No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Middle interhemispheric variant of holoprosencephaly: A distinct cliniconeuroradiologic subtype
Abstract
The middle interhemispheric variant (MIH) is a subtype of holoprosencephaly (HPE) in which the posterior frontal and parietal areas lack midline separation, whereas more polar areas of the cerebrum are fully cleaved. While the neuroradiologic features of this subtype have been recently detailed, the clinical features are largely unknown.
To present the clinical manifestations of MIH and to compare them with classic subtypes (alobar, semilobar, and lobar) of HPE.
The authors evaluated 15 patients with MIH in a multicenter study. Neuroimaging and clinical data were collected and correlated. They compared the data with those of 68 patients who had classic HPE.
The frequency of endocrinopathy in MIH (0%) was lower compared with the classic subtypes (72%) (p < 0.0001). This correlated with the lack of hypothalamic abnormalities. The percentage of patients with seizures (40%) did not significantly differ from classic HPE. Spasticity was the most common motor abnormality, seen in 86% of MIH patients, similar to other subtypes. The frequency of choreoathetosis in MIH (0%) was lower than that for semilobar HPE (41%) (p < 0.0039). This correlated with the lack of caudate and lentiform nuclei abnormalities. Developmental functions, including mobility, upper-extremity function, and language, of the MIH group were similar to the least severe classic type, lobar HPE.
MIH is a recognizable variant of HPE with differing clinical prognosis. Similar to the lobar subtype by functional measures, MIH differs from classic HPE by the absence of endocrine dysfunction and choreoathetosis.
... 27 In some reports, five fetuses and 15 children displayed facial dysmorphia such as cleft lip and palate and hypertelorism, limb abnormalities, external genitalia, and renal hypoplasia. 18,28 In these cases, the genetic studies (karyotype) were normal, with the exception of five cases where a 13q monosomy was found. 18 Moreover, craniofacial anomalies are common in HPE but the majority of MIHV patients present moderate facial dysmorphia or even a normal face, 18,28 like in our case. ...
... 17 Regarding the postnatal clinical outcome of our case, the patient has no dysmorphism and she seems to present subnormal neurological development at 11 months. Previous studies identified spasticity as the main clinical sign of MIHV (found in 86% of children in Lewis's study 28 ), probably due to the fact that the abnormal fusion zone of the cortex is close to the motor cortex. In addition, 57% of patients display some degree of hypotonia, overlapping with our patient who needed physiotherapy support for hypotonia at 9 months. ...
... Although choreoathetosis has been frequently found in semilobar holoprosencephaly, no cases displaying this symptom have been described in MIHV. 28 This is probably due to the fact that, conversely to HPE, caudate and lenticular nuclei are normal in MIHV. ...
We present a case of a middle interhemispheric variant of antenatal discovery associated with a de novo missense variant (NM_007129.5: c.1109G>A p.(Cys370Tyr)) in the ZIC2 gene. Our case represents the first prenatal description of a ZIC2 missense mutation found in association with syntelencephaly. We present a case of a middle interhemispheric variant of antenatal discovery associated with a de novo missense variant (NM_007129.5: c.1109G>A p.(Cys370Tyr)) in the ZIC2 gene. Our case represents the first prenatal description of a ZIC2 missense mutation found in association with syntelencephaly.
... In a study of aborted embryos, 1/250 had holoprosencephaly (Matsunaga & Shiota, 1977;Orioli & Castilla, 2010). More recent work, aided by advances in imaging, shows the holoprosencephaly spectrum can include other variants, including the middle interhemispheric (Lewis et al., 2002;Simon et al., 2002) and the septopreoptic variants (Hahn, Barnes, Clegg, & Stashinko, 2010). ...
... However, there is lack of prosencephalic separation that involves different portions of the more posterior aspects of the frontal lobes and the parietal lobes. Abnormal cortex extending across the midline can appear as a "seam-like" structure (Figure 5c-f) (Barkovich & Quint, 1993;Lewis et al., 2002;Picone et al., 2006;Pulitzer, Simon, Crombleholme, & Golden, 2004;Simon et al., 2002). In syntelencephaly, a normal body of the corpus callosum is absent (Figure 5c,e); the genu and the splenium are usually present . ...
... The frontal horns of the lateral ventricles may be normal but the septum pellucidum is absent . The third ventricle is formed but a dorsal cyst can be present in 25-40% of individuals Lewis et al., 2002). Like the other variants, the thalamus and caudate nuclei may be incompletely separated, but the hypothalamus and lentiform nuclei are separated Simon et al., 2002). ...
Holoprosencephaly is a spectrum of congenital defects of forebrain development characterized by incomplete separation of the cerebral hemispheres. In vivo diagnosis can be established with prenatal brain imaging and disease severity correlates with extent of abnormally developed brain tissue. Advances in magnetic resonance imaging (MRI) over the past 25 years and their application to the fetus have enabled diagnosis of holoprosencephaly in utero. Here, we report on the prenatal diagnosis of holoprosencephaly using MRI as part of a diagnostic and management evaluation at a tertiary and quaternary referral center. Using an advanced MRI protocol and a 1.5‐Tesla magnet, we show radiographic data diagnostic for the holoprosencephaly spectrum, including alobar, semilobar, lobar, middle interhemispheric, and septopreoptic variant. Accurate prenatal evaluation is important because the severity of imaging findings correlates with postnatal morbidity and mortality in holoprosencephaly. Therefore, this work has implications for the evaluation, diagnosis, management, and genetic counseling that families can receive during a pregnancy.
... Although some of the imaging features in the middle interhemispheric variant may be seen in classic subtypes of holoprosencephaly (particularly lobar and semilobar subtypes), the previously described neuroradiologic features are distinguishing factors of the middle interhemispheric variant from other subtypes of holoprosencephaly (1). From a clinical standpoint, patients with the middle interhemispheric variant of holoprosencephaly have the mildest clinical findings within the holoprosencephaly spectrum (2). Mild to moderate spasticity is the most common motor symptom, followed by hypotonia (2). ...
... From a clinical standpoint, patients with the middle interhemispheric variant of holoprosencephaly have the mildest clinical findings within the holoprosencephaly spectrum (2). Mild to moderate spasticity is the most common motor symptom, followed by hypotonia (2). Delayed speech and oromotor development are usually present. ...
... Accurate radiologic diagnosis of holoprosencephaly is challenging and important. Different studies have reported that 20%-50% of the patients referred with diagnosis of holoprosencephaly did not receive the correct diagnosis (2,3,7). Prior to the first description of the middle interhemispheric variant of holoprosencephaly, most of these cases were labeled as lobar holoprosencephaly (4). ...
History A 13-year-old girl presented for evaluation and further management of spastic diplegia cerebral palsy. Absence of the corpus callosum was noted at screening prenatal head ultrasonography. She was born at full term via spontaneous vaginal delivery. Physical examination revealed decreased axial muscle tone and increased muscle tone in her extremities; the latter was more severe. She was nonambulatory. No midline craniofacial anomaly was seen. She had dysarthria but was able to speak in full sentences. She was in sixth grade with an individualized education program. She had mild behavioral problems, such as "acting out" in school. Brain magnetic resonance (MR) imaging, including three-dimensional T1- and T2-weighted sequences, was performed without intravenous administration of contrast material to evaluate the brain.
... The middle interhemispheric (MIH) variant of HPE or syntelencephaly was originally described as a type of semi-lobar HPE 3 but was then classified as a different and distinct cliniconeuroradiologic subtype of HPE. 4,5 The MIH variant has similar incidence when compared with other HPE variants. 3,6 By definition, it is an abnormal midline connection of the cerebral hemispheres in the posterior frontal and the anterior parietal regions, with normal interhemispheric separation of the basal forebrain, anterior frontal lobes and occipital regions. ...
... 3,4 Typically, the genu and splenium of the corpus callosum are formed, but the body is absent. [3][4][5]7 High-resolution conventional MRI can usually reveal sufficient anatomic information about cerebral parenchyma, but diffusion tensor imaging (DTI) can provide more detailed information, which cannot be obtained by conventional MRI, about the visualization and connectivity of white matter structures and anomalies. [8][9][10][11][12][13] In this article, we aimed to describe the additional knowledge of DTI over conventional MRI obtained by using a 3-T MRI scanner in five patients with MIH variant of HPE and discuss our findings with previously published data. ...
