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John L Waddington - One of the best experts on this subject based on the ideXlab platform.
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translational genetic modelling of 3d craniofacial Dysmorphology elaborating the facial phenotype of neurodevelopmental disorders through the prism of schizophrenia
Current Behavioral Neuroscience Reports, 2017Co-Authors: John L Waddington, Stanislav Katina, Colm M P Otuathaigh, Adrian BowmanAbstract:In the context of human developmental conditions, we review the conceptualisation of schizophrenia as a neurodevelopmental disorder, the status of craniofacial Dysmorphology as a clinically accessible index of brain dysmorphogenesis, the ability of genetically modified mouse models of craniofacial Dysmorphology to inform on the underlying dysmorphogenic process and how geometric morphometric techniques in mutant mice can extend quantitative analysis. Mutant mice with disruption of neuregulin-1, a gene associated meta-analytically with risk for schizophrenia, constitute proof-of-concept studies of murine facial Dysmorphology in a manner analogous to clinical studies in schizophrenia. Geometric morphometric techniques informed on the topography of facial Dysmorphology and identified asymmetry therein. Targeted disruption in mice of genes involved in individual components of developmental processes and analysis of resultant facial Dysmorphology using geometric morphometrics can inform on mechanisms of dysmorphogenesis at levels of incisiveness not possible in human subjects.
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craniofacial Dysmorphology in 22q11 2 deletion syndrome by 3d laser surface imaging and geometric morphometrics illuminating the developmental relationship to risk for psychosis
American Journal of Medical Genetics Part A, 2015Co-Authors: Sarah E Prasad, Stanislav Katina, Adrian Bowman, Robin J Hennessy, Kieran C Murphy, John L WaddingtonAbstract:Persons with 22q11.2 deletion syndrome (22q11.2DS) are characterized inter alia by facial Dysmorphology and greatly increased risk for psychotic illness. Recent studies indicate facial Dysmorphology in adults with schizophrenia. This study evaluates the extent to which the facial Dysmorphology of 22q11.2DS is similar to or different from that evident in schizophrenia. Twenty-one 22q11.2DS-sibling control pairs were assessed using 3D laser surface imaging. Geometric morphometrics was applied to 30 anatomical landmarks, 480 geometrically homologous semi-landmarks on curves and 1720 semi-landmarks interpolated on each 3D facial surface. Principal component (PC) analysis of overall shape space indicated PC2 to strongly distinguish 22q11.2DS from controls. Visualization of PC2 indicated 22q11.2DS and schizophrenia to be similar in terms of overall widening of the upper face, lateral displacement of the eyes/orbits, prominence of the cheeks, narrowing of the lower face, narrowing of nasal prominences and posterior displacement of the chin; they differed in terms of facial length (increased in 22q11.2DS, decreased in schizophrenia), mid-face and nasal prominences (displaced upwards and outwards in 22q11.2DS, less prominent in schizophrenia); lips (more prominent in 22q11.2DS; less prominent in schizophrenia) and mouth (open mouth posture in 22q11.2DS; closed mouth posture in schizophrenia). These findings directly implicate dysmorphogenesis in a cerebral-craniofacial domain that is common to 22q11.2DS and schizophrenia and which may repay further clinical and genetic interrogation in relation to the developmental origins of psychotic illness.
