A case of Rapp-Hodgkin syndrome featuring prominent oral leukokeratosis linked to a TP63 gene variant

A case of Rapp-Hodgkin syndrome featuring prominent oral leukokeratosis linked to a TP63 gene variant | 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 A case of Rapp-Hodgkin syndrome featuring prominent oral leukokeratosis linked to a TP63 gene variant Weiai Gan, Jie Wei, Zhengyan Zhao, Ying Zhang, Lan Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8632040/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Apr, 2026 Read the published version in BMC Oral Health → Version 1 posted 16 You are reading this latest preprint version Abstract Background: Rapp-Hodgkin syndrome (RHS) is a rare autosomal dominant disorder caused by TP63 gene mutations. This case warrants reporting due to the presence of significant limb malformations, extensive caries in the maxillary teeth, and congenital absence of multiple mandibular teeth, accompanied by remarkably widespread oral leukokeratosis. Its novelty lies in exploring the synergistic role of chronic local mechanical irritation acting upon the TP63 mutation-induced epithelial developmental defect in the pathogenesis of the widespread oral leukokeratosis, offering a new clinical perspective on the mechanism of such lesions. Case presentation: The patient presented with extensive leukokeratosis on the bilateral buccal mucosa and tongue margins, accompanied by congenital absence of most mandibular teeth and extensive caries in the maxillary teeth. Physical examination revealed significant limb malformations, including bilateral absence of the index and middle fingers with flexion deformities of the thumbs. Genetic testing confirmed the diagnosis of RHS by identifying a heterozygous mutation in the TP63 gene (c.953G>A, p.Arg318His). Management involved multidisciplinary assessment and supportive care. Conclusions: This case expands the oral clinical spectrum of RHS. When patients present with such concurrent complex oral mucosal lesions and limb malformations, genetic syndromes should be considered, warranting a multidisciplinary assessment including genetic counseling. It highlights the importance of recognizing systemic genetic signs in the diagnosis and management of rare oral diseases. Rapp-Hodgkin Syndrome Leukokeratosis TP63 gene Ectodermal Dysplasia Case Report Figures Figure 1 Introduction RHS( OMIM #129400) is a member of the TP63 gene-related disorder spectrum, which also includes EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome) and AEC syndrome, among others. This spectrum comprises a group of rare disorders caused by functional defects in the TP63 gene and typically follows an autosomal dominant inheritance pattern. Functional defects or genetic variations in the TP63 protein primarily affect tissue development originating from the three germ layers, variably impacting tissues derived from both ectoderm and mesenchyme. Consequently, these disorders are characterized by varying degrees of ectodermal defects and limb malformations [1]. Clinically, the diagnosis of RHS is based on a constellation of characteristic features, primarily including ectodermal dysplasia, orofacial malformations, and limb malformations[2, 3]. The classic oral manifestations of RHS, such as microstomia, high-arched palate, extensive congenital tooth agenesis, and enamel hypoplasia, have been well-documented in previous literature[4, 5]. However, existing literature has paid relatively limited attention to lesions of the oral mucosa itself in RHS, particularly extensive oral mucosal hyperkeratosis. Case reports where this finding serves as a primary diagnostic clue are even rarer. This report presents a case of RHS where prominent oral lesions were the chief complaint, aiming to enhance clinicians' awareness and diagnostic vigilance regarding its oral features. Case Report A 17-year-old male presented to our oral medicine department with the chief complaint of "extensive whitening of the oral mucosa for over five years." Intraoral examination revealed extensive, homogeneous leukokeratotic patches, slightly raised above the mucosal surface, on the bilateral buccal mucosa and tongue margins(fig.1a,1b,1d,1e). Dental examination showed widespread caries in the maxillary permanent teeth and congenital multiple tooth agenesis in the mandibular arch(fig.1c,1f). Physical examination identified distinctive facial features, including hypertelorism and a flattened nasal bridge. Both thumbs exhibited a flexed posture, and the index and middle fingers were absent bilaterally(fig.1g,1h). No significant abnormalities were noted in the skin, hair, or nails. Based on the extensive oral leukokeratosis, characteristic severe dental problems, and definitive limb malformations, a hereditary ectodermal dysplasia syndrome was strongly suspected. To confirm the diagnosis, the patient underwent genetic evaluation. Whole-exome sequencing identified a heterozygous missense variant in the TP63 gene [NM_003722.5: c.953G>A, p.