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Holoprosencephaly
Selected AbstractsEmbryonic holoprosencephaly: pathology and phenotypic variabilityCONGENITAL ANOMALIES, Issue 4 2006Shigehito Yamada ABSTRACT Holoprosencephaly (HPE) is one of the major brain anomalies caused by the failure of cleavage of the prosencephalon during the early stage of development. Over 200 cases of HPE in the Kyoto Collection of Human Embryos were observed grossly and histologically, with special emphasis on the anomalies of the brain, face and eye. The facial anomalies of HPE human embryos after Carnegie stage (CS) 18 could be classified into cyclopia, synophthalmia, ethmocephaly, cebocephaly, and premaxillary agenesis, similarly as the classical classification for postnatal cases. On the other hand, HPE embryos at CS 13,17 showed some characteristic facies which are different from those in older embryos. In the present paper, pathology and phenotypic variability in HPE embryos were discussed from the embryopathological point of view. Recently, the molecular mechanism of HPE has been clarified by the techniques of gene manipulation, and various HPE genes have been identified by gene analysis of familial HPE cases. HPE is one of the major CNS anomalies which have been extensively studied and provides a clue to the mechanisms of normal and abnormal development of craniofacial structures. [source] Holoprosencephaly: A mythologic and teratologic distillate,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010M. Michael Cohen Jr.§ Abstract This review of holoprosencephaly provides a mythologic and teratologic distillate of the subject under the following headings: Babylonian tablets; Greek mythology; pictures from the 16th through the 20th Centuries; 19th Century teratology; history of more modern concepts and their terminologies; and ocean-going ships named "Cyclops." © 2010 Wiley-Liss, Inc. [source] Early pathogenesis of holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Kohei Shiota Abstract Holoprosencephaly (HPE) is one of the most common malformations encountered in early human embryos. It is assumed that more than 90% of HPE embryos die in utero and are eliminated by spontaneous abortion. Embryonic HPE displays some characteristic craniofacial phenotypes, which are not necessarily comparable to those in postnatal HPE cases. In this article, we summarize our studies on HPE in human embryos and discuss the pathogenesis of HPE malformations. © 2010 Wiley-Liss, Inc. [source] Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010John Klingensmith Abstract Holoprosencephaly (HPE) is the most common malformation of the forebrain, resulting from a failure to completely septate the left and right hemispheres at the rostral end of the neural tube. Because of the tissue interactions that drive head development, these forebrain defects are typically accompanied by midline deficiencies of craniofacial structures. Early events in setting up tissue precursors of the head, as well as later interactions between these tissues, are critical for normal head formation. Defects in either process can result in HPE. Signaling by bone morphogenetic proteins (BMPs), a family of secreted cytokines, generally plays negative roles in early stages of head formation, and thus must be attenuated in multiple contexts to ensure proper forebrain and craniofacial development. Chordin and Noggin are endogenous, extracellular antagonists of BMP signaling that promote the normal organization of the forebrain and face. Mouse mutants with reduced levels of both factors display mutant phenotypes remarkably analogous to the range of malformations seen in human HPE sequence. Chordin and Noggin function in part by antagonizing the inhibitory effects of BMP signaling on the Sonic hedgehog and Nodal pathways, genetic lesions in each being associated with human HPE. Study of Chordin;Noggin mutant mice is helping us to understand the molecular, cellular, and genetic pathogenesis of HPE and associated malformations. © 2010 Wiley-Liss, Inc. [source] The molecular genetics of holoprosencephaly,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Erich Roessler§ Abstract Holoprosencephaly (HPE) has captivated the imagination of Man for millennia because its most extreme manifestation, the single-eyed cyclopic newborn infant, brings to mind the fantastical creature Cyclops from Greek mythology. Attempting to understand this common malformation of the forebrain in modern medical terms requires a systematic synthesis of genetic, cytogenetic, and environmental information typical for studies of a complex disorder. However, even with the advances in our understanding of HPE in recent years, there are significant obstacles remaining to fully understand its heterogeneity and extensive variability in phenotype. General lessons learned from HPE will likely be applicable to other malformation syndromes. Here we outline the common, and