... 6,16 In terms of severity, the MIH variant is somewhere between the semi-lobar and lobar forms, closer to the lobar than alobar form, according to functional measures. [3][4][5]17 Contrary to the severe impairment in the early embryonic development causing the classical HPE forms, such as insufficient ventralization or excessive dorsalization of the forebrain, 3,4 a less severe impairment such as a defect of dorsal-ventral induction of the telencephalon and more specifically a lack of induction of the dorsal 5,16 By means of this partial lack of dorsal-ventral induction, the impaired cleavage of cerebral hemispheres is more posteriorly located in the MIH variant (posterior frontal and parietal lobes) than in other classical HPE forms, in which the lack of separation is dedicated to the anterior hemispheres, i.e. mainly to the frontal lobes in variable degrees. Owing to the more posterior location of this cortical incomplete separation in the MIH variant, the other associated structural anomalies are also more posteriorly (i.e. ...
Objective:
The middle interhemispheric (MIH) variant of holoprosencephaly (HPE) is the incomplete separation of midline cerebral hemispheres with the absence of callosal body. We aimed to describe the additional knowledge of diffusion tensor imaging (DTI) over conventional magnetic resonance imaging (MRI) in the evaluation of patients with MIH variant of HPE: Methods: Conventional MRI and DTI data of five patients were retrospectively evaluated. The parenchymal anomalies as well as changes at white matter tracts were systematically reviewed.
Results:
Except the callosal body and central cingulum fibers, which were missing in all patients, all other major white matter tracts (superior and inferior longitudinal, superior and inferior fronto-occipital, subcallozal and uncinate fasciculi, and anterior commissure) had normal course, thickness and integrity on DTI images. The genial and splenial callosal fibers were altered and rarefied on tractography. All patients had a central ventricular notch extending into the non-cleaved heterotopic grey matter involving the body of corpus callosum, which is very typical for the middle interhemispheric variant of holoprosencephaly. The remnant traversing white matter fibers above non-cleaved heterotopic grey matter and incomplete partition of interhemispheric fissure were also identified. No Probst bundles were detected. A single common ventricle without septum pellucidum was noted in all patients. One patient had incomplete partition of thalami, and two patients had abnormally oriented thalami without any prominent interthalamic connection. Vertically oriented hippocampi were detected in four out of five patients. Three patients had relatively flat and vertically oriented Sylvian fissures and in two patients, fissures were abnormally connected over the vertex.
Conclusion:
Additional DTI findings not only can clearly reveal the white matter alterations better than conventional MRI but also can provide a better understanding of the etiological changes that cause the MIH variant of HPE. Advances in knowledge: DTI can provide a better analysis of cerebral white matter connectivity and promotes understanding the underlying microstructural changes that occur in patients with the MIH variant of HPE.
... Por la falta de división de la porción frontal posterior y parietal de los hemisferios, su resultado es hipoplasia o aplasia del tubo neural. [10][11][12] El objetivo de presentar el caso de una recién nacida con sintelencefalia tiene la finalidad de favorecer el reconocimiento de la variante menos común de la holoprosencefalia. ...
... A las cuales posteriormente se agregó la variante interhemisférica media, así como la septopreóptica o displasia septopreóptica. 12,13 La variante alobar es considerada la de peor pronóstico, con una completa o casi completa falta de separación de los hemisferios cerebrales, un único ventrículo en el prosencéfalo y, usualmente, con comunicación con la cisterna dorsal. Los pacientes con ésta pueden presentar hipotonía y convulsiones al nacer. ...
Introducción:
La sintelencefalia es una malformación del cerebro anterior, la cual es una variante de holoprosencefalia. Se han publicado pocos casos en la literatura latinoamericana.
Presentación del caso:
Paciente femenino, hija de madre diabética. Se hace diagnóstico de holoprosencefalia a las 21 semanas de gestación. Al nacimiento también se detectó labio y paladar hendido, pie equino varo, ectasia pielocalicial bilateral y cardiopatía congénita compleja. Por esta última, la paciente fallece en la primera semana de vida. Mediante resonancia magnética se identificaron las imágenes compatibles con sintelencefalia.
Conclusiones:
Los pacientes con sintelencefalia y que, además, tienen otras múltiples enfermedades congénitas tienen un pronóstico desfavorable. Su manejo debe ser multidisciplinario, incluyendo especialistas de Genética.
... Although defined as a subtype of holoprosencephaly (HPE), MIVH is different from classic holoprosencephaly in terms of the developmental mechanism, the features of structural abnormalities, and the clinical presentation. 1,2 HPE is defined as an incomplete separation of the cerebral hemispheres which develops as the result of a defect in the shaping of the basal forebrain during the first month of embryogenesis. 3 In relation to the severity of the defect, HPE has been classically divided into three types: alobar, semilobar, and lobar. ...
... 40% of patients had a history of at least one seizure, 86% had mild-to-moderate spasticity, 57% had hypotonia of various degrees, and 50% had dystonia. 2 Speech and oromotor development were delayed in all patients. Endocrinopathies, choreoathetosis, or severe midline craniofacial anomalies which are commonly observed in other forms of HPE were not present in any of the 15 patients. ...
Middle interhemispheric variant of holoprosencephaly is an uncommon subtype of holoprosencephaly which is characterized by a midline connection of the two cerebral hemispheres in the posterior frontal and parietal regions with the separation of the anterior frontal and occipital lobes. It usually presents in early childhood with facial dysmorphism, seizures, motor dysfunction and mental-motor retardation. We herein present an unusual case of middle interhemispheric variant of holoprosencephaly which was asymptomatic and incidentally found in adulthood.
... Holoprosencephaly (HPE) represents a complex malformation of the forebrain, determined by an absence or incomplete cleavage of the prosencephalon (forebrain) during the 4 th week of embryogenesis [1,2]. The condi-tion includes a wide spectrum of anatomical variants that are characterized by lack of midline separation of the cerebral hemispheres (telencephalon) and diencephalic structures, extending from the anterior to the posterior depending on the severity. ...
... In the "middle interhemispheric" variant of HPE or syntelencephaly, first described by Barkovich et al, a degree of middle interhemispheric fusion was encountered [13]. Though it was considered at first a subtype of semilobar HPE, close analysis of the few cases reported [18][19][20][21] led to the conclusion that the MIH is a different and distinct clinic-neuro-radiologic form of HPE, and it is classified as a new 4th type of HPE, alongside the 3 "classic" types described by DeMyer [2,22]. In both of our cases of middle interhemisheric variant, we observed an abnormal midline continuity in the posterior frontal and anterior parietal regions of the cerebral hemispheres with fusion of the bodies of the lateral ventricles, but with normal interhemispheric separation of the anterior frontal lobes and occipital region as described in literature [12,15]. ...
Aim:
Holoprosencephaly (HPE) is the most common brain malformation. A wide spectrum of anatomical variants are characterized by a lack of midline separation of the cerebral hemispheres. The aim of this study was to assess the ultrasound diagnostic criteria for HPE.
Material and method:
A database of 175 fetuses with central nervous system anomalies identified by ultrasound was collected retrospectively from 2006 to 2016 in this multicenter, retrospective, observational study. Among them 18 cases (10.2%) with HPE were identified.
Results:
The prevalence of HPE was 2.5:10.000 with the sex distributionmale:female of 1:1.6. Six cases were alobar subtype, 3 were semilobar, 7 were lobar and 2 were middle interhemispheric variant. In the second trimester, we consider that the abnormal fusion of the lateral ventricles and the absence of the cavum septum pellucidum are the most important landmarks for HPE. Facial abnormalities varied considerably.
Conclusion:
This study illustrates the heterogeneity of HPE with different cerebral and facial appearances.
... In contrast to classic HPE, MIHV HPE (also known as syntelencephaly) presents with normal separation of the basal forebrain, anterior frontal lobes and occipital regions but a failure to divide the posterior frontal and parietal regions of the cerebral hemispheres along the dorsal midline (Barkovich and Quint 1993;Simon et al. 2002;Lewis et al. 2002). Additional structures, such as the caudate nuclei, thalami and mesencephalon, can also be affected in MIHV cases. ...