(Arg318His)] (fig.1i). This variant was not detected in either parent's genome and was classified as "pathogenic." The TP63 gene is associated with autosomal dominant disorders, including ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 and Rapp-Hodgkin syndrome. Integrating the classic clinical presentation with definitive molecular genetic evidence established a confirmed diagnosis of Rapp-Hodgkin syndrome. Discussion and conclusions Extensive oral mucosal leukokeratosis has been relatively infrequently reported in RHS, TP63 is a key regulatory factor in maintaining normal differentiation and homeostasis of stratified epithelium, including the oral mucosa [6, 7]. Its functional inactivation may lead to abnormalities in the proliferation and differentiation programs of mucosal basal cells, forming the intrinsic genetic basis for the development of hyperkeratosis. Previous case reports of RHS have described "hyperkeratosis" on skin histopathology[4], suggesting that TP63 mutations may lead to keratinization abnormalities. This supports the possibility that oral mucosal involvement shares the same underlying pathogenic mechanism. Concurrently, dental developmental anomalies in this patient resulted in occlusal disturbances, reduced vertical dimension, and altered oral functional space. These conditions likely led to chronic, repetitive cheek or tongue biting, providing sustained physical irritation to the mucosa already predisposed by genetic defect. Such mechanical stimulation may have acted upon the foundation of hereditary keratinization dysfunction, further inducing and exacerbating localized hyperkeratosis, particularly in friction-prone areas like the buccal and lateral tongue borders. In summary, the diagnostic process in this case underscores the importance of combining meticulous clinical observation with precise genetic testing. When encountering complex presentations involving multiple systems such as oral mucosa, dentition, and limbs, clinicians, especially dental practitioners, should maintain a high index of suspicion for rare genetic syndromes. Upon identifying such multi-system involvement during initial assessment, it is imperative to actively initiate a multidisciplinary collaborative management model, engaging specialists from genetics, pediatrics, dermatology, and related fields. This approach is essential for achieving early diagnosis, precise intervention, and comprehensive management of the disease. Abbreviations RHS: Rapp-Hodgkin Syndrome EEC: Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome AEC: Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome. Declarations Funding ： This study was supported by Shanghai Municipal Health Committee (ZHYYZXYYD-2025011), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2025-2027)-2-2-1] Conflicts of Interest: All authors declare no conflicts of interest. Ethics approval and consent to participate The study protocol was approved by the Ethics Committee of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Furthermore, written informed consent was obtained from the patient's legal guardian for the publication of this case report and any accompanying identifiable clinical images. Consent for publication Written and signed consent to publish the medical history, clinical photos, and radiographs in this case report was obtained from the parents’ of the patient. Data availability The datasets analysed during the current study are available in the OMIX repository (accession no OMIX014709 at https://ngdc.cncb.ac.cn/omix/preview/UqiHCyQg)[8, 9]. Competing interests The authors declare no competing interests. Funding This study was supported by Shanghai Municipal Health Committee (ZHYYZXYYD-2025011), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2025-2027)-2-2-1]. Authors ’ contributions L.W. conceived and designed the study, and provided administrative support and study materials. W.G. and J.W. collected and assembled the data. W.G. and Z.Z. performed data analysis and interpretation. All authors contributed to manuscript writing and gave final approval of the manuscript. Acknowledgements We sincerely thank our patient with LMS and his families for their invaluable participation in this study. References Rinne T, Hamel B, van Bokhoven H, Brunner HG. Pattern of p63 mutations and their phenotypes–update. Am J Med Genet A. 2006;140(13):1396–406. Silengo MC, Davi GF, Bianco R, Costa M, DeMarco A, Verona R, Franceschini P. Distinctive hair changes (pili torti) in Rapp-Hodgkin ectodermal dysplasia syndrome. Clin Genet. 