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frontonasal Dysmorphology in bipolar disorder by 3d laser surface imaging and geometric morphometrics comparisons with schizophrenia
Schizophrenia Research, 2010Co-Authors: Robin J Hennessy, Patrizia A Baldwin, David J Browne, Anthony Kinsella, John L WaddingtonAbstract:Any developmental relationship between bipolar disorder and schizophrenia engenders continuing debate. As the brain and face emerge in embryological intimacy, brain dysmorphogenesis is accompanied by facial dysmorphogenesis. 3D laser surface imaging was used to capture the facial surface of 13 male and 14 female patients with bipolar disorder in comparison with 61 male and 75 female control subjects and with 37 male and 32 female patients with schizophrenia. Surface images were analysed using geometric morphometrics and 3D visualisations to identify domains of facial shape that distinguish bipolar patients from controls and bipolar patients from those with schizophrenia. Both male and female bipolar patients evidenced significant facial Dysmorphology: common to male and female patients was overall facial widening, increased width of nose, narrowing of mouth and upward displacement of the chin; Dysmorphology differed between male and female patients for nose length, lip thickness and tragion height. There were few morphological differences in comparison with schizophrenia patients. That Dysmorphology of the frontonasal prominences and related facial regions in bipolar disorder is more similar to than different from that found in schizophrenia indicates some common dysmorphogenesis. Bipolar disorder and schizophrenia might reflect similar insult(s) acting over slightly differing time-frames or slightly differing insult(s) acting over a similar time-frame.
Derek M Steinbacher - One of the best experts on this subject based on the ideXlab platform.
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orbital Dysmorphology in untreated children with crouzon and apert syndromes
Plastic and Reconstructive Surgery, 2015Co-Authors: Antonio J Forte, John A. Persing, Derek M Steinbacher, Eric D Brooks, Tom W Andrew, Nivaldo AlonsoAbstract:BACKGROUND Orbital Dysmorphology and midface retrusion are the hallmarks of Crouzon and Apert syndromes. The precise nature of this deficiency is not known. METHODS Untreated Crouzon and Apert syndrome patients and age- and sex-matched controls were included. Computed tomographic scans were digitized and reconstructed. Craniometric and volumetric data relating to the orbit were collected. RESULTS Thirty-one scans were included (control, n = 12; Crouzon; n = 9; Apert, n = 10). The mean age of the Apert group was 5.31 ± 5 years; Crouzon, 5.77 ± 2.7 years; and control, 6.4 ± 3.6 years. The bony orbit length was 12 percent shorter in Apert (p = 0.004) and 17 percent shorter in the Crouzon group when compared to controls (p < 0.0001). The bony orbital volume was 21 percent smaller in the Apert children (p = 0.0006) and 23 percent smaller in Crouzon when compared to controls (p = 0.003). Globe volume was 15 percent larger in Apert (p = 0.008) and 36 percent larger in the Crouzon group when compared to controls (p < 0.0001). Orbital soft-tissue volume was 19 percent less in the Apert group (p = 0.004) and 29 percent less in the Crouzon group (p = 0.001) when compared to controls. CONCLUSIONS A shortened bony orbit, decreased orbital and orbital soft-tissue volumes, and an increased volume of the globe were found in both conditions. Despite normal volume of the overall orbital contents, the contents are altered, and the bony orbit is shorter and holds less volume.
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three dimensional orbital Dysmorphology in metopic synostosis
Journal of Plastic Reconstructive and Aesthetic Surgery, 2014Co-Authors: Harib H Ezaldein, John A. Persing, Philipp Metzler, Derek M SteinbacherAbstract:Summary Background Metopic synostosis is characterized by trigonocephaly, lateral supraorbital retrusion, and hypotelorism. Most phenotypic evaluations have focused on the forehead without much emphasis on the orbits. The study seeks to explore differences in orbital Dysmorphology for metopic and control patients, along with different degrees of metopic synostosis. Methods Demographic and craniometric data were compiled. CT scans were digitized (Materialise) and metopic and control groups were compared. Degree of trigonocephaly was classified into moderate and severe cases based on endocranial bifrontal angle. Orbital plane angle, width, depth, volume, and corneal projection were measured. Statistical two-paired t -tests were used, with significance determined as p Results Forty-six CT scans were analyzed (23 affected, 23 controls). Mean ages (6 months metopic, 7 months control) and genders (18 males metopic, 10 males control) were determined. Orbital plane angle measurements showed differences between the metopic and the control ( p = 0.0002), along with a correlation to trigonocephaly ( p = 0.0097). Orbital width and height were insignificant between controls and overall metopics, though height was less in severe metopics ( p = 0.046 left, p = 0.0337 right). Orbital Depth was significant between control and metopics ( p = 0.0106 left, p = 0.0025 right), and pronounced in severe cases p = 0.0349 left, p = 0.0071 right). Corneal Projection correlates with metopic severity ( p Conclusions Orbital Dysmorphology worsens with increasing degree of trigonocephaly, presenting additional functional defects. The true exorbitism most directly correlates with worsening trigonocephaly. Expanding and advancing the lateral orbital wall is a critical treatment element in correction. Level of evidence III.
