8122-cf0c8653ca93","order_by":4,"name":"Abdullah Bokhari","email":"data:image/png;base64,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","orcid":"","institution":"McLaren Oakland Hospital","correspondingAuthor":true,"prefix":"","firstName":"Abdullah","middleName":"","lastName":"Bokhari","suffix":""}],"badges":[],"createdAt":"2025-07-10 08:23:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7090616/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7090616/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90300394,"identity":"3a1b6d68-aa0d-4617-9778-79d1443d52c1","added_by":"auto","created_at":"2025-09-01 08:54:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":458717,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnnular Plaques in the Groin\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e• \u003cstrong\u003eLegend:\u003c/strong\u003e Clinical photograph of the patient’s groin showing multiple annular plaques with raised edges. This finding, along with some fluorescence under a black light, initially suggested a possible fungal (tinea) infection as part of the polymorphic presentation.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7090616/v1/d619433800c7e5608b8bb5de.png"},{"id":90298453,"identity":"6be953b6-0b44-4008-9e64-96d2727a8aaa","added_by":"auto","created_at":"2025-09-01 08:46:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":686463,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTargetoid Lesions on the Foot\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e• \u003cstrong\u003eLegend:\u003c/strong\u003e Plantar surface of the patient’s foot demonstrating numerous round to oval erythematous macules and papules. Some lesions presented with central dusky zones and peripheral erythema, consistent with the targetoid lesions characteristic of erythema multiforme.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7090616/v1/4e626c28bef88762ef95ecf5.png"},{"id":90298500,"identity":"a3404125-526f-4bd2-97b1-77881e667c4f","added_by":"auto","created_at":"2025-09-01 08:46:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":889819,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePerianal Ulcerations Mimicking Anal Fissures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e• \u003cstrong\u003eLegend:\u003c/strong\u003e Perianal examination revealing two superficial ulcers at the anal verge with surrounding erythema. These lesions were clinically mistaken for anal fissures but were ultimately identified as manifestations of the HSV-2 infection.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7090616/v1/ca4615757c6310f1365d76f1.png"},{"id":90300694,"identity":"91d46bb6-a96f-450e-a1d7-3ec5fb85f157","added_by":"auto","created_at":"2025-09-01 08:54:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3209649,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7090616/v1/8a9a6798-9175-4527-8dff-8a7c7ed32170.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Polymorphic mimicry - When Herpes Isn’t Just Herpes: Genital Herpes Mimicking Secondary Syphilis: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHerpes simplex virus type 2 (HSV-2) is a prevalent sexually transmitted infection. While its classic presentation involves painful clusters of vesicles or ulcers on the genitals, its clinical manifestations can vary significantly. These atypical presentations can cause diagnostic confusion, leading to HSV-2 masquerading as other conditions, from anal fissures to dermatophytosis. (1,4)\u003c/p\u003e\n\u003cp\u003eSyphilis, known as \"the great imitator,\" is a primary consideration in patients with genital ulcers and rashes, particularly when the palms and soles are involved. The potential for clinical overlap between secondary syphilis and an atypical HSV-2 infection can mislead clinicians, especially in high-risk patients. (2)\u003c/p\u003e\n\u003cp\u003eFurthermore, HSV is a well-known trigger for erythema multiforme (EM), an acute, immune-mediated condition characterized by targetoid lesions often appearing on the extremities. When an HSV outbreak is accompanied by secondary EM, the resulting polymorphic rash can create a highly deceptive clinical picture.\u003c/p\u003e\n\u003cp\u003eWe present a case of a 47-year-old male whose HSV-2 infection, complicated by erythema multiforme, was misdiagnosed as secondary syphilis. This report aims to highlight the diagnostic challenges of this presentation and underscore the importance of including HSV in the differential diagnosis of atypical rashes.\u003c/p\u003e"},{"header":"Case Report ","content":"\u003cp\u003e\u003cstrong\u003ePatient Presentation\u003c/strong\u003e A 47-year-old male with no significant past medical history presented to the emergency department with uncomplicated genital lesions and a rash on his extremities. The patient had a several-month history of recurrent, genital sores with and without pain, for which he had been seen multiple times in an emergency department. Previous treatments included doxycycline and, two months prior to this visit, intramuscular penicillin for presumed syphilis.