1982;21(5):297–300. Salinas CF, Montes GM. Rapp-Hodgkin syndrome: observations on ten cases and characteristic hair changes (pili canaliculi). Birth Defects Orig Artic Ser. 1988;24(2):149–68. Chatterjee M, Neema S, Mukherjee S. Rapp Hodgkin Syndrome. Indian dermatology online J. 2017;8(3):215–6. Biswas A, Dutta K, Khatua A, Banerjee A, Puttanavar R. Rapp-Hodgkin Syndrome: A Case Report on its Clinical and Dental Manifestations. J Clin Diagn Res. 2024;18(11):ZD13–6. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398(6729):708–13. Koster MI, Roop DR. Transgenic mouse models provide new insights into the role of p63 in epidermal development. Cell Cycle. 2004;3(4):411–3. Zhang S, Chen X, Jin E, Wang A, Chen T, Zhang X, Zhu J, Dong L, Sun Y, Yu C et al. The GSA Family in 2025: A Broadened Sharing Platform for Multi-omics and Multimodal Data. Genom Proteom Bioinform 2025, 23(4). Members C-N, Partners. Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2025. Nucleic Acids Res. 2024;53(D1):D30–44. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 30 Apr, 2026 Read the published version in BMC Oral Health → Version 1 posted Editorial decision: Revision requested 03 Apr, 2026 Reviews received at journal 01 Apr, 2026 Reviews received at journal 28 Mar, 2026 Reviewers agreed at journal 28 Mar, 2026 Reviewers agreed at journal 24 Mar, 2026 Reviews received at journal 24 Mar, 2026 Reviewers agreed at journal 24 Mar, 2026 Reviews received at journal 23 Mar, 2026 Reviewers agreed at journal 17 Mar, 2026 Reviews received at journal 16 Mar, 2026 Reviewers agreed at journal 09 Mar, 2026 Reviewers invited by journal 05 Mar, 2026 Editor invited by journal 24 Feb, 2026 Editor assigned by journal 28 Jan, 2026 Submission checks completed at journal 28 Jan, 2026 First submitted to journal 28 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-8632040","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":602501312,"identity":"be5d3572-e06e-4f13-bba2-1164a6d67440","order_by":0,"name":"Weiai Gan","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Weiai","middleName":"","lastName":"Gan","suffix":""},{"id":602501313,"identity":"5ce54388-8198-40b5-bc32-49ef8dff004b","order_by":1,"name":"Jie Wei","email":"","orcid":"","institution":"Shanghai Jiao Tong University, National Clinical Research Center for Oral Diseases, Shanghai Research Institute of Stomatology","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Wei","suffix":""},{"id":602501314,"identity":"7600f68d-517f-45ee-bd32-590a3cbda988","order_by":2,"name":"Zhengyan Zhao","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zhengyan","middleName":"","lastName":"Zhao","suffix":""},{"id":602501316,"identity":"f91c2cbc-9a56-4ab5-b844-8945957f16ab","order_by":3,"name":"Ying Zhang","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Zhang","suffix":""},{"id":602501317,"identity":"1cb3927b-06fc-4bdc-be2c-dc6639b957fc","order_by":4,"name":"Lan Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtElEQVRIiWNgGAWjYDADfgbGBuJU8sAYkg0kazE4QKx77Nmbnz34wXA4cfP5w21Ahp2cLiHLeHiOmRv2ALVsu5HYDmQkG5sRso5HIsFMgofhNlALYxuQcSBxG0Et8s+/Sf4Batncf7ANyCBGiwSPmTTIlg0MiW3SxNlyJqdMWobhv/GMG0AtMgZE+IW9/fg2yTcMabL9/cefSb6psJMjqAUMGP/BWAbEKB8Fo2AUjIJRQBAAAGvnPh7abId9AAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Lan","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2026-01-18 14:53:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8632040/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8632040/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12903-026-08478-1","type":"published","date":"2026-04-30T15:57:08+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":104338471,"identity":"4076bf58-609a-451f-ae7d-b65eb5ee98c2","added_by":"auto","created_at":"2026-03-10 16:19:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":898511,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea, b, d, e\u003c/strong\u003e: Leukokeratosis on the bilateral buccal mucosa and tongue margins.\u003cstrong\u003ec\u003c/strong\u003e: Extensive caries were present in the maxillary permanent teeth. \u003cstrong\u003ef\u003c/strong\u003e: The mandibular permanent teeth exhibited extensive loss.\u003cstrong\u003e g, h\u003c/strong\u003e: Bilateral flexion deformities of the thumbs and absence of the index and middle fingers were noted. \u003cstrong\u003ei\u003c/strong\u003e:Genetic testing results:A heterozygous pathogenic variant (c.953G\u0026gt;A, p.Arg318His) in the \u003cem\u003eTP63 \u003c/em\u003egene was identified, which was confirmed to be a de novo mutation (both parents were non-carriers). This variant is associated with both EEC syndrome type 3 and Rapp-Hodgkin syndrome.