... Notably, many genes associated with classic HPE do not cause MIHV HPE. In mice, Zic2 and Fgf8, as well as the BMP ligands, BMP antagonists Chrd and Nog, BMP receptors Bmpr1a and Bmpr1b and the transcription factors Lhx5 and Rfx4, have all been associated with MIHV (Nagai et al. 2000;Simon et al. 2002;Anderson et al. 2002;Lewis et al. 2002;Cheng et al. 2006;Storm et al. 2006;Fernandes et al. 2007;Warr et al. 2008;Solomon et al. 2010a;Dubourg et al. 2016). In contrast, relatively few genes (ZIC2, FGF8, deletion of EYA4) have been associated with MIHV HPE in humans (Abe et al. 2009;Solomon et al. 2010a;Dubourg et al. 2016), of which ZIC2 and FGF8 are also associated with classic HPE. ...
The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes.
... holoprosencephaly is traditionally classified into three grades of severity: alobar, semilobar and lobar. In addition to these classic forms, a subtype of HCP, the middle interhemispheric variant or syntelencephaly has been characterized [4,5]. Septopreopticholoprosencephaly is a mild subtype associated with midline craniofacial anomalies [6]. ...
Surgical treatment protocols for rare types of clefts do not exist, especially when they are associated with severe anomalies of the brain and face. Surgical treatment of a newborn with holoprosencephaly, premaxillary agenesis and median cleft lip is a big challenge for the surgeon. The complete lack of bone in the nasal bones and premaxilla make surgical therapy almost impossible. The role of pre-surgical orthodontic therapy plays a major role in creating the conditions for surgical repair of cleft-damaged parts of the face.Case presentation. The paper presents presurgical orthodontic therapy in a newborn with a median cleft lip using the RBJ stimulator. Conclusion. The use of stimulators of a specific construction in the therapy of rare clefts is the method of choice.
... In addition, patients with the MIH variant usually do not present any associated craniofacial anomalies [22]. ...
Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management.
... A dorsal cyst appears in 25-40% of MIH cases. MIH is usually not associated with midline craniofacial anomalies [65] (Figure 9). Cortical continuity between the hemispheres restricted to the posterior frontal and parietal areas is a diagnostic feature of MIH. ...
This paper describes the contemporary state of knowledge regarding processes that regulate normal development of the embryonic–fetal central nervous system (CNS). The processes are described according to the developmental timetable: dorsal induction, ventral induction, neurogenesis, neuronal migration, post-migration neuronal development, and cortical organization. We review the current literature on CNS malformations associated with these regulating processes. We specifically address neural tube defects, holoprosencephaly, malformations of cortical development (including microcephaly, megalencephaly, lissencephaly, cobblestone malformations, gray matter heterotopia, and polymicrogyria), disorders of the corpus callosum, and posterior fossa malformations. Fetal ventriculomegaly, which frequently accompanies these disorders, is also reviewed. Each malformation is described with reference to the etiology, genetic causes, prenatal sonographic imaging, associated anomalies, differential diagnosis, complimentary diagnostic studies, clinical interventions, neurodevelopmental outcome, and life quality.
... Comparatively, the MIH variant affects the midline of the posterior-dorsal forebrain during development and is characterized by the abnormal separation of the posterior frontal and parietal lobes in the presence of relatively normal antero-ventral forebrain structures ( Figure 1 4b-d). The facial malformations associated with classic HPE are absent in the MIH variant (Bulakbasi et al., 2016;Kousa et al., 2018;Lewis et al., 2002). This article will focus on classic HPE and the mechanisms that pattern the anteroventral region of the mammalian forebrain. ...
Adult form and function are dependent upon the activity of specialized signaling centers that act early in development at the embryonic midline. These centers instruct the surrounding cells to adopt a positional fate and to form the patterned structures of the phylotypic embryo. Abnormalities in these processes have devastating consequences for the individual, as exemplified by holoprosencephaly in which anterior midline development fails, leading to structural defects of the brain and/or face. In the 25 years since the first association between human holoprosencephaly and the sonic hedgehog gene, a combination of human and animal genetic studies have enhanced our understanding of the genetic and embryonic causation of this congenital defect. Comparative biology has extended the holoprosencephaly network via the inclusion of gene mutations from multiple signaling pathways known to be required for anterior midline formation. It has also clarified aspects of holoprosencephaly causation, showing that it arises when a deleterious variant is present within a permissive genome, and that environmental factors, as well as embryonic stochasticity, influence the phenotypic outcome of the variant. More than two decades of research can now be distilled into a framework of embryonic and genetic causation. This framework means we are poised to move beyond our current understanding of variants in signaling pathway molecules. The challenges now at the forefront of holoprosencephaly research include deciphering how the mutation of genes involved in basic cell processes can also cause holoprosencephaly, determining the important constituents of the holoprosencephaly permissive genome, and identifying environmental compounds that promote holoprosencephaly.
This article is categorized under: Congenital Diseases > Stem Cells and Development
Congenital Diseases > Genetics/Genomics/Epigenetics
Congenital Diseases > Molecular and Cellular Physiology
Congenital Diseases > Environmental Factors
... The posterior frontal and parietal lobes fail to separate, with or without fusion of the deep grey matter, and absence of the body of the corpus callosum. 64,65 Chromosomal anomalies are seen in 24% to 54% of holoprosencephaly, typically trisomy 13, 59,62,66 and at least 10% will have microdeletions or microduplications on microarray; 66,67 19% to 25% have a single gene disorder, with autosomal dominant, autosomal recessive, and X-linked inheritance patterns described. 66 Alobar holoprosencephaly has traditionally been associated with stillbirth or death in the neonatal period. ...
After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst‐case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide‐memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling.
... HPE arises from developmental failure at the rostral end of the neural tube during early embryogenesis (15). The phenotypic spectrum shows inter and intrafamilial variability, from severe CNS and facial anomalies to clinically normal phenotypes (16,17). ...
ABSTRACT
Objective: Holoprosencephaly (HPE, #MIM 236100) is the most
common developmental defect of midline cleavage in the human forebrain. Environmental, genetic, and multifactorial causes
are involved in its etiology. About half of the cases have chromosome aberrations such as trisomies 13 and 18, triploidy and
structural imbalances. Single gene mutations have been shown
in ~25% of cases. In this retrospective study, we aimed to determine the etiological factors related to HPE in 127 fetuses.
Material and Method: This study comprises 127 prenatally
diagnosed fetal HPE samples from a period of 25 years, which
were evaluated by karyotyping, fluorescence in situ hybridization
(FISH) and aCGH investigation.
Results: A total of 64 (50.39%) chromosome aberrations were
identified in this cohort. The predominant chromosomal abnormality was trisomy 13 (n=38), which was followed by trisomy
18 (n=8) and triploidy (n=5). Terminal 7q deletion was the most
frequent structural anomaly (n=10, of which 5 were de novo deletion, 4 were an unbalanced product of maternal translocations
and one unknown in origin) and the deletion of 18p was detected in one case. In the remaining two cases, we detected trisomy
20 and pericentric inversion 11 coincidentally.
Conclusion: This study, indicates that in the presence of clinical
findings suggesting HPE, cytogenetic and molecular cytogenetic studies should be performed. An aCGH study must also be
done for submicroscopic chromosomal anomalies, to determine their sizes, real breakpoints and identify possible novel genes
that might play a role in HPE etiology.
... 'Microform holoprosencephaly' is a much milder form where the brain is structurally normal, but there are subtle craniofacial anomalies with or without mild neurocognitive impairment. [7][8][9] A marked variability of phenotype is a constant finding in the Mendelian disorders associated with holoprosencephaly, and this variability is seen within families, and between individuals in different families with the same mutation. 2 10 The degree of phenotypical variability seen in dominant disorders that cause holoprosencephaly is unusually marked, and this variability is also seen in the recessive disorder Smith-Lemli-Opitz syndrome (SLOs), where consistency of phenotype may have been expected. ...
Background
Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in
which there is failed or incomplete separation of the prosencephalon into two cerebral
hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked inter- and intrafamilial phenotypic
variability.
Methods
We describe two families in which offspring had holoprosencephaly spectrum and
homozygous predicted-deleterious variants in PLCH1. Immunocytochemistry was used to
examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of
developmental stage and of early embryonic anatomy.