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zygomatic Dysmorphology in unicoronal synostosis
Journal of Plastic Reconstructive and Aesthetic Surgery, 2013Co-Authors: Miles J Pfaff, John A. Persing, Kenneth Wong, Derek M SteinbacherAbstract:Summary Introduction Unicoronal synostosis (UCS) imparts a fronto-facial deformity, the hallmark feature being orbital and forehead Dysmorphology. The facial and malar regions also consistently display asymmetry, however, zygomatic structural characteristics have not been investigated. The purpose of this study is to objectively analyze the zygomata of UCS patients compared to normal controls. Methods Three dimensional-computed tomographic images and demographic information were obtained from normal control and UCS patients. Volumetric and morphometric analyses were performed and results statistically analyzed. P values Results A total of 68 zygomatic sides were analyzed: twelve control (6 females; mean age: 6.6 months) and 22 UCS patients (10 females; mean age: 5.1 months). The affected side was right in 55% ( n = 12) and left in 45% ( n = 10) of UCS patients. The affected zygomata were volumetrically deficient compared to unaffected and normal control zygomata. Unaffected zygomata demonstrated diminished volume compared to norms. Morphometrically, affected zygomata differed, while both the unaffected and control zygomata were similar. Age stratification revealed marked differences in zygomatic volume and morphometry between the affected and unaffected zygomata was greatest at an early age interval. Conclusion The affected UCS zygomata are on average smaller compared to unaffected and normal control zygomata. Moreover, distinct morphometric differences exist on the affected zygomata versus both unaffected and control zygomata. These differences are not addressed by commonly employed treatment approaches. Further studies evaluating the growth effect of UCS zygomatic morphology should be entertained.
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bilateral orbital Dysmorphology in unicoronal synostosis
Plastic and Reconstructive Surgery, 2013Co-Authors: Joel S Beckett, John A. Persing, Derek M SteinbacherAbstract:Background:Orbital Dysmorphology is believed to cause ipsilateral ocular abnormalities in unicoronal synostosis. Recently, there has been increasing evidence of visual problems in the contralateral eye. The purpose of this study was to explore morphology of both the ipsilateral and contralateral uni
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classification of trigonocephaly in metopic synostosis
Plastic and Reconstructive Surgery, 2012Co-Authors: Joel S Beckett, Priyanka Chadha, John A. Persing, Derek M SteinbacherAbstract:Background:The orbitofrontal deformity in metopic synostosis is recognized clinically but has not been quantitatively defined in a large patient population. The authors' purpose was to document the Dysmorphology in metopic synostosis and define subtype gradations.Methods:Demographic and computed tom
Stanislav Katina - One of the best experts on this subject based on the ideXlab platform.
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translational genetic modelling of 3d craniofacial Dysmorphology elaborating the facial phenotype of neurodevelopmental disorders through the prism of schizophrenia
Current Behavioral Neuroscience Reports, 2017Co-Authors: John L Waddington, Stanislav Katina, Colm M P Otuathaigh, Adrian BowmanAbstract:In the context of human developmental conditions, we review the conceptualisation of schizophrenia as a neurodevelopmental disorder, the status of craniofacial Dysmorphology as a clinically accessible index of brain dysmorphogenesis, the ability of genetically modified mouse models of craniofacial Dysmorphology to inform on the underlying dysmorphogenic process and how geometric morphometric techniques in mutant mice can extend quantitative analysis. Mutant mice with disruption of neuregulin-1, a gene associated meta-analytically with risk for schizophrenia, constitute proof-of-concept studies of murine facial Dysmorphology in a manner analogous to clinical studies in schizophrenia. Geometric morphometric techniques informed on the topography of facial Dysmorphology and identified asymmetry therein. Targeted disruption in mice of genes involved in individual components of developmental processes and analysis of resultant facial Dysmorphology using geometric morphometrics can inform on mechanisms of dysmorphogenesis at levels of incisiveness not possible in human subjects.