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8632040/v1/47e41be0deed8c06d1062f4a.png"},{"id":108437586,"identity":"20f66bf8-8261-4bcd-8460-d1cbf72b63b2","added_by":"auto","created_at":"2026-05-04 15:59:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1026390,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8632040/v1/319d1bbe-cf99-4fa4-8f33-3ce56867b4de.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A case of Rapp-Hodgkin syndrome featuring prominent oral leukokeratosis linked to a TP63 gene variant","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRHS( OMIM #129400) is a member of the \u003cem\u003eTP63\u003c/em\u003e gene-related disorder spectrum, which also includes EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome) and AEC syndrome, among others. This spectrum comprises a group of rare disorders caused by functional defects in the \u003cem\u003eTP63\u003c/em\u003e gene and typically follows an autosomal dominant inheritance pattern. Functional defects or genetic variations in the\u003cem\u003e\u0026nbsp;TP63\u003c/em\u003e protein primarily affect tissue development originating from the three germ layers, variably impacting tissues derived from both ectoderm and mesenchyme. Consequently, these disorders are characterized by varying degrees of ectodermal defects and limb malformations [1].\u003c/p\u003e\n\u003cp\u003eClinically, the diagnosis of RHS is based on a constellation of characteristic features, primarily including ectodermal dysplasia, orofacial malformations, and limb malformations[2, 3]. The classic oral manifestations of RHS, such as microstomia, high-arched palate, extensive congenital tooth agenesis, and enamel hypoplasia, have been well-documented in previous literature[4, 5]. However, existing literature has paid relatively limited attention to lesions of the oral mucosa itself in RHS, particularly extensive oral mucosal hyperkeratosis. Case reports where this finding serves as a primary diagnostic clue are even rarer.\u003c/p\u003e\n\u003cp\u003eThis report presents a case of RHS where prominent oral lesions were the chief complaint, aiming to enhance clinicians\u0026apos; awareness and diagnostic vigilance regarding its oral features.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 17-year-old male presented to our oral medicine department with the chief complaint of \u0026quot;extensive whitening of the oral mucosa for over five years.\u0026quot; Intraoral examination revealed extensive, homogeneous leukokeratotic patches, slightly raised above the mucosal surface, on the bilateral buccal mucosa and tongue margins(fig.1a,1b,1d,1e). Dental examination showed widespread caries in the maxillary permanent teeth and congenital multiple tooth agenesis in the mandibular arch(fig.1c,1f). Physical examination identified distinctive facial features, including hypertelorism and a flattened nasal bridge. Both thumbs exhibited a flexed posture, and the index and middle fingers were absent bilaterally(fig.1g,1h). No significant abnormalities were noted in the skin, hair, or nails. Based on the extensive oral leukokeratosis, characteristic severe dental problems, and definitive limb malformations, a hereditary ectodermal dysplasia syndrome was strongly suspected.\u003c/p\u003e\n\u003cp\u003eTo confirm the diagnosis, the patient underwent genetic evaluation. Whole-exome sequencing identified a heterozygous missense variant in the \u003cem\u003eTP63\u003c/em\u003e gene [NM_003722.5: c.953G\u0026gt;A, p.(Arg318His)] (fig.1i). This variant was not detected in either parent\u0026apos;s genome and was classified as \u0026quot;pathogenic.\u0026quot; The \u003cem\u003eTP63\u003c/em\u003e gene is associated with autosomal dominant disorders, including ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 and Rapp-Hodgkin syndrome. Integrating the classic clinical presentation with definitive molecular genetic evidence established a confirmed diagnosis of Rapp-Hodgkin syndrome.\u003c/p\u003e"},{"header":"Discussion and conclusions","content":"\u003cp\u003eExtensive oral mucosal leukokeratosis has been relatively infrequently reported in RHS, \u003cem\u003eTP63\u003c/em\u003e is a key regulatory factor in maintaining normal differentiation and homeostasis of stratified epithelium, including the oral mucosa [6, 7]. Its functional inactivation may lead to abnormalities in the proliferation and differentiation programs of mucosal basal cells, forming the intrinsic genetic basis for the development of hyperkeratosis. Previous case reports of RHS have described \u0026quot;hyperkeratosis\u0026quot; on skin histopathology[4], suggesting that \u003cem\u003eTP63\u003c/em\u003e mutations may lead to keratinization abnormalities. This supports the possibility that oral mucosal involvement shares the same underlying pathogenic mechanism. Concurrently, dental developmental anomalies in this patient resulted in occlusal disturbances, reduced vertical dimension, and altered oral functional space. These conditions likely led to chronic, repetitive cheek or tongue biting, providing sustained physical irritation to the mucosa already predisposed by genetic defect. Such mechanical stimulation may have acted upon the foundation of hereditary keratinization dysfunction, further inducing and exacerbating localized hyperkeratosis, particularly in friction-prone areas like the buccal and lateral tongue borders.