rare, genetic and environmental influences on this conserved developmental program of forebrain development and illustrate the similarities and differences between these malformations in humans and those of animal models. Published 2010 Wiley-Liss, Inc. [source] Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study,,§AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Eric A. Miller¶ Abstract Holoprosencephaly (HPE) is a complex structural brain anomaly that results from incomplete cleavage of the forebrain. The prevalence of HPE at birth is low, and risk factors have been difficult to identify. Using data from a large multi-state population-based case-control study, we examined risk factors for non-syndromic HPE. Data from maternal telephone interviews were available for 74 infants with HPE and 5871 controls born between 1997 and 2004. Several characteristics and exposures were examined, including pregnancy history, medical history, maternal diet and use of nutritional supplements, medications, tobacco, alcohol, and illegal substances. We used ,2 -tests and logistic regression (excluding women with pre-existing diabetes) to examine associations with HPE. Except for diet (year before pregnancy) and sexually transmitted infections (STIs) (throughout pregnancy), most exposures were examined for the time period from the month before to the third month of pregnancy. HPE was found to be associated with pre-existing diabetes (,2,=,6.0; P,=,0.01), aspirin use [adjusted odds ratio (aOR),=,3.4; 95% confidence interval (CI) 1.6,6.9], lower education level (aOR,=,2.5; 95%CI 1.1,5.6), and use of assisted reproductive technologies (ART) (crude OR,=,4.2; 95%CI 1.3,13.7). Consistent maternal folic acid use appeared to be protective (aOR,=,0.4; 95%CI 0.2,1.0), but the association was of borderline statistical significance. While some of these findings support previous observations, other potential risk factors identified warrant further study. Published 2010 Wiley-Liss, Inc. [source] Non-genetic risk factors for holoprosencephaly,,§AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Candice Y. Johnson¶ Abstract Holoprosencephaly (HPE) is a congenital defect of the brain characterized by incomplete cleavage of the embryonic forebrain into left and right hemispheres. Although a substantial proportion of cases of HPE can be attributed to genetic abnormalities, the etiology in many cases remains unknown, with non-genetic risk factors believed to be important contributors. Due to the low birth prevalence of this defect, it has proven difficult to conduct studies of sufficient size to identify risk factors with certainty. This article provides a summary of non-genetic risk factors for HPE that have been investigated in case reports and case series, animal studies, and epidemiologic studies, including maternal illnesses, therapeutic and non-therapeutic exposures, nutritional factors, and sociodemographic factors. The article also highlights challenges in study design and further areas for research to better understand the etiology of HPE. Published 2010 Wiley-Liss, Inc. [source] Holoprosencephaly: An update on cytogenetic abnormalities,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Claude Bendavid Abstract Holoprosencephaly (HPE), the most common developmental defect of the forebrain and midface, is caused by a failure of midline cleavage early in gestation. Isolated HPE, which is highly genetically heterogeneous, can be due to major chromosomal abnormalities. Initially, karyotype approach led to the identification of several recurrent chromosomal anomalies predicting different HPE loci. Subsequently, several genes were isolated from these critical HPE regions, but point mutations and deletions in these genes were found only in 25% of the genetic cases. In order to identify other HPE genes, a more accurate investigation of the genome in HPE patients was necessary. To date, high-resolution cytogenetic techniques such as subtelomeric multiplex ligation-dependent probe amplification (MLPA) and microarray-based comparative genomic hybridization (array CGH) have enhanced chromosomal aberration analysis. In this article, we have updated the cytogenetic anomalies associated with HPE in a map listing all the subtelomeric and interstitial deletions that have been characterized either by karyotype, MLPA, or array CGH. The accumulation of recurrent genomic imbalances will lead to the further delineation of minimal critical HPE loci, which is the first step to the identification of new HPE genes. © 2010 Wiley-Liss, Inc. [source] Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Daniel E. Pineda-Alvarez§ Abstract Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans and is typically characterized by different degrees of hemispheric separation that are often accompanied by similarly variable degrees of craniofacial and midline anomalies. HPE is a classic example of a complex genetic trait with "pseudo"-autosomal dominant transmission showing incomplete penetrance and variable expressivity. Clinical suspicion of HPE is typically based upon compatible craniofacial findings, the presence of developmental delay or seizures, or specific endocrinological abnormalities, and is then followed up by confirmation with brain imaging. Once a clinical diagnosis is made, a thorough genetic evaluation is necessary. This usually includes analysis of chromosomes by high-resolution karyotyping, clinical assessment to rule-out well recognized syndromes that are associated with HPE (e.g., Pallister-Hall syndrome, Smith-Lemli-Opitz syndrome and others), and molecular studies of the most common HPE associated genes (e.g., SHH, ZIC2 and SIX3). In this review, we provide current step-by-step recommendations that are medically indicated for the genetic evaluation of patients with newly diagnosed HPE. Moreover, we provide a brief review of several available methods used in molecular diagnostics of HPE and describe the advantages and limitations of both currently available and future tests as they relate to high throughput screening, cost, and the results that they may provide. Published 2010 Wiley-Liss, Inc. [source] Abnormal sterol metabolism in holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Dorothea Haas Abstract Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The HPE phenotype is extremely variable and the etiology is heterogeneous. Among a variety of embryological toxins that can induce HPE, inhibitors, and other pertubations of cholesterol biosynthesis have been shown to be important factors, most likely because cholesterol is required in the Sonic hedgehog signaling cascade. Decreased levels of maternal cholesterol during pregnancy increase the risk for preterm delivery, but they are not associated with congenital malformations. However, if the fetus is affected by an inborn error of endogenous cholesterol synthesis, a reduction of maternal cholesterol concentration and cholesterol transport over the placenta aggravates the phenotypic expression. Exposure to lipophilic statins in early pregnancy may be associated with a substantial risk for structural CNS defects. © 2010 Wiley-Liss, Inc. [source] Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Jin S. Hahn Abstract Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally completed by the fifth week of gestation. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE in living humans. This has led to better classification of types of HPE, identification of newer subtypes, and understanding of the pathogenesis. Currently, there are four generally accepted subtypes of HPE: alobar, semilobar, lobar, and middle interhemispheric variant. These subtypes are defined primarily by the degree and region of neocortical nonseparation. Rather than there being four discrete subtypes of HPE, we believe that there is a continuum of midline neocortical nonseparation resulting in a spectrum disorder. Many patients with HPE fall within the border zone between the neighboring subtypes. In addition, there are patients with very mild HPE, where the nonseparation is restricted to the preoptic (suprachiasmic) area. In addition to the neocortex, other midline structures such as the thalami, hypothalamic nuclei, and basal ganglia are often nonseparated in HPE. The cortical and subcortical involvements in HPE are thought to occur due to a disruption in the ventral patterning process during development. The severity of the abnormalities in these structures determines the severity of the neurodevelopmental outcome and associated sequelae. © 2010 Wiley-Liss, Inc. [source] Holoprosencephaly due to numeric chromosome abnormalities,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Benjamin D. Solomon§ Abstract Holoprosencephaly (HPE) is the most common malformation of the human forebrain. When a clinician identifies a patient with HPE, a routine chromosome analysis is often the first genetic test sent for laboratory analysis in order to assess for a structural or numerical chromosome anomaly. An abnormality of chromosome number is overall the most frequently identified etiology in a patient with HPE. These abnormalities include trisomy 13, trisomy 18, and triploidy, though several others have been reported. Such chromosome number abnormalities are almost universally fatal early in gestation or in infancy. Clinical features of specific chromosome number abnormalities may be recognized by phenotypic manifestations in addition to the HPE. Published 2010 Wiley-Liss, Inc. [source] Holoprosencephaly and holoprosencephaly-like phenotypes: Review of facial and molecular findings in patients from a craniofacial hospital in Brazil,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Antonio Richieri-Costa Abstract Here we report on the clinical and genetic data for a large sample of Brazilian patients studied at the Hospital de Reabilitação de Anomalas