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craniofacial Dysmorphology in 22q11 2 deletion syndrome by 3d laser surface imaging and geometric morphometrics illuminating the developmental relationship to risk for psychosis
American Journal of Medical Genetics Part A, 2015Co-Authors: Sarah E Prasad, Stanislav Katina, Adrian Bowman, Robin J Hennessy, Kieran C Murphy, John L WaddingtonAbstract:Persons with 22q11.2 deletion syndrome (22q11.2DS) are characterized inter alia by facial Dysmorphology and greatly increased risk for psychotic illness. Recent studies indicate facial Dysmorphology in adults with schizophrenia. This study evaluates the extent to which the facial Dysmorphology of 22q11.2DS is similar to or different from that evident in schizophrenia. Twenty-one 22q11.2DS-sibling control pairs were assessed using 3D laser surface imaging. Geometric morphometrics was applied to 30 anatomical landmarks, 480 geometrically homologous semi-landmarks on curves and 1720 semi-landmarks interpolated on each 3D facial surface. Principal component (PC) analysis of overall shape space indicated PC2 to strongly distinguish 22q11.2DS from controls. Visualization of PC2 indicated 22q11.2DS and schizophrenia to be similar in terms of overall widening of the upper face, lateral displacement of the eyes/orbits, prominence of the cheeks, narrowing of the lower face, narrowing of nasal prominences and posterior displacement of the chin; they differed in terms of facial length (increased in 22q11.2DS, decreased in schizophrenia), mid-face and nasal prominences (displaced upwards and outwards in 22q11.2DS, less prominent in schizophrenia); lips (more prominent in 22q11.2DS; less prominent in schizophrenia) and mouth (open mouth posture in 22q11.2DS; closed mouth posture in schizophrenia). These findings directly implicate dysmorphogenesis in a cerebral-craniofacial domain that is common to 22q11.2DS and schizophrenia and which may repay further clinical and genetic interrogation in relation to the developmental origins of psychotic illness.
Matthew A Deardoff - One of the best experts on this subject based on the ideXlab platform.
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recognition of the cornelia de lange syndrome phenotype with facial Dysmorphology novel analysis
Clinical Genetics, 2016Co-Authors: Lina Baselvanagaite, Lior Wolf, Melanie Orin, Lidia Larizza, Cristina Gervasini, Ian D Krantz, Matthew A DeardoffAbstract:Facial analysis systems are becoming available to healthcare providers to aid in the recognition of dysmorphic phenotypes associated with a multitude of genetic syndromes. These technologies automatically detect facial points and extract various measurements from images to recognize dysmorphic features and evaluate similarities to known facial patterns (gestalts). To evaluate such systems' usefulness for supporting the clinical practice of healthcare professionals, the recognition accuracy of the Cornelia de Lange syndrome (CdLS) phenotype was examined with FDNA's automated facial Dysmorphology novel analysis (FDNA) technology. In the first experiment, 2D facial images of CdLS patients with either an NIPBL or SMC1A gene mutation as well as non-CdLS patients which were assessed by dysmorphologists in a previous study were evaluated by the FDNA technology; the average detection rate of experts was 77% while the system's detection rate was 87%. In the second study, when a new set of NIPBL, SMC1A and non-CdLS patient photos was evaluated, the detection rate increased to 94%. The results from both studies indicated that the system's detection rate was comparable to that of Dysmorphology experts. Therefore, utilizing such technologies may be a useful tool in a clinical setting.
Robert J Lipinski - One of the best experts on this subject based on the ideXlab platform.