Results
In the first family, two siblings had congenital hydrocephalus, significant developmental
delay, and a mono-ventricle or fused thalami with a homozygous PLCH1 c.2065C>T,
p.(Arg689*) variant. In the second family two siblings had alobar holoprosencephaly and
cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All
parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the sub-cellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum, and dermatomyosome; all tissues producing or responding to SHH. Furthermore, the embryonic sub-cellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mis-localisation contributing to the pathogenicity of the
p.(Cys1079ValfsTer16) variant.
Conclusion
Our data supports the contention that PLCH1 has a role in prenatal mammalian
neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly
spectrum phenotype
... Classically recognized forms are alobar HPE in which the telencephalon is a totally noncleaved holosphere, semi-lobar forms with the presence of an inter-hemispheric fissure only at the posterior pole, and lobar forms in which cerebral hemispheres are completely separated but a bridge of cerebral cortex connecting the two sides and passing over the corpus callosum is present. Other forms have been described more recently (Barkovich and Quint, 1993;Lewis et al., 2002;Simon et al., 2002). HPE presents different transmission patterns and is in a proportion of the cases associated with chromosomal abnormalities (Mercier et al., 2011;Dubourg et al., 2018). ...
Development of the forebrain critically depends on the Sonic Hedgehog (Shh) signaling pathway, as illustrated in humans by the frequent perturbation of this pathway in holoprosencephaly, a condition defined as a defect in the formation of midline structures of the forebrain and face. The Shh pathway requires functional primary cilia, microtubule-based organelles present on virtually every cell and acting as cellular antennae to receive and transduce diverse chemical, mechanical or light signals. The dysfunction of cilia in humans leads to inherited diseases called ciliopathies, which often affect many organs and show diverse manifestations including forebrain malformations for the most severe forms.
The purpose of this review is to provide the reader with a framework to understand the developmental origin of the forebrain defects observed in severe ciliopathies with respect to perturbations of the Shh pathway. We propose that many of these defects can be interpreted as an imbalance in the ratio of activator to repressor forms of the Gli transcription factors, which are effectors of the Shh pathway.
We also discuss the complexity of ciliopathies and their relationships with forebrain disorders such as holoprosencephaly or malformations of cortical development, and emphasize the need for a closer examination of forebrain defects in ciliopathies, not only through the lens of animal models but also taking advantage of the increasing potential of the research on human tissues and organoids.
... These classic types, however, are part of a continuum with no discrete distinction between each category [4]. A milder type, the middle interhemispheric variant, has since also been described in which the posterior frontal and anterior parietal lobes fail to separate in the perirolandic region [5]. ...
Background
Septopreoptic holoprosencephaly is a mild form of holoprosencephaly in which the midline non-separation is restricted to the septal or preoptic regions. This entity has only been described in a small case series in which associated intracranial abnormalities were limited to the midline structures.Objective
To describe the radiologic findings of septopreoptic holoprosencephaly and highlight that it can be associated with a variety of intracranial abnormalities, not merely with abnormalities restricted to midline structures as previously reported.Materials and methodsWe retrospectively identified 22 children whose MRIs were confirmed to have non-separation restricted to the septal and preoptic region, fulfilling the criteria for septopreoptic holoprosencephaly. We then categorized MRIs as having, in addition, either intracranial abnormalities limited to the midline structures or major abnormalities not limited to the midline structures.ResultsFive children had intracranial abnormalities limited to the midline structures. Seventeen children had major intracranial abnormalities not limited to the midline structures. The major abnormalities included: patterning defects of the midbrain-hindbrain (elongated midbrain, shortened pons, shortened/elongated medulla, partial rhombencephalosynapsis), bilateral perisylvian polymicrogyria, microcephaly, megalencephaly and a spheno-ethmoidal encephalocele. Recognized syndromes/chromosomal abnormalities were also observed in this patient group.Conclusion
Our results suggest that septopreoptic holoprosencephaly has been under-recognized and under-reported to date. We propose that searching for this anomaly should be part of the complete assessment of the midline in all children undergoing brain MRI for intracranial malformations.
... Classically recognized forms are as follows: alobar holoprosencephaly (in which the telencephalon is a totally uncleaved holosphere), semi-lobar forms (with a presence of an incomplete interhemispheric fissure which is present at the posterior pole but absent at the frontal pole), and lobar forms (cerebral hemispheres are then completely separated but a bridge of cerebral cortex connecting the two sides and passing over the corpus callosum is present). Other forms have been isolated more recently: the septo-preoptic forms in which cleavage is perturbed in the septal or preoptic regions (Hahn et al., 2010), the middle hemispheric variants in which the defect of cleavage involves only the posterior frontal and anterior parietal cortex ( Fig. 18; Barkovich and Quint, 1993;Lewis et al., 2002;Simon et al., 2002). Mouse models have been very informative in the mechanisms of HPE. ...
Primary cilia are essential for central nervous system development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rgprip1l ciliopathy gene is disrupted. At the end of gestation, Ftm-/- fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm-/- embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. We analyzed the molecular causes of these defects. In Ftm-/- embryos, Sonic hedgehog (Shh) expression was lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mid-diencephalic organizer. In the diencephalon, Gli activity was dampened in regions adjacent to the Shh-expressing ZLI but displayed a higher Hh-independent ground level in the other regions. Our data uncover a complex role of cilia in development of the diencephalon, hypothalamus and eyes via the region-specific control of the ratio of activator and repressor forms of the Gli transcription factors. They call for a closer examination of forebrain defects in severe ciliopathies and for a search for ciliopathy genes as modifiers in other human conditions with forebrain defects.
... Middle interhemispheric variant of holoprosencephaly (MIH) or syntelencephaly is a rare brain malformation characterized by an abnormal midline connection of the cerebral hemispheres in the posterior frontal and parietal regions [4]. MIH results from a failure of induction and patterning along the rostrocaudal axis of the neural tube, and leads to GDDs and seizures [5]. ...
RAC3 is a member of the Rho GTPases family, which has important regulatory functions in aspects of neuronal morphogenesis. Rho GTPases show a conformational change in two regions (switch I and II) through GTP binding, which provides a platform for selective interactions with functionally diverse proteins. Missense variants in the switch I and II regions of RAC3 were recently suggested to cause severe intellectual disability and brain malformations. Here, we report an individual with a novel de novo RAC3 variant (c.101 C>G, p.(Pro34Arg)), which substitutes for an evolutionarily conserved amino acid within the switch I region. The patient showed severe global developmental delay, intellectual disability, epilepsy, and laryngeal dystonia. An imaging study revealed characteristic brain dysplasia, including coexistence of the middle interhemispheric variant of holoprosencephaly and brainstem dysmorphism. Our study supports that RAC3 variants cause syndromic neurodevelopmental disorders and brain structural abnormality, and expands the phenotypic spectrum of RAC3-related disorders.
... 13 Children with middle hemispheric variant may ambulate with assistance, and speak and function with mild impairment, 14 but the developmental outcome is similar to that in lobar HPE. 15 ...
Holoprosencephaly (HPE) is a group of complex structural malformations of the forebrain that results from complete or incomplete nonseparation of the prosencephalon that yields an incomplete division of the cerebral hemispheres and of the telencephalon from the diencephalon. According to the severity of the malformation, HPE is categorized into four subtypes: Alobar HPE, semilobar HPE, lobar HPE, and a middle interhemispheric fusion variant (syntelencephaly). The incidence of HPE is 1 in 10,000 to 15,000 births. The etiology of HPE is very heterogeneous, and the identified causes until now are: Chromosomal (most commonly trisomy 13), monogenic, and teratogenic. The first step of the diagnostics is based on the ultrasound visualization of cerebral ventricular abnormalities, on the axial plane of the fetal brain, and on the facial anomalies.
How to cite this article
Vladareanu R, Munteanu A, Ionescu CA, Navolan D, Vladareanu S. How to understand Holoprosencephaly. Donald School J Ultrasound Obstet Gynecol 2017;11(4):282-287.
... Central Diabetes Insipidus is the most common endocrine manifestation. Midline Interhemispheric forms have been shown to have no endocrine dysfunction in one study (10). Respiratory and cardiac morbidity, repeated pulmonary infections, diabetes insipidus and seizure disorders are some of the common conditions leading to death (9). ...
