Dental Anomalies and Genetic Polymorphisms as Predictors of Maxillofacial Growth in Individuals Born with Cleft Lip and Palate

Cleft lip and palate have a complex inheritance, and 90% of its variation in the population is due to genetic contributors. The impact of surgical procedures on maxillofacial growth is well known, but the interference of intrinsic factors in these growth outcomes is not elucidated. The present study aimed to analyze genetic polymorphisms and frequency of dental anomalies as predictors of maxillofacial growth in patients born with cleft lip with or without cleft palate. From a cohort of 537 individuals, operated on by the same surgeon, 121 were analyzed 2 times, to define changes in maxillary growth prognosis by occlusal scores in a minimum 4-y follow-up. In a second step, a subset of 360 individuals had maxillofacial growth outcomes evaluated using Wits, nasion perpendicular to point A, and occlusal scores. The markers MMP2 rs9923304, GLI2 rs3738880 and rs2279741, TGFA rs2166975, and FGFR2 rs11200014 and rs10736303 were genotyped, and frequency of dental anomalies and cleft severity were determined to define evidence of overrepresentation of alleles associated with maxillofacial growth outcomes. Age and age at primary surgical treatment, sex, and cleft laterality were variables adjusted in the analysis. We found an association between the frequency of dental anomalies and the maxillofacial growth in unilateral (P = 0.001) and bilateral (P = 0.03) individuals with clefts. MMP2 rs9923304 and maxillofacial growth were associated (P < 0.0001). There was also an association between GLI2 rs3738880 and TGFA rs2166975 and maxillary outcomes in individuals born with unilateral cleft lip and palate (P = 0.003 and P = 0.004, respectively), as well as between FGFR2 rs11200014 and maxillary outcomes regardless of cleft type (P = 0.005). Statistical evidence of an interaction between MMP2 rs9923304 and GLI2 rs3738880 was observed (P < 0.0001). Presence of dental anomalies and genetic variation in MMP2, GLI2, TGFA, and FGFR2 were associated with worse maxillofacial growth outcomes in individuals born with clefts.