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Quantitative Measures of Craniofacial Dysmorphology in a Family Study of Schizophrenia and Bipolar Illness.

ABSTRACT: Several laboratories, including ours, have reported an overrepresentation of craniofacial (CF) anomalies in schizophrenia (SZ). How might this dysmorphology arise in a brain-based disorder? Because the brain and face derive from shared embryologic primordia and morphogenetic forces, maldevelopmental processes may result in both CF and brain dysmorphology.Our approach is 2-pronged. First, we have employed, for the first time in the study of psychiatric disorders, objective measures of CF morphology that utilize an extensive normative database, permitting computation of standardized scores for each subject. Second, we have rendered these findings biologically interpretable by adopting principles of embryology in the analysis of dysmorphology.Dependent measures in this investigation focused on derivatives of specific embryonic primordia and were contrasted among probands with psychotic disorders, their first-degree relatives, and normal controls (NC). Subject groups included patients with a diagnosis of SZ (N = 39) or bipolar (BP) disorder with psychotic features (N = 32), their clinically unaffected relatives (N = 82 and N = 41, respectively), and NC (N = 95) subjects.Anomalies involving derivatives of frontonasal and mandibular embryonic primordia showed a clear association with psychotic illness, as well as familial aggregation in relatives in both diagnostic groups. In contrast, one class of CF anomalies emerged only among SZ probands and their first-degree relatives: dysmorphology arising along the junction of the frontonasal and maxillary prominence derivatives, manifested as marked asymmetries. This class was not overrepresented among the BP patients nor among their relatives, indicating that this dysmorphology appears to be specific to SZ and not a generalized feature of psychosis. We discuss these findings in light of embryologic models that relate brain regions to specific CF areas.

SUBMITTER: Deutsch CK

PROVIDER: S-EPMC4601702 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Quantitative Measures of Craniofacial Dysmorphology in a Family Study of Schizophrenia and Bipolar Illness.

Deutsch Curtis K CK Levy Deborah L DL Price Selya F R SF Bodkin J Alexander JA Boling Lenore L Coleman Michael J MJ Johnson Fred F Lerbinger Jan J Matthysse Steven S Holzman Philip S PS

Schizophrenia bulletin 20150320 6

Several laboratories, including ours, have reported an overrepresentation of craniofacial (CF) anomalies in schizophrenia (SZ). How might this dysmorphology arise in a brain-based disorder? Because the brain and face derive from shared embryologic primordia and morphogenetic forces, maldevelopmental processes may result in both CF and brain dysmorphology.Our approach is 2-pronged. First, we have employed, for the first time in the study of psychiatric disorders, objective measures of CF morpholo ...[more]

PMID: 25795453

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Project description:BackgroundThe 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.MethodInstitutional-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.ResultsFive 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).Conclusionour 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.

Project description:Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and is caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous males, a phenomenon called cellular interference that results from EPHRIN-B1 mosaicism. In Efnb1 heterozygous mice, mosaicism for EPHRIN-B1 results in cell sorting and more severe phenotypes than Efnb1 hemizygous males, 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 mutant 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, neural tissue-specific disruption of Efnb1 does not appear to contribute to CFNS craniofacial 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 fully recapitulate the severity of CFNS-like Efnb1 heterozygosity. 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 etiology and signaling interactions underlying CFNS dysmorphology.

Dataset Information

Quantitative Measures of Craniofacial Dysmorphology in a Family Study of Schizophrenia and Bipolar Illness.

Publications

Quantitative Measures of Craniofacial Dysmorphology in a Family Study of Schizophrenia and Bipolar Illness.

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