Orofacial clefts are the most common craniofacial anomalies that affect the lip, palate and/or both structures (Harila et al., 2013; Li et al., 2019). Approximately 30% of oral clefts are associated with a known genetic syndrome (syndromic clefts), however, the remaining 70% occur without a known identified syndrome (non-syndromic clefts; Mossey and Modell, 2012; Saleem et al., 2019). Orofacial clefts (OFCs) are divided into three different subtypes on an anatomically basis; cleft lip (CL), cleft lip and palate (CLP) and cleft palate only (CPO; Lithovius et al., 2014). The higher risk of mental disorders in individuals born with non-syndromic OFCs is well documented in the literature (Richman and Ryan, 2003; Nopoulos et al., 2005, 2010; Boes et al., 2007; Richman et al., 2012; Pedersen et al., 2016; Tillman et al., 2018; Gallagher and Collett, 2019). These children are disproportionately afflicted by psychiatric disorders including schizophrenia, intellectual disability, autism spectrum disorder, anxiety disorders and ADHD (Pedersen et al., 2016; Ansen-Wilson et al., 2018; Tillman et al., 2018). Children with non-syndromic OFCs are also at high risk for learning disabilities (Richman and Ryan, 2003; Tillman et al., 2018; Gallagher and Collett, 2019). Multiple stress factors including repetitive cleft repair surgeries, aesthetics, and functional consequences such as speech difficulty were believed to be the basis of such deficits (Gallagher and Collett, 2019). However, the underlying mechanisms for these deficits have not been clarified (Yang et al., 2012; Gallagher and Collett, 2019). A unified maldevelopment of the brain and facial structures is a possible etiology behind the observed neuropsychiatric disorders in this patient population (Speltz, 2000; Nopoulos et al., 2005; Boes et al., 2007; Weinberg et al., 2009; Yang et al., 2012; Adamson et al., 2014; Ansen-Wilson et al., 2018; Gallagher and Collett, 2019).

Executive dysfunction occurs when cognitive skills responsible for organizing and self-regulating behaviors are impaired (Shaheen, 2014; Zelazo, 2015). Executive functions are interconnected with the maturation of the prefrontal cortex, and their dysfunctions are common in neurodevelopmental and psychiatric disorders (Shaheen, 2014; Zelazo, 2015; Bausela-Herreras et al., 2019; Faedda et al., 2019). Specific patterns of executive dysfunction manifest according to different types of neurodevelopmental disorder and may even be a precursor before the diagnosis of these conditions (Zelazo, 2015; Bausela-Herreras et al., 2019; Otterman et al., 2019). Neuroimaging studies and the underlying cognitive deficits suggest that frontal and prefrontal cortical function may be impaired in children with non-syndromic OFCs (Nopoulos et al., 2010; Adamson et al., 2014; Chollet et al., 2014), and recommend further examination of executive functioning during follow-up (Tillman et al., 2018). Previous studies have examined the executive system in children with non-syndromic OFCs (Nopoulos et al., 2002; Laasonen et al., 2004; Conrad et al., 2009; Lemos and Feniman, 2010; Bodoni et al., 2021), but screened only one or two of its dimensions. It is often unclear whether syndromic participants were excluded from these studies (Gallagher and Collett, 2019), and may include a mixed population of both syndromic and non-syndromic forms (Nopoulos et al., 2000, 2002). Underlying genetic abnormalities—which are present in syndromic oral clefts—often affect proper brain development and function (McDonald-McGinn et al., 2015; Berg et al., 2016) and may therefore misrepresent the non-syndromic population (Rincic et al., 2016; Sándor-Bajusz et al., 2022).

The primary goal of our study was to screen cognitive deficits in children with non-syndromic OFCs to identify an at-risk subpopulation for neurodevelopmental disorders. We further aimed to identify risk factors that may additionally affect the overall neurodevelopmental course of these children. We hypothesized that children with non-syndromic OFCs would present with more cognitive difficulties compared to their non-cleft peers.

We analyzed the cognitive functioning and clinical characteristics of 40 children with non-syndromic OFCs and 44 age-matched controls. All participants performed well on the executive function tasks, except for the CPT; children with non-syndromic OFCs scored lower and missed targets more often than controls (omission errors, see Table 4). The results raise the possibility of an underlying attention deficit in these children described previously by other studies (Nopoulos et al., 2010; Pedersen et al., 2016). The two groups scored within normal ranges on the IQ test, however controls scored higher on the PRI and WMI subtests. Subgroup analysis of the cleft group revealed significant relationships between parental SES and IQ scores: children of parents with a higher educational background scored significantly higher on the IQ test, specifically reflected in perceptual reasoning and the full-scare IQ score. We also observed a significant association between early intervention and IQ: children who received speech and language therapy achieved higher scores specifically reflected in the verbal component (VCI) of the WISC-IV (see Table 7). We further observed the influence of family structure on mental health outcomes: children raised by single parents were diagnosed with psychiatric conditions more often than children raised by married parents.