\u003c/p\u003e\n\u003cp\u003eHis current presentation was prompted by a four-day history of irritated blisters on his penis , followed by the new onset of a spreading, painful rash on the palms of his hands and soles of his feet. He also reported new-onset soreness in the perianal area with bowel movements. The patient was sexually active with multiple partners and used condoms inconsistently.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePhysical Examination\u003c/strong\u003e On examination, the patient was afebrile and hemodynamically stable. The genital exam revealed multiple irritated, vesiculopustular lesions and shallow ulcers on the glans and penile shaft. Bilateral tender inguinal lymphadenopathy was present. The groin and base of the penis had annular plaques with raised edges, some of which fluoresced under a black light. (See Figure 1).\u003c/p\u003e\n\u003cp\u003eThe hands and feet showed numerous erythematous macules and papules, some with the classic targetoid appearance of EM (central dusky zones with peripheral erythema). (See Figure 2). Anal inspection revealed two superficial longitudinal ulcers at the anal verge, clinically resembling anal fissures, with mild perianal erythema. (See Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInitial Management and Diagnosis\u003c/strong\u003e Given the combination of genital ulcers and an acral rash in a high-risk patient, secondary syphilis was the leading presumptive diagnosis. The differential diagnosis also included HSV with erythema multiforme, disseminated gonococcal infection, reactive arthritis, and tinea infection. (See Table 1).\u003c/p\u003e\n\u003cp\u003eA syndromic management approach was initiated in the emergency department. Laboratory panels for CBC, CMP, HIV, and STIs were sent. The patient received empiric treatment with benzathine penicillin and doxycycline.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-Up and Definitive Diagnosis\u003c/strong\u003e The patient returned for follow-up one week later with only marginal improvement. Laboratory results were unremarkable except for the HSV testing, which was positive. A polymerase chain reaction (PCR) test from the lesions confirmed an active HSV-2 infection. The hand and foot rash was clinically diagnosed as EM secondary to the acute HSV infection. The anal lesions were attributed to HSV proctitis mimicking anal fissures. The patient was started on high-dose valacyclovir.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e At a two-week follow-up, the patient’s genital and anal lesions had nearly healed, and the palmoplantar rash had resolved. He was counseled on HSV transmission and recurrence. Given the severity of this polymorphic presentation, he was placed on suppressive antiviral therapy to prevent future episodes.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case illustrates a significant diagnostic challenge where an atypical HSV-2 infection presented with polymorphic features that resulted in a misdiagnosis of secondary syphilis. The initial diagnosis was guided by the classic combination of genital lesions and a palmoplantar rash, a hallmark of syphilis. However, the irritated, vesicular nature of the genital ulcers was more characteristic of herpes.\u003c/p\u003e\n\u003cp\u003eThe critical confounding factor was the rash on the hands and feet. While secondary syphilis can cause a papular acral rash, the targetoid appearance of this patient's lesions was highly suggestive of erythema multiforme. HSV is the most common infectious trigger for EM, which is an immune-mediated reaction to the virus rather than a sign of dissemination. The co-occurrence of the HSV outbreak and the EM rash created a convincing but misleading picture of secondary syphilis.(3) This highlights the importance of closely examining lesion morphology, as detailed in Table 1.\u003c/p\u003e\n\u003cp\u003eFurthermore, the patient’s perianal pain and ulcers were initially thought to be anal fissures or anal abrasions, a common anorectal condition thought to be from constipation. However, HSV is a known cause of proctitis and perianal ulceration, which can directly mimic the appearance of fissures. This anorectal manifestation added another layer of complexity to the diagnosis that was missed.\u003c/p\u003e\n\u003cp\u003eThe initial syndromic treatment approach, while covering multiple pathogens, did not lead to significant improvement until the correct diagnosis was made and targeted high-dose antiviral therapy was initiated. This case underscores the limitation of purely syndromic management in atypical cases and emphasizes the utility of definitive diagnostic tools like PCR, which confirmed HSV-2 and clarified the entire clinical picture.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAtypical presentations of HSV-2 can present with polymorphic lesions that mimic other diseases. When an HSV-2 outbreak is complicated by secondary erythema multiforme, the resulting clinical syndrome of genital ulcers and an acral rash can be easily mistaken for secondary syphilis. This case emphasizes that clinicians should consider HSV and its immune-mediated sequelae in their differential diagnosis to avoid diagnostic errors and ensure patients receive timely and appropriate antiviral treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: None.