Craniofaciais,Universidade de São Paulo (HRAC-USP) who presented with either the classic holoprosencephaly or the holoprosencephaly-like (HPE-L) phenotype. The sample included patients without detected mutations in some HPE determinant genes such as SHH, GLI2, SIX3, TGIF, and PTCH, as well as the photographic documentation of the previously reported patients in our Center. The HPE-L phenotype has been also called of HPE "minor forms" or "microforms." The variable phenotype, the challenge of genetic counseling, and the similarities to patients with isolated cleft lip/palate are discussed. © 2010 Wiley-Liss, Inc. [source] Holoprosencephaly and agnathia spectrum: Presentation of two new patients and review of the literature,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Emily F. Kauvar§ Abstract Holoprosencephaly (HPE), the most common developmental disorder of the human forebrain, is occasionally associated with the spectrum of agnathia, or virtual absence of the mandible. This condition results in a constellation of structural cerebral and craniofacial abnormalities. Here we present two new patients and review 30 patients from the literature with HPE and variants of agnathia. The majority of these patients are female and have the most severe forms of HPE, with cyclopia present more frequently than is usually observed in cohorts of patients with HPE. Also, many patients have additional clinical findings not typical in patients with classic HPE, particularly situs abnormalities. Recent animal studies suggest that the association of HPE and agnathia may relate to alterations in signaling from forebrain and foregut endoderm organizing centers and subsequent first pharyngeal arch development, although present models are inadequate to explain all of the clinical findings of this enigmatic human syndrome. Further research is required to better elucidate the causal and pathogenic basis of this association. Published 2010 Wiley-Liss, Inc. [source] Holoprosencephaly and ectrodactyly: Report of three new patients and review of the literature,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Amelia A. Keaton§ Abstract Holoprosencephaly (HPE) and ectrodactyly represent congenital malformations of the developing forebrain and developing digits, respectively. The combination of these conditions is rare, with only 15 cases known to date (12 previously reported, and 3 new cases described here). While the findings in these patients overlap with previously described genetic conditions, the similarity in phenotypes among these patients has led to the establishment of a at least one distinct syndrome: HPE, ectrodactyly, and bilateral cleft lip-palate syndrome (OMIM 300571). There has been great interest in identifying a genetic cause for the findings in patients with HPE and ectrodactyly; however the cause(s) of this rare association still remain unknown. Published 2010 Wiley-Liss, Inc. [source] Holoprosencephaly and craniosynostosis: A report of two siblings and review of the literature,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Manu S. Raam§ Abstract Holoprosencephaly (HPE) and craniosynostosis are separate conditions that have occasionally been observed to occur simultaneously in the same patient. Here, we compile patients with both conditions who have been documented in the literature thus far; moreover, we report on two additional siblings who have not been previously described. We also compare the clinical features of these patients and discuss the previously hypothesized possibility of an independent association including both HPE and craniosynostosis. Published 2010 Wiley-Liss, Inc. [source] Management of children with holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Eric B. Levey Abstract Holoprosencephaly (HPE) is the most common malformation of the embryonic forebrain in humans. Although HPE occurs along a continuous spectrum, it has been categorized into four types from most severe to least severe: alobar, semilobar, lobar, and middle interhemispheric (MIH) variant. Facial malformations are often associated with HPE and usually correlate with the severity of brain malformation. With the most severely affected newborns, there is a high mortality rate in the first month of life, however, with milder forms of HPE, the majority survive beyond infancy. The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations have enrolled 182 living children in a prospective research study. Based on previously published reports using this database, reports from other investigators, as well as our experience and personal observations, the range of developmental, neurological, and medical problems found in children with HPE is described in this article. Virtually all children with HPE have some developmental disability and the severity correlates with the severity of the brain malformation on neuroimaging. Common medical problems include hydrocephalus, seizures, motor