Holoprosencephaly is the most common embryonic brain defect. Foetuses who survive during intrauterine life are born with varying grades of brain and facial deformities. Extra craniofacial manifestations are common. Vertebral segmentation defects are rarely seen with holoprosencephaly, mainly in association with holoprosencephaly diencephalic hamartoblastoma (HDH) association. A female infant was born at term by normal delivery. Birth head circumference was below the 3rd percentile. Antenatal scan had showed microcephaly as the only abnormality. Physical examination revealed microcephaly, ocular hypotelorism, left ear skin tag and short neck. MRI of the brain showed semilobar holoprosencephaly. Neck radiograph revealed gross vertebral segmentation defect involving cervical and upper thoracic vertebrae.
She had initial feeding difficulties. She showed severe global developmental delay and had underlying central diabetes insipidus. Vertebral segmentation defect is rare in holoprosencephaly.
... Compared to previous reports, 30,31 DI was less prevalent in this study (25% vs. 54-70%). This may be the result of a bias toward milder HPE subtypes, since there is a correlation between the degree of hypothalamic separation and the presence of DI. 32,33 Speech and swallow evaluations performed on seven individuals showed that some subjects had the ability to swallow modified textures safely. Still, many individuals with HPE require a G tube to manage diabetes insipidus, receive enough nutrition, and prevent occasional aspirations which may lead to severe complications. ...
PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.Methods
Participants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.Conclusion
Individuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.GENETICS in MEDICINE advance online publication, 22 June 2017; doi:10.1038/gim.2017.68.
... Holoprosencephaly (HPE; OMIM %236100) is a brain malformation resulting from an incomplete cleavage of the prosencephalon between the 18th and 28th d of the human embryo. The HPE phenotype can be manifested by a variable spectrum of severity, from a severe form of alobar HPE, presenting a single ventricle without separation of hemispheres to a milder subtype of HPE, middle interhemispheric form (12). Facial midline anomalies with a normal brain were described within the same family with severe forms of HPE and referred to as microforms (13). Forebrain malformations are generally associated with facial anomalies, ranging from anophthalmia or cyclopia in the most severe cases to midline cleft lip, a simple hypotelorism, or even no anomalies in the less severe HPE forms. ...
... There is a reported female preponderance 3:1 in alobar and 1:1 in lobar HPE [1,7,9,10]. HPE is categorised into four subgroups based on increasing severity, alobar, semilobar, lobar [3] and middle interhemispheric (MIH) (syntelencephaly) [11][12][13]. The alobar form is defined as a total absence of two cerebral hemispheres due to complete failure to separate into the left and right halves, resulting in a single ventricle with fused thalami, arrhinencephaly and agenesis of the corpus callosum. ...
Objectives
The objectives of this study are to ascertain the clinical outcome and overall survival of holoprosencephaly (HPE) patients diagnosed antenatally and postnatally, to determine the accuracy of antenatal diagnosis and to determine the role of neurosurgical intervention in HPE. DesignThis is a retrospective review over a 10-year period. PatientsSixty-three patients were included in the study, 45 were diagnosed by antenatal radiological imaging and 18 were diagnosed by postnatal radiological imaging. Patient data was drawn from Temple Street Children’s University Hospital (the national paediatric neurosurgery centre), the National Maternity Hospital in Holle’s Street, Dublin, and Our Lady of Sick Children Hospital, Dublin. Methods
The study was carried out through a review of antenatal and postnatal radiological imaging and reports, clinical charts, GP letters from patient follow-up and telephone conversations with parents of HPE patients. ResultsFour patients in the antenatal diagnosis group had follow-up foetal MRI confirming HPE. Twelve in this group had radiological follow-up postnatally, and in five of these, HPE was confirmed. The remaining seven were identified as false positive. Alobar HPE constituted 55 % (21/38) of patients with 95 % mortality. Fifty-one percent had a normal karyotype. The overall survival in the antenatal diagnosis group was 13 %.In the postnatal group, 18 patients were identified, 67 % (12/18) lobar and 33 % (6/18) semilobar. Normal karyotype was found in 72 % (13/18), with an overall survival rate of 56 % (10/18). Neurosurgical intervention in both groups mainly consisted of CSF diversion in the form of ventriculoperitoneal (VP) or cystoperitoneal shunt (CP) (13/67). Conclusion
Foetal MRI should be routinely performed in suspected cases of HPE, and reliance on ultrasound alone in the antenatal period may not be sufficient. In our study, there is a high early mortality noted in severe cases of HPE, while milder forms of HPE in children tend to survive beyond infancy albeit with associated complications that required neurosurgical intervention and medical management for other associated systemic anomalies.
The forebrain comprises those structures that are derived from the most rostral part of the neural plate, i.e. the primary prosencephalon. The primary prosencephalon divides into two major components: the caudal (epichordal) diencephalon and the rostral secondary prosencephalon. The secondary prosencephalon is the entire prechordal part of the neural tube, and includes the hypothalamus, the optic vesicles, the preoptic region and the telencephalon. The two major telencephalic subdivisions are the pallium (the roof) and the subpallium (the base). The pallium gives rise to the cerebral cortex, whereas the basal ganglia and most cortical interneurons derive from the subpallium. The amygdala has pallial as well as subpallial origins. Like the rest of the neural tube, the embryonic forebrain appears to be organized into transverse (prosomeres) and longitudinal subdivisions (alar and basal plates). The diencephalon, including the pretectum, the epithalamus, the thalamus and the prethalamus or ventral thalamus, arising from the alar plate and tegmental parts, arising from the basal plate, originate from the prosomeres 1–3. The hypothalamus arises from two hypothalamic prosomeres and the acroterminal region, the most rostral part of the secondary prosencephalon, which gives rise to the commissural plate, the eye vesicles, the most rostral part of the hypothalamus and the neurohypophysis (► Sect. 9.2).Patterning of the forebrain involves the two general sets of mechanisms common to the neural plate, one along the anteroposterior axis and the other along the mediolateral axis. An additional dorsal-ventral pattterning mechanism is important for subdividing the telencephalon into dorsal, pallial and ventral, subpallial structures. Defects in mediolateral patterning lead to the prosencephalies, a group of complex malformations of the forebrain, involving the hypothalamus, the eyes and the basal telencephalon. Holoprosencephaly is the most common developmental malformation of the forebrain, ranging from 1 in 16,000 live births to 1 in 250 in therapeutic abortions.In this chapter, the development of the various derivatives of the embryonic forebrain and disorders that may appear during their development is discussed: in ► Sect. 9.3 the diencephalon, in ► Sect. 9.4 the hypothalamus, the preoptic region and the pituitary gland, in ► Sect. 9.5 the visual system, in ► Sect. 9.6 the telencephalon, and in ► Sect. 9.7 the rhinencephalon. The prosencephalies are discussed in ► Sect. 9.8 and illustrated in various Clinical cases with magnetic resonance imaging and autopsy data. Finally, in ► Sects. 9.9 and 9.10, the development and developmental disorders of the basal ganglia and of the amygdala are discussed, respectively.KeywordsDevelopment forebrainDevelopment diencephalonDevelopment hypothalamusDevelopment basal gangliaCongenital malformations basal gangliaDevelopment eyeCongenital malformations eyeProsomeresProsencephaliesHoloprosencephaly
During neural development, after primary neurulation, the cranial end of the neural tube forms three vesicles—the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain) [1–3]. The prosencephalon develops from the process of ventral induction, which consists of three interconnected events—formation, cleavage, and midline development. Prosencephalon further differentiates to form telencephalon that develops into cerebrum-lateral ventricles and diencephalon which forms the thalami-III ventricle. There is also cleavage and midline development occurring in prosencephalon. Abnormalities of formation result in aprosencephaly and atelencephaly. Abnormalities of cleavage lead to holoprosencephaly. Abnormalities of midline development result in agenesis of the corpus callosum, septo-optic dysplasia, and isolated septal agenesis [1].
Background:
Alobar holoprosencephaly (HPE) is easily detected during a first-trimester screening examination, conversely, recognizing the lesser varieties may be difficult even in the second trimester.
Objectives:
To describe the imaging findings of a cohort of fetuses with holoprosencephaly (HPE) and to elucidate the appearances of the different anatomical varieties.
Materials and methods:
We reviewed medical records and stored images of pregnant women referred to our clinic because of a diagnosis or the suspicion of various forms of HPE. We reported the imaging characteristics, the presence of other associated anomalies, magnetic resonance findings, karyotype and autoptic examinations when available.
