Embryologically Based Classification Specifies Gender Differences in the Prevalence of Orofacial Cleft Subphenotypes

Background: A recently published validated classification system divides all orofacial cleft (OFC) subphenotypes into groups based on underlying developmental mechanisms, that is, fusion and differentiation, and their timing, that is, early and late periods, in embryogenesis of the primary and secondary palates. Aims: The aim of our study was to define gender differences in prevalence for all subphenotypes in newborns with OFC in the Netherlands. Methods: This was a retrospective cross-sectional study on children with OFC born from 2006 to 2016. Clefts were classified in early (E-), late (L-), and early/late (EL-) embryonic periods, in primary (P-), secondary (S-), and primary/secondary (PS-) palates, and further divided into fusion (F-), differentiation (D-), and fusion/differentiation (FD-) defects, respectively. Results: A total of 2089 OFC children were analyzed (1311 males and 778 females). Orofacial cleft subphenotypes in females occurred significantly more frequent in the L-period compared to males (66% vs 55%, P = .000), whereas clefts in males occurred significantly more in the EL-periods (40% vs 27%, P = .000). Females had significantly more S-palatal clefts (42% vs 23%, P = .000), while males had significantly more PS-palatal clefts (44% vs 30%, P = .000). Furthermore, the clefts in females were significantly more frequent the result of an F-defect (60% vs 52%, P = .000). Conclusions: Orofacial cleft in females mainly occur in the L-period are mostly S-palatal clefts, and are usually the result of an F-defect. Orofacial cleft in males more commonly occur in the EL-periods, are therefore more often combined PS-palatal clefts, and are more frequent D- and FD-defects.