\u003c/p\u003e\n\u003cp\u003eConflict of interest: None.\u003cbr\u003e\u0026nbsp;1. Ethics Declaration\u003c/p\u003e\n\u003cp\u003eThis case report was conducted in accordance with the ethical principles of the Declaration of Helsinki. Patient privacy has been protected, and all identifying information has been anonymized.\u003c/p\u003e\n\u003cp\u003e2. Consent to Participate\u003c/p\u003e\n\u003cp\u003eWritten informed consent to participate in this case report was obtained from the patient while in the emergency department. The consent was witnessed by three physicians at the time of signing and has been retained by the authors.\u003c/p\u003e\n\u003cp\u003e3. Consent to Publish\u003c/p\u003e\n\u003cp\u003eThe patient provided written informed consent for the publication of this case report and any accompanying images. All images were viewed by the patient and found appropriate for inclusion in the publication.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u0026nbsp;4. Patient Consent: This was obtained while the patient was in the emergency department. \u0026nbsp;All images obtained were viewed by the patient and found appropriate for inclusion by the patient. \u0026nbsp;Written consent was witnessed by three physicians at the time of signing and has been retained by the authors listed herein.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSrinivasan, D., Kaul, C. M., Buttar, A. B., Nottingham, F. I., \u0026amp; Greene, J. B. (2021). Disseminated Herpes Simplex Virus-2 (HSV-2) as a Cause of Viral Hepatitis in an Immunocompetent Host. The American journal of case reports, 22, e932474. https://doi.org/10.12659/AJCR.932474\u003c/li\u003e\n \u003cli\u003eLarsen, C. N., \u0026amp; Larsen, H. K. (2020). Herpetiform Manifestation of Primary Syphilis: A Case Series. Acta dermato-venereologica, 100(6), adv00072. https://doi.org/10.2340/00015555-3414\u003c/li\u003e\n \u003cli\u003eBrom A, Goren I, Carmel NN, Segal G. \u003cem\u003eThe \u0026quot;Great Masquerader\u0026quot; Strikes Again: Secondary Syphilis Presentation with Erythema Multiforme (EM)-Like Lesions\u003c/em\u003e. EJCRIM. 2014. https://doi.org/10.12890/2014_000161.\u003c/li\u003e\n \u003cli\u003eWinceslaus J, Jones PA. \u003cem\u003eGenital herpes masquerading as anal fissures\u003c/em\u003e. J R Coll Surg Edinb. 1997;42(4):276-277.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Differential Diagnosis of Genital Ulcers with an Acral Rash\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eLegend:\u003c/strong\u003e This table outlines the key clinical features and distinguishing points for conditions considered in the differential diagnosis. It compares the presentation of secondary syphilis, genital HSV with and without erythema multiforme, and other potential etiologies based on lesion characteristics, systemic symptoms, and diagnostic testing.\u003c/li\u003e\n\u003c/ul\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eDifferential Diagnosis\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eKey Features\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eDistinguishing Points\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eSecondary syphilis\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eGeneralized rash often involving palms and soles; mucous patches; condyloma lata; systemic symptoms (fever, lymphadenopathy). Genital lesions (primary chancre or condyloma lata) may be present but often painless.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003ePalmar/plantar rash can appear coppery or scaly, not typically \u0026ldquo;target\u0026rdquo; lesions. Genital ulcer of primary syphilis is classically solitary and painless (though variations occur). Serologic tests (RPR, treponemal antibody) are usually positive in the secondary stage.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eGenital HSV infection\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003ePainful clusters of vesicles or ulcers on genital or anal area; may recur. Often associated with localized pain, burning, with or without fever. Typical lesions heal with crusting.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eLesions are usually painful and in crops. HSV can be confirmed by PCR or culture from lesions. Unlike syphilis, HSV does not typically cause a diffuse rash (any widespread eruption suggests coexistent EM or dissemination).\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eHSV with erythema multiforme\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eTarget lesions on hands, feet, or elsewhere following an HSV outbreak. Target lesions have concentric rings (dark center, pale intermediate ring, outer red ring). May have some lesions with central blister or crust.