impairment, oromotor dysfunction with risk of poor nutrition and aspiration, chronic lung disease, gastroesophageal reflux, constipation, hypothalamic dysfunction with disturbed sleep,wake cycles and temperature dysregulation, as well as endocrine dysfunction. Diabetes insipidus in particular is found in about 70% of children with classic HPE. Recommendations for management of these problems are given based on experiences of the authors and familiarity with the literature. © 2010 Wiley-Liss, Inc. [source] Genetic counseling and "molecular" prenatal diagnosis of holoprosencephaly (HPE),AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Sandra Mercier Abstract Holoprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. The poor prognosis in the most severe forms justifies the importance of genetic counseling in affected families. The genetic counseling requires a thorough clinical approach given the extreme variability of phenotype and etiology. The karyotype is an essential diagnostic tool. Since mutations in the four major genes (SHH, ZIC2, SIX3, and TGIF) have been identified in HPE patients, molecular study is performed routinely in nonsyndromic HPE. New molecular tools, such as array-CGH analysis, are now part of the diagnostic process. Prenatal diagnosis is based primarily on fetal imaging, but "molecular" prenatal diagnosis can be performed if a mutation has been previously identified in a proband. Interpretations of molecular diagnosis must be given with caution, given the lack of strict genotype,phenotype correlation, and should be offered in addition to fetal imaging, using ultrasound followed by fetal MRI. We report on our experience of 15 molecular prenatal diagnoses from chorionic villi or amniotic fluid sampling. In eight instances, we were able to reassure the parents after taking into account the absence of the mutation in the fetus, previously identified before in a parent and/or a proband. Fetal RMI was normal later in pregnancy, and no child had medical problems after birth. The mutation was found in the seven other cases: four children were born, either without brain malformation and asymptomatic, or had a less severe form than the index case. © 2010 Wiley-Liss, Inc. [source] The ups and downs of holoprosencephaly: dorsal versus ventral patterning forcesCLINICAL GENETICS, Issue 5 2008M Fernandes Holoprosencephaly (HPE), characterized by incomplete separation of forebrain and facial components into left and right sides, is a common developmental defect in humans. It is caused by both genetic and environmental factors and its severity covers a wide spectrum of phenotypes. The genetic interactions underlying inherited forms of HPE are complex and poorly understood. Animal models, in particular mouse mutants, are providing a growing understanding of how the forebrain develops and how the cerebral hemispheres become split into left and right sides. These insights, along with the characterization to date of some of the genes involved in human HPE, suggest that two distinct mechanisms underlie the major classes of HPE, ,classic' and midline interhemispheric (MIH). Disruption either directly or indirectly of the ventralizing effect of sonic hedgehog signaling appears central to all or most forms of classic HPE, while disruption of the dorsalizing effect of bone morphogenetic protein signaling may be key to cases of MIH HPE. [source] Embryonic holoprosencephaly: pathology and phenotypic variabilityCONGENITAL ANOMALIES, Issue 4 2006Shigehito Yamada ABSTRACT Holoprosencephaly (HPE) is one of the major brain anomalies caused by the failure of cleavage of the prosencephalon during the early stage of development. Over 200 cases of HPE in the Kyoto Collection of Human Embryos were observed grossly and histologically, with special emphasis on the anomalies of the brain, face and eye. The facial anomalies of HPE human embryos after Carnegie stage (CS) 18 could be classified into cyclopia, synophthalmia, ethmocephaly, cebocephaly, and premaxillary agenesis, similarly as the classical classification for postnatal cases. On the other hand, HPE embryos at CS 13,17 showed some characteristic facies which are different from those in older embryos. In the present paper, pathology and phenotypic variability in HPE embryos were discussed from the embryopathological point of view. Recently, the molecular mechanism of HPE has been clarified by the techniques of gene manipulation, and various HPE genes have been identified by gene analysis of familial HPE cases. HPE is one of the major CNS anomalies which have been extensively studied and provides a clue to the mechanisms of normal and abnormal development of craniofacial structures. [source] Expression and functional analysis of Tgif during mouse midline developmentDEVELOPMENTAL DYNAMICS, Issue 2 2006Jiu-Zhen Jin Abstract The Tgif gene encodes a homeodomain protein that functions as a transforming growth factor beta (TGF-,) repressor