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definition of critical periods for hedgehog pathway antagonist induced holoprosencephaly cleft lip and cleft palate
PLOS ONE, 2015Co-Authors: Galen W Heyne, Cal G Melberg, Padydeh Doroodchi, Kia F Parins, Henry W Kietzman, Joshua L Everson, Lydia J Ansenwilson, Robert J LipinskiAbstract:The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of Dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain Dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in “non-syndromic” orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.
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the teratogenic effects of prenatal ethanol exposure are exacerbated by sonic hedgehog or gli2 haploinsufficiency in the mouse
PLOS ONE, 2014Co-Authors: Henry W Kietzman, Joshua L Everson, Robert J Lipinski, Kathleen K SulikAbstract:Disruption of the Hedgehog signaling pathway has been implicated as an important molecular mechanism in the pathogenesis of fetal alcohol syndrome. In severe cases, the abnormalities of the face and brain that result from prenatal ethanol exposure fall within the spectrum of holoprosencephaly. Single allele mutations in the Hh pathway genes Sonic Hedgehog (SHH) and GLI2 cause holoprosencephaly with extremely variable phenotypic penetrance in humans. Here, we tested whether mutations in these genes alter the frequency or severity of ethanol-induced Dysmorphology in a mouse model. Timed pregnancies were established by mating Shh+/− or Gli2+/− male mice backcrossed to C57BL/6J strain, with wildtype females. On gestational day 7, dams were treated with two ip doses of 2.9 g/kg ethanol (or vehicle alone), administered four hrs apart. Fetuses were then genotyped and imaged, and the severity of facial Dysmorphology was assessed. Following ethanol exposure, mean Dysmorphology scores were increased by 3.2- and 6.6-fold in Shh+/− and Gli2+/− groups, respectively, relative to their wildtype littermates. Importantly, a cohort of heterozygous fetuses exhibited phenotypes not typically produced in this model but associated with severe holoprosencephaly, including exencephaly, median cleft lip, otocephaly, and proboscis. As expected, a correlation between the severity of facial Dysmorphology and medial forebrain deficiency was observed in affected animals. While Shh+/− and Gli2+/− mice have been described as phenotypically normal, these results illustrate a functional haploinsufficiency of both genes in combination with ethanol exposure. By demonstrating an interaction between specific genetic and environmental risk factors, this study provides important insights into the multifactorial etiology and complex pathogenesis of fetal alcohol syndrome and holoprosencephaly.
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The teratogenic effects of prenatal ethanol exposure are exacerbated by sonic Hedgehog or
2014Co-Authors: Henry W Kietzman, Joshua L Everson, Kathleen K Sulik, Robert J LipinskiAbstract:Disruption of the Hedgehog signaling pathway has been implicated as an important molecular mechanism in the pathogenesis of fetal alcohol syndrome. In severe cases, the abnormalities of the face and brain that result from prenatal ethanol exposure fall within the spectrum of holoprosencephaly. Single allele mutations in the Hh pathway genes Sonic Hedgehog (SHH) and GLI2 cause holoprosencephaly with extremely variable phenotypic penetrance in humans. Here, we tested whether mutations in these genes alter the frequency or severity of ethanol-induced Dysmorphology in a mouse model. Timed pregnancies were established by mating Shh+/2 or Gli2+/2 male mice backcrossed to C57BL/6J strain, with wildtype females. On gestational day 7, dams were treated with two ip doses of 2.9 g/kg ethanol (or vehicle alone), administered four hrs apart. Fetuses were then genotyped and imaged, and the severity of facial Dysmorphology was assessed. Following ethanol exposure, mean Dysmorphology scores were increased by 3.2- and 6.6-fold in Shh+/2 and Gli2+/2 groups, respectively, relative to their wildtype littermates. Importantly, a cohort of heterozygous fetuses exhibited phenotypes not typically produced in this model but associated with severe holoprosencephaly, including exencephaly, median cleft lip, otocephaly, and proboscis. As expected, a correlation between the severity of facial Dysmorphology and medial forebrain deficiency was observed in affected animals. While Shh+/2 and Gli2+/2 mice have been described as phenotypically normal, these results illustrate a functional haploinsufficiency of both genes in combination wit