Results:
Alobar forms show great distortion of normal brain anatomy, with a single ventricle detectable during the first trimester of pregnancy. Extracerebral, face and karyotype abnormalities are often associated. In semilobar and lobar forms the septum pellucidum is typically absent in axial planes, with fused frontal horns, while posterior fossa is often normal. At multiplanar neurosonogram, anomalies involving corpus callosum and cortex development can be detected. Face abnormalities are mild in lobar forms: receding forehead, various degrees of hypotelorism and the presence of a single central maxillary incisor are reported.
Conclusions:
The alobar forms are detectable since the first trimester, with a peculiar single ventricle and extremely frequent extracerebral and karyotype abnormalities. The semilobar and lobar forms are more challenging and the diagnosis is easily missed in a mid-trimester screening exam unless a careful evaluation of both cavum septi pellucidi and frontal horns as well is conducted.
Prenatal detection of fetal anomalies is considered to be an important goal of obstetric care and in many countries fetal ultrasound is an established part of routine care. This chapter provides an overview of the prenatal diagnosis of some of the most common malformations and their associated abnormalities. Neural tube defects develop when a part of the neural tube fails to close before 5 weeks of gestation. The prenatal detection rate is positively influenced by appropriate training and the application of a standardized protocol. One of the most frequent genetic syndromes associated with encephalocele is Meckel–Gruber syndrome. The sonographic findings in Dandy–Walker malformation are an enlarged fossa posterior with hypoplasia of the cerebellar vermis, dilatation of the fourth ventricle and a persistent Blake’s pouch cyst. Congenital pulmonary airway malformation is a mass of abnormal fetal lung tissue that forms in pregnancy. Congenital heart disease is the most common congenital malformation.
Objective
Middle interhemispheric (MIH) variant of holoprosencephaly (HPE) or syntelencephaly is a rare prosencephalic cleavage disorder. In literature, few cases of accurate prenatal diagnosis have been reported. We report on four additional prenatally diagnosed cases.
Methods
Between 2012 and 2017, four cases of MIH HPE were retrieved. Data on prenatal imaging, genetic analysis, and pathological investigation are collected. A “PubMed” and “Trip database” search were conducted revealing six papers reporting on 11 prenatally diagnosed cases.
Results and discussion
Four additional cases of MIH HPE were diagnosed at an earlier gestational age (between 17 and 25 weeks of gestation) compared with 11 cases from the literature review (15–39 weeks). First trimester transvaginal ultrasound facilitates correct differentiation between the severe HPE variants. Frequent association with ZIC2 mutation was found in nearly 50% of the cases (5/11) compared with one case in our series.
Conclusions
MIH variant of HPE is detectable from the early second trimester and should be considered in the differential diagnosis when the cavum septi pellucidi (CSP) is absent. Genetic analysis and autopsy should be conducted to investigate this more recent and rare variant.
Septopreoptic holoprosencephaly (HPE) is a type of HPE characterized by failure of separation of the septal and preoptic regions. Vascular anomalies associated with septopreoptic HPE include twig-like cerebral vessels and azygos anterior cerebral artery, the latter common to all forms of HPE. Here, we describe an 8-year-old boy presenting with developmental delay and abnormal movements who was found to have septopreoptic HPE associated with persistent trigeminal artery in magnetic resonance neuroimaging. This persistence of fetal trigeminal artery in HPE provides a further understanding of the pathogenesis of HPE.
This chapter describes the midline malformations such as holoprosencephaly (HPE), atelencephaly/aprosencephaly (AT/AP), agenesis of the corpus callosum (ACC), and septo-optic dysplasia. The Classic HPE is divided into lobar, semilobar, and alobar forms, which represent a continuous phenotypic spectrum. In addition, a distinct middle interhemispheric subtype, also known as syntelen-cephaly, has been established. Interestingly, the HPE gene SIX3 has been associated with AT/AP in a family that also included an individual with HPE, raising the possibility that AT/AP represents the most severe end of the HPE phenotypic spectrum. ACC phenotypes are associated with some HPE genes, which link ACC and HPE pathogeneses despite their differing severity gradients. Whilst the polygenic nature of ACC reflects its pathogenetic complexity, which arises from intrinsic defects of callosal neurons and axons, mid-line glial populations, or other aspects of the midline environment that impact attractive and repulsive cues for callosal axons. It is to be noted that many mouse mutants have ACC which reflect the pathogenetic complexity.
The prosencephalon develops at the rostral end of the recently closed neural tube, starting early in the second month of gestation. Through a series of cleavages, the prosencephalon develops the optic and olfactory apparatus and divides transversely into the telencephalon (which then divides in the sagittal plane to form the cerebral hemispheres) and the diencephalon (which goes on to form the thalamus, the caudate nucleus and putamen, and the hypothalamus). Developmental disturbances of the prosecephalon result in some of the most common (agenesis of the corpus callosum) and most profound (e.g., holoprosencephaly) clinical conditions confronting the child neurologist. Advances in fetal and neonatal imaging have significantly increased our understanding of the spectrum of prosencephalic malformations and their associated conditions.
Holoprosencephaly (HPE) is a heterogeneous central nervous system (CNS) anomaly that results from a primary defect in induction and patterning of the rostral neural tube (basal forebrain), leading to varying degrees of incomplete separation of the cerebral hemispheres and facial anomalies. HPE is graded as alobar, semilobar, and lobar, and a mild version called middle interhemispheric variant of HPE. The variable facial anomalies are: (1) cyclopia, with or without proboscis; (2) ethmocephaly with ocular hypotelorism and proboscis located between the eyes; (3) cebocephaly with ocular hypotelorism and single-nostril nose; and (4) median cleft lip/palate (premaxillary agenesis) and ocular hypotelorism.The prevalence of severe HPE in embryonic population is approximately 50?:?10,000, whereas in nonselected fetal population it is approximately 1.26?:?10,000. HPE study populations differ depending on the age of the specimens, the time of the detection of HPE, the number of cases, identified subgroups (e.g., chromosomal, nonchromosomal, not karyotyped), and the type of population (selected or nonselected).There are various etiological factors involved in HPE (environmental and chromosomal factors, genetic syndromes). Depending on the etiology., a wide range of associated anomalies have been reported.US remains the primary imaging modality for examination of the fetal brain and thus HPE. MRI can be an important supplement in suspected fetal HPE, especially in the middle interhemispheric variant of HPE.There is a high prenatal and perinatal mortality rate of severe cases of isolated HPE. No treatment options are available. Surviving children with HPE have developmental disabilities correlating with the severity of brain malformation.
For general radiologists, congenital brain malformations pose substantial challenges in terms of recognition, description, and classification. This review describes a practical approach to imaging and classifying the most common supratentorial brain malformations. It begins with a discussion of embryology and optimal imaging technique and then summarizes distinguishing imaging features for several major categories of cerebral malformation, including holoprosencephaly, gray matter heterotopia, lissencephaly/pachygyria, focal cortical dysplasia, polymicrogyria, and cobblestone malformation. The importance of identifying abnormalities in the corpus callosum and basal ganglia is also discussed, both for detection and characterization of cerebral malformations.
At present, ultrasonography is an inexpensive and widely available real-time investigation and remains the imaging technique of choice for prenatal assessment of the fetus. Major developmental structures of the fetus, particularly the central nervous system (CNS), lungs, and major abdominal viscera, can be adequately evaluated by MRI as early as the beginning of the second trimester. Magnetic resonance imaging (MRI) is useful in evaluating abnormalities seen or suspected on ultrasound and has been shown to be particularly helpful in cases of agenesis of the corpus callosum, posterior fossa anomalies, migrational disorders, cortical dysgenesis, intracranial hemorrhage, porencephaly, absent cavum septi pellucidi, ventriculomegaly, myelomeningocele, and space occupying lesions. Malformations of cortical development such as schizencephaly, gray matter heterotopias, polymicrogyria, and lissencephaly are better demonstrated with MRI than ultrasound. MRI may be helpful in cases of multiple gestations to confirm the number, size, and location of placentas and evaluate for complications.