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eEM lesions are immune-mediated and not infectious. Diagnosis is clinical. HSV is a known trigger. Syphilitic rashes can mimic but usually lack classic target appearance.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eReactive arthritis (Reiter\u0026rsquo;s syndrome)\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eTriad: arthritis, urethritis, conjunctivitis. Cutaneous: keratoderma blennorrhagica (hyperkeratotic pustules on palms/soles), circinate balanitis. Often follows \u003cem\u003eChlamydia\u003c/em\u003e infection.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eGenital lesions usually painless. Associated with joint pain and eye symptoms. Palmar/plantar lesions are wart-like. Chlamydia testing may help. HSV PCR is negative.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eDisseminated gonococcal infection (DGI)\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eDermatitis, migratory polyarthralgia, tenosynovitis. Few pustular or vesicular lesions on extremities (including palms). Genital symptoms minimal or absent.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eRash is sparse and systemic signs may be present. Confirmed via culture or NAAT from mucosal or blood specimens. Prominent genital ulcers are atypical.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eHand-foot-and-mouth disease\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eCoxsackievirus infection, usually pediatric. Fever, oral erosions, and vesicular palm/sole lesions.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eGenital lesions rare. Epidemiology, age, and exposure history help. PCR from throat or lesions confirms enterovirus.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eChancroid\u003c/u\u003e\u003c/strong\u003e\u003cu\u003e\u0026nbsp;(\u003cem\u003eHaemophilus ducreyi\u003c/em\u003e)\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003ePainful genital ulcer(s) with ragged undermined edges, suppurative inguinal nodes. Rare in developed countries.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eDeep purulent ulcers. Confirmed via culture or PCR. Rash on hands/feet is absent.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cu\u003eOthers (e.g., Beh\u0026ccedil;et\u0026rsquo;s, SJS, pemphigus syphiliticus)\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eRare causes of genital ulcers and palm involvement. Beh\u0026ccedil;et\u0026rsquo;s: oral/genital ulcers + uveitis. SJS: mucosal erosion + drug trigger. Pemphigus: bullae.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cu\u003eRuled out by mucosal sparing, lack of drug history, and systemic features. Important to consider if refractory.\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Herpes Simplex Virus-2 (HSV-2), Erythema Multiforme, Secondary Syphilis, Atypical Presentation, Genital Ulcers, Case Report, HSV Proctitis, Anal Lesions, Anal Fissures, Sexually transmitted diseases","lastPublishedDoi":"10.21203/rs.3.rs-7090616/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7090616/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Herpes simplex virus (HSV) infections can present atypically, mimicking a variety of other dermatologic and sexually transmitted diseases. This clinical variability can lead to misdiagnosis and delayed treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003e We present the case of a 47-year-old male with a history of recurrent genital sores who presented with uncomplicated genital and anal ulcers along with a new targetoid rash on his palms and soles. The clinical picture, particularly the acral rash, strongly suggested secondary syphilis, for which he was empirically treated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis and Outcome:\u003c/strong\u003e Subsequent laboratory testing was negative for syphilis but polymerase chain reaction (PCR) testing of the lesions returned positive for HSV type 2. The acral rash was clinically diagnosed as erythema multiforme (EM) secondary to the HSV infection. The patient’s symptoms and lesions resolved completely following treatment with high-dose valacyclovir.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This case highlights that HSV-triggered erythema multiforme can create a clinical presentation that strongly mimics secondary syphilis. Clinicians should maintain a high index of suspicion for HSV and its polymorphic manifestations in the differential diagnosis of patients presenting with genital ulcers and associated acral rashes.\u003c/p\u003e","manuscriptTitle":"Polymorphic mimicry - When Herpes Isn’t Just Herpes: Genital Herpes Mimicking Secondary Syphilis: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 08:46:05","doi":"10.21203/rs.3.rs-7090616/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f5edf690-49ab-4022-afe2-081637828823","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T08:46:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 08:46:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7090616","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7090616","identity":"rs-7090616","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}