\u003c/p\u003e\n\u003cp\u003eIn summary, the diagnostic process in this case underscores the importance of combining meticulous clinical observation with precise genetic testing. When encountering complex presentations involving multiple systems such as oral mucosa, dentition, and limbs, clinicians, especially dental practitioners, should maintain a high index of suspicion for rare genetic syndromes. Upon identifying such multi-system involvement during initial assessment, it is imperative to actively initiate a multidisciplinary collaborative management model, engaging specialists from genetics, pediatrics, dermatology, and related fields. This approach is essential for achieving early diagnosis, precise intervention, and comprehensive management of the disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRHS: Rapp-Hodgkin Syndrome\u003c/p\u003e\n\u003cp\u003eEEC: Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome\u003c/p\u003e\n\u003cp\u003eAEC: Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThis study was supported by Shanghai Municipal Health Committee (ZHYYZXYYD-2025011), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2025-2027)-2-2-1]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eAll authors declare no conflicts of interest.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Ethics Committee of Shanghai Ninth People\u0026apos;s Hospital, Shanghai Jiao Tong University School of Medicine. Furthermore, written informed consent was obtained from the patient\u0026apos;s legal guardian for the publication of this case report and any accompanying identifiable clinical images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten and signed consent to publish the medical history, clinical photos, and radiographs in this case report was obtained from the parents\u0026rsquo; of the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analysed during the current study are available in the OMIX repository (accession no OMIX014709 at https://ngdc.cncb.ac.cn/omix/preview/UqiHCyQg)[8, 9].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Shanghai Municipal Health Committee (ZHYYZXYYD-2025011), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2025-2027)-2-2-1].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.W. conceived and designed the study, and provided administrative support and study materials. W.G. and J.W. collected and assembled the data. W.G. and Z.Z. performed data analysis and interpretation. All authors contributed to manuscript writing and gave final approval of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank our patient with LMS and his families for their invaluable participation in this\u003c/p\u003e\n\u003cp\u003estudy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRinne T, Hamel B, van Bokhoven H, Brunner HG. Pattern of p63 mutations and their phenotypes\u0026ndash;update. Am J Med Genet A. 2006;140(13):1396\u0026ndash;406.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilengo MC, Davi GF, Bianco R, Costa M, DeMarco A, Verona R, Franceschini P. Distinctive hair changes (pili torti) in Rapp-Hodgkin ectodermal dysplasia syndrome. Clin Genet. 1982;21(5):297\u0026ndash;300.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalinas CF, Montes GM. Rapp-Hodgkin syndrome: observations on ten cases and characteristic hair changes (pili canaliculi). Birth Defects Orig Artic Ser. 1988;24(2):149\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChatterjee M, Neema S, Mukherjee S. Rapp Hodgkin Syndrome. Indian dermatology online J. 2017;8(3):215\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBiswas A, Dutta K, Khatua A, Banerjee A, Puttanavar R. Rapp-Hodgkin Syndrome: A Case Report on its Clinical and Dental Manifestations. J Clin Diagn Res. 2024;18(11):ZD13\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398(6729):708\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoster MI, Roop DR. Transgenic mouse models provide new insights into the role of p63 in epidermal development. Cell Cycle. 