Alterations in Perioral and Velopharyngeal Musculature in Cleft Lip and/or Palate: A Systematic Review

ObjectiveTo systematically characterize anatomical, histopathological and ultrastructural alterations of perioral and velopharyngeal muscles in patients with nonsyndromic cleft lip and/or palate (CL/P).DesignSystematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.SettingSystematic literature search of PubMed, EMBASE, Scopus, CNKI, Cochrane Database of Systematic Reviews, and gray literature sources (ClinicalTrials.gov, International Clinical Trials Registry Platform, Conference Proceedings Citation Index-Science, ProQuest Dissertations and Theses, GreyNet International) from January 1980 to June 2025, supplemented by manual reference screening.PatientsPatients with nonsyndromic CL/P of any age, sex, or cleft severity. Comparator groups included individuals without CL/P or nonaffected contralateral sides.Interventions:Not applicable. This review synthesized observational evidence from cohort, case-control, and cross-sectional studies.Main Outcome(s)Morphological characteristics (imaging and cadaveric dissection), and histopathological features (light microscopy and histochemical staining) of cleft-affected perioral and velopharyngeal muscles.ResultsA total of 21 studies were included. Anatomical investigations consistently demonstrated ectopic muscle insertions, aberrant fiber orientation, and muscle hypoplasia in both the lip and velopharyngeal musculature. Histopathological analyses revealed fiber disorganization, increased myofiber diameter variability, extensive interstitial fibrosis, mitochondrial dysfunction, and, in some studies, a shift toward type II fiber predominance. But the ultrastructural findings are limited to a small number of studies with inconsistent results, yielding low confidence. Methodological heterogeneity and risk of bias precluded meta-analysis. Confidence in findings, assessed using CERQual, was high for anatomical outcomes and moderate for histopathological features.ConclusionsPerioral and velopharyngeal muscles in patients with CL/P exhibit distinct but incompletely characterized pathological alterations. Future research should clarify muscle-specific pathology, regenerative dynamics, and clinically relevant strategies that may improve long-term functional recovery after cleft repair.RegistrationPROSPERO CRD420251115465.