Holoprosencephaly (HPE) is a complex brain malformation caused by incomplete fusion of cleavage of the cerebral hemispheres and deep brain structures affecting 6 to 12:10,000 live-born infants. There are three categories of HPE ranging in severity, with alobar holoprosencephaly being the most severe, followed by semilobar holoprosencephaly, and lobar holoprosencephaly being the mildest form. Facial anomalies as well as chromosome anomalies are often associated with HPE. This case study describes a transabdominal sonographic diagnosis of alobar HPE with cebocephaly originally found at 27 weeks 3 days on a patient with no prenatal care.
Objective.
The middle interhemispheric variant of holoprosencephaly (MIHV) is a mild, rare variant of holoprosencephaly. Only a few cases of children with MIHV have been reported. Here we report in detail an adult case.
Method.
The patient is a female in her 30s. The patient underwent an extensive neuropsychological examination, a neurological examination and a magnetic resonance imaging.
Results.
Neuroradiologically, the patient had a typical finding of MIHV, with the absence of the central corpus callosum and union of posterior frontal and anterior parietal gyri. In neuropsychological examination, the patient had average or above average performance in verbal comprehension, naming, reading and writing, and below average performance in perceptual reasoning, visuospatial abilities, processing speed and memory. Also difficulties in mathematical abilities, psychomotor skills, and executive functions were found. No gross neurological involvement was noted. She was diagnosed with atypical depression, post-traumatic stress disorder and a dissociative disorder in early adulthood. Despite cognitive deficits, she was able to achieve a tertiary level education.
Conclusions.
This is the first adult case of MIHV described in detail. Our case emphasizes the possibility of a missed diagnosis of marked brain malformations in patients with craniofacial abnormalities. More cases and prospective follow-up studies are needed to understand the evolvement of both neuropsychological and psychiatric symptoms in these patients.
Malformations of cortical development are arranged in different ways. Recently, the ILAE published a consensus classification incorporating pathological, imaging, and genetic findings (Blümcke et al. 2011). Some lesions (namely FCD 2B) from this classification are clearly visible on MRI and pathologically classified with a high concordance between different pathologists. If they are fully resected, seizure freedom rate is > 80 %. Other lesions (namely FCD 1) are more difficult to detect or “unvisible” even with voxel-based MRI analyses and harbored with a high interrater-variability between different pathologists. Chance of postsurgical seizure freedom is distinctly < 50 %. A patient will likely benefit from surgery if a distinct MRI lesion is found underlining the importance of high-quality MRI acquisition and interpretation.
A 3-month-old boy presented with bilateral profound hearing loss. Examination of ears was unremarkable. Brain MRI revealed syntelencephaly with associated other anomalies (figures 1 and 2).
Introduction This chapter focuses on some of the more common brain malformations that are encountered early in life. Tremendous advances in neuroimaging with MRI in the past two decades have significantly improved our ability to diagnose brain malformations. In conjunction, there have been rapid advances in neurobiology that have led to better understanding of how the brain develops and what disturbances to the development lead to malformation. Each year more and more genes responsible for malformations are being discovered. Furthermore, modern fetal ultrasonography and more recently fetal MRI have increased the ability to detect a large variety of central nervous system malformations in utero. Prenatal detection and anatomic diagnosis of the malformations will better allow the medical caregivers to provide prognosis and management counseling. Normal brain development A brief overview of normal embryonic and fetal brain development will help to clarify the timing and etiology of brain malformations. Normal human brain development occurs in a highly defined spatial and temporal sequence of events in utero (Table 22.1). The temporal sequence consists of several overlapping phases. During the induction phase, signals sent to the ectoderm cause it to develop into neural tissue. The neural plate, a sheet of cells that will ultimately develop into the nervous system, develops by the 17th to 20th day of gestation. Neurulation occurs next, where the neural plate begins to fold into the neural tube, a process that begins by the 21st day.
Definition, pathogenesis, and epidemiology Definition and pathogenesis Congenital arachnoid cysts (AC) are also called leptomeningeal cysts. This term excludes secondary “arachnoid” cysts (i.e., post-traumatic, post-infectious, etc.), lined with diseased or inflammatory arachnoidal membranes, and glio-ependymal cysts, lined with glial tissue and epithelial cells. True AC are developmental lesions that arise from the splitting or duplication of the arachnoid membrane (thus they are in fact intra-arachnoid cysts). The etiology of these lesions has long been the subject of debate. The most accepted theory is that they develop from a minor aberration in the development of the arachnoid mater from around week 15 of gestation onward, when the cerebrospinal fluid (CSF) is generated to gradually replace the extracellular ground substance between the external and the internal arachnoid membrane (endomeninx) (Di Rocco 1996). The malformative hypothesis is supported by the common location of arachnoid cysts at the level of normal arachnoid cisterns, their occasional occurrence in siblings, the presence of accompanying anomalies of the venous architecture (i.e., the absence of the sylvian vein), and the association with other congenital anomalies (agenesis of the corpus callosum and Marfan syndrome). Specific problems in the definition of the pathogenesis concern intraventricular AC. For some authors, they represent a kind of “internal” meningocele; for others, they derive from the arachnoid layer and are transported along with the vascular mesenchyme when it invaginates through the choroidal fissure (Di Rocco 1996; Eskandari et al. 2005).
Holoprosencephaly is a developmental abnormality of the fetal brain, resulting from failure of cleavages of the prosencephalon. It is rare among live born infants but common in embryogenesis. It has a prevalence of 1:250 in embryos and approximately 1:10,000 among live-born infants. The severity of the craniofacial phenotype tends to mirror the severity of the brain malformations and correlates inversely with survival. The most severe facial phenotypes include pronounced micro-cephaly, cyclopia,synophthalmia and a proboscis. But combination of holoprosencephaly with nasoethmoidalencephalocele has not been reported in literature to the best of our search and has a very poor prognosis. We hereby, report a new born having swelling at bridge of the nose diagnosed to have AlobarHoloprosencephaly with Nasoethmoidalencephalocele.
Mutation in human ZIC2, a zinc finger protein homologous to Drosophila odd-paired, causes holoprosencephaly (HPE), which is a common, severe malformation of the brain in humans. However, the pathogenesis is largely unknown. Here we show that reduced expression (knockdown) of mouse Zic2 causes neurulation delay, resulting in HPE and spina bifida. Differentiation of the most dorsal neural plate, which gives rise to both roof plate and neural crest cells, also was delayed as indicated by the expression lag of a roof plate marker, Wnt3a. In addition the development of neural crest derivatives such as dorsal root ganglion was impaired. These results suggest that the Zic2 expression level is crucial for the timing of neurulation. Because the Zic2 knockdown mouse is the first mutant with HPE and spina bifida to survive to the perinatal period, the mouse will promote analyses of not only the neurulation but also the pathogenesis of human HPE.
Although holoprosencephaly has been known for many years, few detailed analyses have been performed in a large series of patients to outline the range of morphology in this disorder, particularly regarding the deep gray nuclear structures. We reviewed a large patient cohort to elucidate the combinations of morphologic aberrations of the deep gray nuclei and to correlate those findings with recent discoveries in embryology and developmental neurogenetics.
A retrospective review of the imaging records of 57 patients (43 MR studies and 14 high-quality CT studies) to categorize the spectrum of deep gray nuclear malformations. The hypothalami, caudate nuclei, lentiform nuclei, thalami, and mesencephalon were graded as to their degree of noncleavage. Spatial orientation was also evaluated, as was the relationship of the basal ganglia to the diencephalic structures and mesencephalon. The extent of noncleavage of the various nuclei was then assessed for statistical association.
In every study on which it could be accurately assessed, we found some degree of hypothalamic noncleavage. Noncleavage was also common in the caudate nuclei (96%), lentiform nuclei (85%), and thalami (67%). Complete and partial noncleavage were more common in the caudate nuclei than in the lentiform nuclei. The degree of thalamic noncleavage was uniformly less than that in the caudate and lentiform nuclei. Abnormalities in alignment of the long axis of the thalamus were seen in 71% of cases, and were associated with degree of thalamic noncleavage; 27% of patients had some degree of mesencephalic noncleavage.
The hypothalamus and caudate nuclei are the most severely affected structures in holoprosencephaly, and the mesencephalic structures are more commonly involved than previously thought in this "prosencephalic disorder." These findings suggest the lack of induction of the most rostral aspects of the embryonic floor plate as the cause of this disorder.
We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes. Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations. Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation. We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame deletion of 12 amino acids. The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect (one case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation.