2004;3(4):411\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang S, Chen X, Jin E, Wang A, Chen T, Zhang X, Zhu J, Dong L, Sun Y, Yu C et al. The GSA Family in 2025: A Broadened Sharing Platform for Multi-omics and Multimodal Data. Genom Proteom Bioinform 2025, 23(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMembers C-N, Partners. Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2025. Nucleic Acids Res. 2024;53(D1):D30\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rapp-Hodgkin Syndrome, Leukokeratosis, TP63 gene, Ectodermal Dysplasia, Case Report","lastPublishedDoi":"10.21203/rs.3.rs-8632040/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8632040/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eRapp-Hodgkin syndrome (RHS) is a rare autosomal dominant disorder caused by \u003cem\u003eTP63\u003c/em\u003egene mutations. This case warrants reporting due to the presence of significant limb malformations, extensive caries in the maxillary teeth, and congenital absence of multiple mandibular teeth, accompanied by remarkably widespread oral leukokeratosis. Its novelty lies in exploring the synergistic role of chronic local mechanical irritation acting upon the \u003cem\u003eTP63\u003c/em\u003e mutation-induced epithelial developmental defect in the pathogenesis of the widespread oral leukokeratosis, offering a new clinical perspective on the mechanism of such lesions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e The patient presented with extensive leukokeratosis on the bilateral buccal mucosa and tongue margins, accompanied by congenital absence of most mandibular teeth and extensive caries in the maxillary teeth. Physical examination revealed significant limb malformations, including bilateral absence of the index and middle fingers with flexion deformities of the thumbs. Genetic testing confirmed the diagnosis of RHS by identifying a heterozygous mutation in the \u003cem\u003eTP63\u003c/em\u003egene (c.953G\u0026gt;A, p.Arg318His). Management involved multidisciplinary assessment and supportive care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e This case expands the oral clinical spectrum of RHS. When patients present with such concurrent complex oral mucosal lesions and limb malformations, genetic syndromes should be considered, warranting a multidisciplinary assessment including genetic counseling. It highlights the importance of recognizing systemic genetic signs in the diagnosis and management of rare oral diseases.\u003c/p\u003e","manuscriptTitle":"A case of Rapp-Hodgkin syndrome featuring prominent oral leukokeratosis linked to a TP63 gene variant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 16:19:37","doi":"10.21203/rs.3.rs-8632040/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-03T07:34:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-01T20:50:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-28T11:46:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186633840031930076097641176135241719484","date":"2026-03-28T10:32:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"54364454198949908866611686427355629784","date":"2026-03-24T16:31:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-24T06:29:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"964427719073781160275813921928079490","date":"2026-03-24T06:22:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T06:36:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247045703498123791209985580669603559412","date":"2026-03-17T08:12:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-16T21:26:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230292789660925876472671512254658931082","date":"2026-03-09T10:20:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-05T05:11:14+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-24T05:31:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-28T16:50:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-28T16:44:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2026-01-28T16:06:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2bc5dd96-faf3-44a0-923f-c5f71c831c0e","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T15:59:18+00:00","versionOfRecord":{"articleIdentity":"rs-8632040","link":"https://doi.org/10.1186/s12903-026-08478-1","journal":{"identity":"bmc-oral-health","isVorOnly":false,"title":"BMC Oral Health"},"publishedOn":"2026-04-30 15:57:08","publishedOnDateReadable":"April 30th, 2026"},"versionCreatedAt":"2026-03-10 16:19:37","video":"","vorDoi":"10.1186/s12903-026-08478-1","vorDoiUrl":"https://doi.org/10.1186/s12903-026-08478-1","workflowStages":[]},"version":"v1","identity":"rs-8632040","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8632040","identity":"rs-8632040","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}