by binding to Smad2. Mutations in the TGIF gene are associated with human holoprosencephaly, a common birth defect caused by the failure of anterior ventral midline formation. However, Smad2-mediated TGF-, signaling in the axial mesendoderm has been demonstrated to be essential for ventral midline formation, and loss of a Smad2 antagonist should in principle promote rather than inhibit ventral midline formation. This suggests a more complex mechanism for the function of TGIF in controlling ventral midline formation. To explore the role of TGIF in ventral forebrain formation and patterning, we investigated Tgif expression and function during mouse development by in situ hybridization and gene targeting. We found that Tgif is highly expressed in the anterior neural plate, consistent with the proposed neural differentiation model in which TGF-, suppression is required for normal neural differentiation. This result suggests a possible role for Tgif in anterior neural differentiation and patterning. However, targeted disruption of the Tgif gene during mouse development does not cause any detectable defects in development and growth. Both histological examination and gene expression analysis showed that Tgif,/, embryos have a normal ventral specification in the central nervous system, including the forebrain region. One interpretation of these results is that the loss of TGIF function is compensated by other TGF-, antagonists such as c-Ski and SnoN during vertebrate anterior neural development. Developmental Dynamics 235:547,553, 2006. © 2005 Wiley-Liss, Inc. [source] The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism,,HUMAN MUTATION, Issue 4 2009Erich Roessler Abstract Mutations of the ZIC2 transcription factor gene are among the most common heterozygous variations detected in holoprosencephaly (HPE) patients, a patient group who lack critical midline forebrain specification due to defective embryonic signaling during development. Recent studies indicate that complete deficiency of the related murine Zic2 transcription factor can also be a contributing factor to variable midline deficiencies, presenting during mid-gastrulation, that could explain similar forebrain anomalies in this model system. Here we collect and summarize all available mutations in the human ZIC2 gene detected in HPE patients (21 published and 62 novel). Our analysis corroborates this mechanism proposed in mice by predicting loss-of-function as the likely pathogenetic mechanism common to most, if not all, of these mutations in HPE. Published 2009 Wiley-Liss, Inc. [source] Investigation of a cyclopic, human, term fetus by use of magnetic resonance imaging (MRI)JOURNAL OF ANATOMY, Issue 5 2002D. Situ Abstract Using magnetic resonance imaging (MRI), the internal neural and craniofacial malformations of a cyclopic fetus are described. External facial features were characterized by a tubular proboscis situated above a single eye slit. The brain was recognized as ,pancake' type alobar holoprosencephaly (a condition where the undifferentiated telencephalon partially surrounds a monoventricle). Displacement of some bones that normally contribute to the orbit could be clearly discerned. Absence of neural structures (e.g. falx cerebri, corpus callosum) and missing components of the ethmoid bone indicated a midline deficit. This correlates with proposed theories of cyclopic embryopathy, which suggest that the prechordal plate and the neural crest cells are affected during the third week of gestation in cyclopia. [source] Magnetic Resonance Microscopy Defines Ethanol-Induced Brain Abnormalities in Prenatal Mice: Effects of Acute Insult on Gestational Day 7ALCOHOLISM, Issue 1 2010Elizabeth A. Godin Background:, This magnetic resonance microscopy (MRM)-based report is the second in a series designed to illustrate the spectrum of craniofacial and central nervous system (CNS) dysmorphia resulting from single- and multiple-day maternal ethanol treatment. The study described in this report examined the consequences of ethanol exposure on gestational day (GD) 7 in mice, a time in development when gastrulation and neural plate development begins; corresponding to the mid- to late third week postfertilization in humans. Acute GD 7 ethanol exposure in mice has previously been shown to result in CNS defects consistent with holoprosencephaly (HPE) and craniofacial anomalies typical of those in Fetal Alcohol Syndrome (FAS). MRM has facilitated further definition of the range of GD 7 ethanol-induced defects. Methods:, C57Bl/6J female mice were intraperitoneally (i.p.) administered vehicle or 2 injections of 2.9 g/kg ethanol on day 7 of pregnancy. Stage-matched control and ethanol-exposed GD 17 fetuses selected for imaging were immersion fixed in a Bouins/Prohance solution. MRM was conducted at either 7.0 Tesla (T) or 9.4 T. Resulting 29 ,m isotropic spatial resolution scans were segmented and reconstructed to provide 3D