The neurodevelopmental basis of schizophrenia: clinical clues from craniofacial dysmorphology in northwest Ethiopia, 2020

Background The neurodevelopmental speculation of schizophrenia states that the pathogenesis of schizophrenia starts with early fetal or neonatal neurocraniofacial development rather than youthful adulthood when manic signs and symptoms are evident. However, there is no direct evidence of a pre-or peri-natal lesion associated with schizophrenia, rather indirect evidence of impaired development can be seen in macroscopic anatomical variations as well as microscopic immunohistochemical anomalies. One approach to studying neurodevelopmental disturbances among schizophrenic patients is somatic physical evidence or neurodevelopmental markers. Thus Our study aimed to assess the neurodevelopmental basis of schizophrenia clinical clues from anthropometric assessment of craniofacial dysmorphology among schizophrenic patients in North West Ethiopia 2019–2020. Method Institutional-based comparative cross-sectional study design was conducted in Debre Markos comprehensive specialized hospitals in 190 schizophrenic patients, 190 1st-degree relatives, and 190 healthy controls. Data were collected using standard methods, entered into EpiData version 3.1, and exports to SPSS version 24 for analysis. Descriptive data were analyzed using descriptive statistics. Welch ANOVA and post hoc comparison, a Games-Howell test, were conducted. Significance was set at a p-value of α = 0.05. Read back analysis was also conducted for the conclusion. Results Five hundred seventy study samples, male 375(65.8%), and female 195 (34.2%), were included in this study. The Games-Howell test revealed that the coronal arc length and sagittal arc length among schizophrenic patients were statistically significantly longer than the healthy controls (p < 0.006; p < 0.001, respectively). However, the difference between schizophrenic and healthy control regarding head circumference was marginally significant (p = 0.056). Schizophrenic patients had a significantly shorter total facial height (p < 0.001) and upper facial height (p < 0.001) than healthy controls. Regarding facial depth, schizophrenic patients had significantly shallow upper facial depth (p < 0.001), middle facial depth (p = 0.046), and lower facial depth (p < 0.001). Conclusion our finding indicated indirect evidence for disturbed craniofacial development in schizophrenia patients, and close and read back analysis of the result supported the neurodevelopmental basis of disease.

Aberrant cell segregation in craniofacial primordia and the emergence of facial dysmorphology in craniofrontonasal syndrome

Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous male patients, a phenomenon called cellular interference that is correlated with cell segregation resulting from EPHRIN-B1 mosaicism. Efnb1 heterozygous mutant mice also exhibit more severe phenotypes than Efnb1 hemizygous males as well as cell segregation, but how craniofacial dysmorphology arises from cell segregation is unknown and CFNS etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal and spatial interrogation of embryonic cell segregation in mouse models to elucidate mechanisms underlying CFNS pathogenesis. By generating ephrin-B1 mosaicism at different developmental timepoints and in specific cell populations, we find that ephrin-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape. Whereas specific craniofacial shape changes are qualitatively similar in Efnb1 heterozygous and hemizygous mutant embryos, heterozygous embryos are quantitatively more severely affected, indicating that Efnb1 mosaicism exacerbates loss of function phenotypes rather than having a neomorphic effect. Notably, tissue-specific disruption of Efnb1 throughout neural development does not appear to contribute to CFNS dysmorphology, but its disruption within neural crest cell-derived mesenchyme results in phenotypes very similar to widespread loss. Ephrin-B1 can bind and signal with EphB1, EphB2, and EphB3 receptor tyrosine kinases, but the signaling partner(s) relevant to CFNS are unknown. Geometric morphometric analysis of an allelic series of Ephb1; Ephb2; Ephb3 mutant embryos indicates that EphB2 and EphB3 are key receptors mediating Efnb1 hemizygous-like phenotypes, but the complete loss of EphB1-3 does not recapitulate CFNS-like Efnb1 heterozygous severity. Finally, by generating Efnb1+/-; Ephb1; Ephb2; Ephb3 quadruple knockout mice, we determine how modulating cumulative receptor activity influences cell segregation in craniofacial development and find that while EphB2 and EphB3 play an important role in craniofacial cell segregation, EphB1 is more important for cell segregation in the brain; surprisingly, complete loss of EphB1-EphB3 does not completely abrogate cell segregation. Together, these data advance our understanding of the morphogenetic etiology and signaling interactions underlying CFNS dysmorphology.Author SummaryCraniofacial anomalies are extremely common, accounting for one third of all birth defects, but even when the responsible genes are known, it often remains to be determined exactly how development has gone wrong. Craniofrontonasal syndrome (CFNS), which affects multiple aspects of craniofacial development, is a particularly mysterious disorder because it is X-linked, but affects females more severely than males, the opposite situation of most X-linked diseases. The responsible gene has been identified as EFNB1, which encodes the EPHRIN-B1 signaling molecule that regulates cellular position. Why EFNB1+/- heterozygous females exhibit severe stereotypical CFNS phenotypes is not well understood, but it is related to the fact that X chromosome inactivation generates mosaicism for EPHRIN-B1. Using mice harboring mutations in the Efnb1 gene in different embryonic tissues, and in receptor genes Ephb1-3, together with quantitative methods to measure craniofacial structures in developing embryos, we establish the tissue-specific contributions of ephrin-B1 mosaicism to craniofacial dysmorphology. We also examine when ephrin-B1 regulates cellular position during different stages of craniofacial development and which EphB receptors are involved. Our results reveal the specific cellular context and signaling interactions that are likely to underlie CFNS, and provide new understanding of how EPHRIN-B1 may regulate normal craniofacial development.

Craniofacial measures and minor physical anomalies in patients with schizophrenia in a cohort of Serbian population

Introduction/Objective. Craniofacial dysmorphology has been shown as the most prominent among physical anomalies in schizophrenia patients. The aim of the present study was to investigate the frequency of craniofacial anomalies in Serbian schizophrenia patients. Methods. A list of 27 minor physical anomalies (modified Waldrop scale) and nine ratios of craniofacial measures was used to detect the presence of craniofacial dysmorphology in 126 schizophrenia patients and 124 healthy controls. Results. Compared to the healthy subjects, schizophrenia patients had significantly higher rates of the following minor physical anomalies: fine hair, two or more hair whorls, fused eyebrows, wide nose basis, low-seated ears, high steepled and high flat palate, and furrowed tongue (most prevalent were vertical fissures and diffusely distributed fissures) with significance of p ? 0.001. The best predicting parameters for distinguishing between schizophrenics and controls were the inner canthus distance, the outer canthus distance, hair whorls (all at level p = 0.000), and high steepled palate (p ? 0.001). Conclusion. The results of the present study confirm the neurodevelopmental concept of schizophrenia, being potentially useful for further psychiatric-anthropological research. Clinical significance is reflected in the possibility of monitoring the potential mental illness in childhood through potential ectodermal markers, as well as the possibility of their comparison with the psychological profile in early adolescence.