{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T03:04:42Z","timestamp":1785899082507,"version":"3.56.0"},"reference-count":62,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T00:00:00Z","timestamp":1763164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background Facial clefts are rare congenital malformations, occurring in approximately 1 in 700 live births for cleft lip and palate and fewer than 1 in 100,000 for atypical Tessier clefts. They pose significant diagnostic and surgical challenges. While genetic, vascular, and environmental factors are well documented, growing embryological evidence suggests that the trigeminal nerve may also contribute to craniofacial development. This narrative review explores the association between trigeminal nerve development and facial clefts, aiming to provide a neurodevelopmental perspective with clinical implications, particularly in the context of personalized medicine, where patient-specific neuroanatomical and developmental factors can guide tailored care. Methods A narrative review of embryological, anatomical, and clinical data was conducted. Histological analyses of malformed fetuses and normal human embryos were integrated with published studies. Clinical findings were compared with Paul Tessier\u2019s facial cleft classification and mapped against trigeminal innervation territories. Results Two groups of facial clefts emerged according to the timing of trigeminal disruption. Early embryonic damage (before 10 weeks of gestation) produces superficial epidermal continuity with fibrotic tissue replacing normal deep structures. Later fetal damage results in complete clefts with full tissue discontinuity. The distribution of these clefts corresponds to trigeminal nerve terminal branch territories, supporting the hypothesis that trigeminal innervation exerts trophic effects on craniofacial morphogenesis through neurohormonal signaling. Conclusions Early impairment of trigeminal development may play a pivotal role in the pathogenesis of certain clefts. The spatial and temporal relationship between nerve development and morphogenesis should be considered in classification and surgical planning. However, limitations of this narrative approach include selective literature coverage and lack of quantitative synthesis. Future directions include single-cell transcriptomics, organoid models, and fetal MRI tractography to clarify trigeminal\u2013mesenchyme interactions and inform therapeutic strategies. These advances may foster a personalized medicine approach, enabling more precise prenatal diagnosis, individualized surgical planning, and optimized long-term outcomes.<\/jats:p>","DOI":"10.3390\/jpm15110556","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T10:02:13Z","timestamp":1763546533000},"page":"556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Facial Clefts and the Trigeminal Nerve: A Narrative Review of the Literature and Clinical Considerations in the Era of Personalized Medicine"],"prefix":"10.3390","volume":"15","author":[{"given":"Natalia","family":"Lucangeli","sequence":"first","affiliation":[{"name":"NESMOS Department, Sant Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde S.","family":"Cannistr\u00e0","sequence":"additional","affiliation":[{"name":"Unity of Plastic Surgery, Department of Surgery, Centre Hospitalier Universitaire Bichat Claude Bernard, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Scopelliti","sequence":"additional","affiliation":[{"name":"Maxillo-Facial Unit, San Filippo Neri Hospital\u2014ASL Roma 1, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9042-8120","authenticated-orcid":false,"given":"Pasquale","family":"Parisi","sequence":"additional","affiliation":[{"name":"NESMOS Department, Sant Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4190-8168","authenticated-orcid":false,"given":"Domenico","family":"Tripodi","sequence":"additional","affiliation":[{"name":"Unity of Plastic Surgery, Department of Surgery, Centre Hospitalier Universitaire Bichat Claude Bernard, 75018 Paris, France"},{"name":"Department of Health Sciences, Uni-Camillus Saint Camillus International University, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Barbet","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pathology, Hospital Necker Enfants Malades, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Cannistr\u00e0","sequence":"additional","affiliation":[{"name":"Unity of Plastic Surgery, Department of Surgery, Centre Hospitalier Universitaire Bichat Claude Bernard, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0002-9416(84)90059-9","article-title":"The influence of the trigeminal nerve on facial growth and development","volume":"85","author":"Beherens","year":"1984","journal-title":"Am. 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