images. Linear and volumetric brain measures, as well as morphological features, were compared for control and ethanol-exposed fetuses. Following MRM, selected specimens were processed for routine histology and light microscopic examination. Results:, Gestational day 7 ethanol exposure resulted in a spectrum of median facial and forebrain deficiencies, as expected. This range of abnormalities falls within the HPE spectrum; a spectrum for which facial dysmorphology is consistent with and typically is predictive of that of the forebrain. In addition, other defects including median facial cleft, cleft palate, micrognathia, pituitary agenesis, and third ventricular dilatation were identified. MRM analyses also revealed cerebral cortical dysplasia/heterotopias resulting from this acute, early insult and facilitated a subsequent focused histological investigation of these defects. Conclusions:, Individual MRM scans and 3D reconstructions of fetal mouse brains have facilitated demonstration of a broad range of GD 7 ethanol-induced morphological abnormality. These results, including the discovery of cerebral cortical heterotopias, elucidate the teratogenic potential of ethanol insult during the third week of human prenatal development. [source] Middle interhemispheric variant of holoprosencephaly associated with bilateral perisylvian polymicrogyriaPEDIATRICS INTERNATIONAL, Issue 2 2008Mehmet H. Atalar First page of article [source] Introduction to the American Journal of Medical Genetics Part C on holoprosencephaly,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Maximilian Muenke§ No abstract is available for this article. [source] Holoprosencephaly flashcards: A summary for the clinician,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Benjamin D. Solomon§ Abstract This material contains general information regarding the approach to patients with holoprosencephaly. For more detailed discussion, please refer to specific articles in this issue. Published 2010 Wiley-Liss, Inc. [source] Holoprosencephaly: A mythologic and teratologic distillate,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010M. Michael Cohen Jr.§ Abstract This review of holoprosencephaly provides a mythologic and teratologic distillate of the subject under the following headings: Babylonian tablets; Greek mythology; pictures from the 16th through the 20th Centuries; 19th Century teratology; history of more modern concepts and their terminologies; and ocean-going ships named "Cyclops." © 2010 Wiley-Liss, Inc. [source] Epidemiology of holoprosencephaly: Prevalence and risk factors,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Iêda M. Orioli Abstract The wide variation in cerebral and facial phenotypes and the recognized etiologic heterogeneity of holoprosencephaly (HPE) contribute to the observed inter-study heterogeneity. High lethality during the early stages of embryonic and fetal development makes HPE detection age dependent. By reviewing 21 HPE epidemiologic articles, the observed prevalence rate differences can be largely explained by the pregnancy outcome status of the studied cohort: livebirth, stillbirth, and terminations of pregnancy (TOPs): lower than 1 per 10,000 when live and still births were included, higher when TOPs were included, and between 40 and 50 per 10,000 in two classical Japanese studies on aborted embryos. The increasing secular trend observed in some studies probably resulted from an increasing use of prenatal sonography. Ethnic variations in birth prevalence rates (BPRs) could occur in HPE, but the available data are not very convincing. Higher BPRs were generally observed in the less favored minorities (Blacks, Hispanics, Pakistanis), suggesting a bias caused by a lower prenatal detection rate of HPE, and consequently less TOPs. Severe ear defects, as well as microstomia, were part of the spectrum of HPE. Non-craniofacial anomalies, more frequently associated with HPE than expected, were genital anomalies (24%), postaxial polydactyly (8%), vertebral defects (5%), limb reduction defects (4%), and transposition of great arteries (4%). The variable female predominance, found in different HPE studies, could also depend on the proportion of early conceptions in each study sample, as males are more likely to be lost through spontaneous abortions. © 2010 Wiley-Liss, Inc. [source] Early pathogenesis of holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Kohei Shiota Abstract Holoprosencephaly (HPE) is one of the most common malformations encountered in early human embryos. It is assumed that more than 90% of HPE embryos die in utero and are eliminated by spontaneous abortion. Embryonic HPE displays some characteristic craniofacial phenotypes, which are not necessarily comparable to those in postnatal HPE cases. In this article, we summarize our studies on HPE in human embryos and discuss the pathogenesis of HPE malformations. © 2010 Wiley-Liss, Inc. [source] | |||||||||||||