Children of the control group reported more symptoms of externalizing disorders (attention, oppositional, behavioral), while children with non-syndromic OFCs reported symptoms of internalizing disorders (affective, anxiety) more than controls (Table 3). Parents of the control group reported higher symptoms across all scales of the CBCL. However, retrospective analysis of past medical history revealed that children with non-syndromic OFCs were clinically diagnosed with psychiatric disorders at a higher proportion and received psychiatric support more often than controls. Larger cohort studies have previously described this observation (Pedersen et al., 2016; Tillman et al., 2018). While there is a clear difference in the proportion of psychiatric disorders between our two study groups, this is not statistically detectable, and the effect size is small. A larger sample may provide conclusive evidence of this observation.

Psychiatric diagnoses varied across cleft subtypes and the affected side: the highest proportion of psychiatric diagnoses were observed in CLP, and bilateral-sided clefts. These observations may suggest that the more complicated clefts more likely present with psychiatric comorbidities (Pedersen et al., 2016; Gallagher et al., 2018). We did not observe psychiatric comorbidities in CPO children, which is in contrast with previous observations (Nilsson et al., 2015; Pedersen et al., 2016; Tillman et al., 2018; Gallagher and Collett, 2019). Interestingly, less than half (29.16%) of the cleft group participants recognized their repaired OFC as a disease or medical condition. This may indicate that the causative stressor is in fact something other than the physical awareness of the defect itself (Aleksieva et al., 2021). Apgar score at 5 min was lower for the cleft group than for controls, but clinically within the normal range. We observed no further complications in the postnatal period between the two study groups. There was a tendency of a slower onset of developmental milestones in children with OFCs; potty-training and the use of two-word phrases presented at a later age compared to controls, also within clinical ranges. Children with OFCs experienced difficulties integrating into preschool, and most required additional support for learning, psychological and physical well-being throughout their education. Difficulties with speech and language development are known to be a consequence related to the primary defect; however, studies highlight the possibility of a central auditory dysfunction, which may cause developmental issues that affect these skills (Čeponien et al., 1999; Yang et al., 2012; Conrad et al., 2021). Based on our results, children with non-syndromic OFCs initially have a slower development and experience difficulties integrating into preschool; however, it seems that they go through a “catch-up phase” around school age and perform well—almost equal to their peers—throughout elementary and high school.

Our study has important limitations. The small sample size of the study, limited us to further explore relationships within gender, cleft subtype and affected side. The sample size varied across the different phases of the study. Most of the children in the cleft group were represented by males. The retrospective nature of the questionnaires may have created bias in the data provided. We could not assess the baseline level of executive functioning prior to the interventional programs (speech and language therapy), and we may observe an overall “corrected” level of cognitive functioning. However, this study has several strengths. Our study is the first to provide data on cognitive performance and clinical characteristics of Hungarian children with non-syndromic OFCs across a wide age-range. We were able to provide data on neurodevelopmental differences in children with non-syndromic OFCs in early infancy and the preschool period. We further demonstrated how these children, despite having previous difficulties during early infancy, can “catch-up” to their peers and perform well. Early intervention, additional help in school and proper parental support seem to have a strong effect on proper cognitive development for this patient population. Our observations suggest the presence of attention deficit in children with non-syndromic OFCs in support of the higher proportion of ADHD diagnosis seen in this population compared to controls. Assessing the executive system at an earlier stage of development, prior to interventional programs, may be useful to screen and identify individuals within the cleft population who are at risk for atypical neurodevelopment.

Children with non-syndromic OFCs seem to be at risk for atypical cognitive and speech development. This may be explained by a unified brain and facial maldevelopment in utero. Future studies with large sample sizes are needed to further explore this underlying etiology to identify this subpopulation, since not all children with non-syndromic OFCs present with such difficulties. Longitudinal studies are needed to provide more evidence of baseline cognitive functioning to study early signs of atypical neurodevelopment and the effect of early interventions. Under the right environment, these children present with similar cognitive strengths as their peers and show significant skill development. A good multidisciplinary team, early interventions, special education programs, and proper parental support allow most children with non-syndromic OFCs to perform just as well as other children.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Regional Ethics Committee of the University of Pécs (approval number: 7967-PTE 2020). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

KS-B, GC, AV, and KH contributed to conception and design of the study. KS-B, ÁT, AZ, KH, EM, and AV collected the data and organized the database. GC supervised the study. TD performed the statistical analysis. KS-B wrote the first draft of the manuscript. GC and TD wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.

The authors received financial support from the University of Pécs for the open-access publication of this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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