Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2025;15(2):4911 1 Congenital Langerhans Cell Histiocytosis Masquerading as Neonatal Herpes Simplex Virus Infection: A Diagnostic Challenge Luca Bettolini1, Stefano Rossi2, Salvatore Aversa3, Stefano Bighetti1, Valeria Boccaletti1 1 Dermatology Department, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy 2 Pediatric Hemato-Oncology and Bone Marrow Transplant Unit, Children’s Hospital, ASST Spedali Civili of Brescia, Brescia, Italy 3 Neonatal Intensive Care Unit, Children’s Hospital, ASST Spedali Civili, Brescia, Italy Citation: Bettolini L, Rossi S, Aversa S, Bighetti S, Boccaletti V. Congenital Langerhans Cell Histiocytosis Masquerading as Neonatal Herpes Simplex Virus Infection: A Diagnostic Challenge. Dermatol Pract Concept. 2025;15(2):4911. DOI: https://DOI.org/10.5826/ dpc.1502a4911 Key words: Langerhans Cell Histiocytosis, Neonatal Skin Lesions, Herpes Simplex Virus, Congenital Infection, Differential Diagnosis Accepted: August 25, 2024; Published: April 2025 Copyright: ©2025 Bettolini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Dr Luca Bettolini. Department of Dermatology, Spedali Civili, University of Brescia, Brescia, Italy. Piazzale Spedali Civili, 1, 25123, Brescia (BS), Italy. ORCID ID: 0000-0003-4374-802X. E-mail: lbettolini@gmail.com Introduction Langerhans cell histiocytosis (LCH) is a rare inflammatory neoplasm characterized by the accumulation of myeloid pre- cursor cells in different organs, affecting 4–5 per million chil- dren annually [1]. We describe a case of a neonate affected by congenital LCH, presenting with skin lesions resembling herpes simplex virus (HSV) congenital infection. Case Presentation The patient was delivered naturally after an uneventful preg- nancy, at 39 weeks. At birth, he displayed widespread, non- confluent, erosive lesions affecting his entire body, including the face, scalp, palms, soles, genitalia, and mucous mem- branes (Figure 1). Blood tests, including a complete blood count, renal and liver function, electrolytes, and C-reactive protein, were all within normal ranges. Additionally, a lum- bar puncture was performed, yielding normal results. Sus- pecting HSV congenital infection, acyclovir 60 mg/kg/daily was started, without improvement. Blood cultures, extensive viral polymerase chain reaction tests, and serologic stud- ies were performed to evaluate the presence of infections caused by various pathogens such as HSV, cytomegalovirus, Epstein-Barr, parvovirus B19, coxsackievirus, varicella-zoster virus, human herpesvirus 6, human herpesvirus 8, Strep- tococcus pyogenes, S. agalactiae, Escherichia coli, Lysteria monocytogenes, Haemophilus influenzae, and Neisseria meningitidis. However, the results showed no evidence of any ongoing infection. Histological examination displayed a thin epidermis with spongiosis and microvesciculation, confluent parakeratosis with intracorneal micropustules, and exoserosis. Furthermore, a diffuse dermal infiltra- tion of immature cells with irregularly indented nuclei and 2 Research Letter | Dermatol Pract Concept. 2025;15(2):4911 inconspicuous nucleoli was observed. Within an inflamma- tory background, the immunophenotypic and immunohis- tochemical profile, including positivity for Langerin, CD1a, S100, CD14, and BRAF, supported the diagnosis of LCH (Figure 2). Extensive assessments, including peripheral blood smear, cardiac and abdominal ultrasounds, full-body X-ray scans, and brain MRI, ruled out multisystemic involvement. One month after birth, the dermatological condition wors- ened, accompanied by elevated liver function. A hepatic bi- opsy revealed diffuse biliary changes, potentially associated with LCH. Treatment was initiated with a combination of vinblastine and dexamethasone. Additionally, vemurafenib, a selective BRAF inhibitor, was introduced, which resulted in partial disease control. Cutaneous congenital LCH typically occurs in newborns and presents as diffuse red-brown pap- ules and nodules that often resolve spontaneously [2], but in some cases, it can progress to multisystemic LCH. In our patient, clinical presentation was suggestive of HSV congeni- tal infection. Although the prepartum serological assessment for neonatal HSV did not match with acute infection, it is important to note that the risk of HSV transmission to the newborn is highest in women who acquire the infection for the first time during pregnancy while having undetectable antibodies [3]. In most cases, women do not report any prior history of HSV infection, nor do they report having genital HSV lesions either before or during delivery. In these cases, histologic examination is critical for the diagnosis. Figure 1. Diffuse skin erosions over the head, trunk, extremities, and genitals. Figure 2. (A, B) The histological analysis revealed a thin epidermis characterized by spongiosis and microvesiculation. Additionally, there was confluent parakeratosis with intracorneal micropustules and exocytosis present. The dermis displayed a diffuse infiltra- tion of immature cells, which possessed irregularly shaped, indented nuclei and subtle nucleoli (H&E, original magnification x2 and x20, respectively). (C) Immunohistochemistry showing positivity to Langerin (original magnification x4), (D) CD1a (original magnification x10), and (E) BRAF (original magnification x4). Research Letter | Dermatol Pract Concept. 2025;15(2):4911 3 Conclusion LCH can present with a wide range of lesions with no typical presentation site [4]. As observed in our case, it may mimic infectious diseases, highlighting the need for prompt diagno- sis and treatment. Long-term follow-up remains crucial to detect and manage multisystem involvement [5], which can result in unfavorable outcomes. References 1. Krooks J, Minkov M, Weatherall AG. Langerhans cell his- tiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis.  J Am Acad Dermatol. 2018;78(6):1035-1044. DOI: 10.1016/j.jaad.2017.05.059. PMID: 29754885. 2. Kapur P, Erickson C, Rakheja D, Carder KR, Hoang MP. Con- genital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease): ten-year experience at Dallas Children’s Medical Cen- ter.  J Am Acad Dermatol. 2007;56(2):290-294. DOI: 10.1016 /j.jaad.2006.09.001. PMID: 17224372. 3. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant.  JAMA. 2003;289(2):203-209. DOI: 10.1001/jama.289.2.203. PMID: 12517231. 4. Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: a disease with many faces.  World J Pediatr. 2019;15(6):536-545. DOI:10.1007/s12519-019-00304-9. PMID: 31456157. 5. Dhar S, Srinivas SM, Dhar S, et al. Langerhans cell histiocytosis in children: A retrospective case series of 126 cases. Pediatr Der- matol. 2020;37(6):1085-1089. DOI:10.1111/pde.14389. PMID: 32981115.