The dorsal cyst is poorly understood, although it is commonly encountered in holoprosencephaly. We endeavor to establish the role of diencephalic malformations in the formation of the dorsal cyst and speculate on the developmental factors responsible. We reviewed the imaging of 70 patients with holoprosencephaly (MRI of 50 and high-quality CT of 20). The presence or absence of a dorsal cyst, thalamic noncleavage and abnormal thalamic orientation were assessed for statistical association, using Fisher's Exact Test and logistical regression. The presence of a dorsal cyst correlated strongly with the presence of noncleavage of the thalamus (P = 0.0007) and with its degree (P < 0.00005). There was a trend toward an association between abnormalities in the orientation of the thalamus and the dorsal cyst, but this was not statistically significant (P = 0.07). We speculate that the unseparated thalamus physically blocks egress of cerebrospinal fluid from the third ventricle, resulting in expansion of the posterodorsal portion of the ventricle to form the cyst.
The middle interhemispheric variant of holoprosencephaly (MIH) is a rare malformation in which the cerebral hemispheres fail to divide in the posterior frontal and parietal regions. We herein describe the structural abnormalities of the brain in a large group of patients with MIH, compare these features with those of classic holoprosencephaly (HPE), and propose a developmental mechanism, based on current knowledge of developmental neurogenetics, by which MIH develops.
Brain images obtained in 21 patients with MIH (MR images in 16 patients and high-quality X-ray CT scans in five patients) were retrospectively reviewed to classify cerebral abnormalities. The cerebral parenchyma, hypothalami, caudate nuclei, lentiform nuclei, thalami, and mesencephalon were examined for the degree of midline separation (cleavage) of the two hemispheres. The orbits, olfactory apparati, and presence or absence of a dorsal cyst were also assessed.
In all patients, by definition, midportions of the cerebral hemispheres were continuous across the midline, with an intervening interhemispheric fissure. The sylvian fissures were abnormally connected across the midline over the vertex in 18 (86%) of 21 patients. Two patients had relatively normal-appearing sylvian fissures; one had unilateral absence of a sylvian fissure owing to substantial subcortical heterotopia. Heterotopic gray matter or dysplastic cerebral cortex was also seen in 18 (86%) of 21 patients. MIH differed from classic HPE as follows. 1) In all subjects, the midline third ventricle separated the hypothalamus and lentiform nuclei. 2) The caudate nuclei were separated by the cerebral ventricles in 17 (89%) of the 19 [corrected] patients in whom they could be assessed. 3) The most commonly affected basal nucleus was the thalamus (non-cleavage in seven [33%] of 21 cases, abnormal alignment in 1 [5%]). 4) Three (18%) of the 17 [corrected] patients in whom the mesencephalon could be assessed showed some degree of mesencephalic non-cleavage. 5) No patients had hypotelorism (four had hypertelorism, the remainder manifested normal intraocular distances). Dorsal cysts were present in five (25%) of the 20 patients in whom they could be assessed (dorsal cysts could not be assessed after shunt surgery), and as in classic HPE, were associated with severe thalamic non-cleavage in three of these five patients.
MIH appears to cause non-cleavage of midline structures in a completely different pattern than does classic HPE. In MIH, impaired induction or expression of genetic factors appears to influence the embryonic roof plate, whereas in classic HPE, induction or expression of the embryonic floor plate seems to be affected.
Analysis of specific features in the brain of patients with holoprosencephaly (HPE) may clarify normal and abnormal brain development and help predict outcomes for specific children. We assessed sulcal and gyral patterns of cerebral cortex in patients with HPE and developed a method of grading brain development.
Neuroimaging studies (75 MR imaging, 21 CT) of 96 patients with HPE were retrospectively reviewed, with specific attention paid to the cerebral cortex. Thickness of cortex, width of gyri, and depth of sulci were assessed subjectively and by measurement. The angle between lines drawn tangential to the sylvian fissures ("sylvian angle") was measured in each patient with HPE and in 20 control patients.
Thickness of cortex was normal in all 96 patients. Gyral shape and width and sulcal depth were normal in 80 patients. Twelve patients, all with very severe HPE and microcephaly, had reduced sulcal depth, diffusely in eight and limited to the anteromedial cortex in four with lobar HPE. Four patients had subcortical heterotopia, located anterior to the interhemispheric fissure, associated with shallow sulci in the overlying cortex. Sylvian fissures were displaced further anteriorly and medially as HPE became more severe, until, in the most severe cases, no sylvian fissures could be identified. Sylvian angle measurements corresponded closely with severity of HPE, being largest in the most severe and smallest in the least severe cases. All patients with HPE had sylvian angles significantly larger than the mean of 15 degrees measured in the control patients.
The only true malformations of cortical development were subcortical heterotopia. However, diffuse and focal abnormal sulci were observed. We propose our sylvian angle measurement of extent of frontal lobe development as an objective means of quantifying the severity of HPE.
The clinical phenotype related to the terminal deletion of the long arm of the chromosome 13 (the so-called 13q- syndrome) includes a considerable number of malformations, especially of the brain. This report describes five cases of a cerebral midline anomaly that leads to a particular clover-shaped type of holoprosencephaly in 13q- fetuses at different stages of the second and third trimesters of gestation. Our cases are compared to those in literature reviews. This malformation has only been described by computer tomography and magnetic resonance imaging in eight children of various ages and has been called "middle interhemispheric fusion" or syntelencephaly. Recently, the human gene ZIC2, the mutation of which leads to holoprosencephaly, has been mapped to the long arm of chromosome 13. on band q32. These findings suggest that this particular type of holoprosencephaly may be related to ZIC2 gene loss of function.
To describe the imaging features of a brain anomaly found on studies of three patients, and to speculate on the embryologic basis leading to the development of this abnormality.
Clinical records (three patients), MR scans (two patients), and CT scans (two patients) of three patients with fusion of the middle portions of the cerebral hemispheres in the presence of nearly normal anterior interhemispheric fissures were retrospectively reviewed. The results were correlated with the present theories of brain development in an attempt to classify the anomaly and define the underlying embryologic abnormalities.
All three patients with middle interhemispheric fusion were severely developmentally delayed. Associated anomalies were identified in all three and included neuronal migration anomalies, callosal dysgenesis, and hypoplasia of the anterior falx cerebri. Correlation of the imaging findings with theories of brain development lead to the suggestion that this anomaly is the result of deficient or dysplastic mesenchyme, which leads to disordered brain development.
Middle interhemispheric fusion may be considered as a variant of holoprosencephaly. It is suggested that the mesenchyme formed by the prechordal plate, notochord, and neural crest play an important part in the early development of the brain and that anomalies of the mesenchyme underlie this disorder as well as other forms of holoprosencephaly.
Holoprosencephaly (HPE) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, we have defined a discrete region in band 13q32 where deletion leads to major developmental anomalies (the 13q32 deletion syndrome). This approximately 1-Mb region lies between markers D135136 and D13S147. Patients in which this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, and digital anomalies such as absent thumbs. We now report that human ZIC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE. Haploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.
Holoprosencephaly is a malformation of the cerebral hemispheres resulting in the absence of the inter-hemispheric fissure along with other defects of brain development. Frequently midline defects of the craniofacial structures are also present. This malformation sequence has been of interest for many years because of the well recognized genetic and environmental pathogeneses, although the molecular pathogenesis remained elusive. Recent studies have begun clarifying the molecular pathogenesis of holoprosencephaly. Herein is reviewed the syndromes associated with holoprosencephaly, the pathology of this disorder, genetic and environment factors, and a current understanding of the molecular pathogenesis of this disorder.
Holoprosencephaly represents a broad spectrum of malformations resulting from a lack of separation of the structures of the forebrain. Recent discoveries in the fields of genetics and developmental neurobiology have advanced our knowledge of this complex disorder. By combining this basic-science knowledge with observations of brain morphology, we can better understand the embryology and genetic factors that influence brain development and, ultimately, form more accurate classification systems and stratification measures for predicting patient outcome.
Hypotheses are presented to explain the pathogenesis of several clinical features of holoprosencephaly, and neuropathologic approaches to testing these hypotheses are suggested. The traditional morphologic classification of holoprosencephaly into alobar, semilobar, and lobar forms is grades of severity, and each occurs in all of the genetic mutations known. Of the four defective genes identified as primary in human holoprosencephaly, three exhibit a ventrodorsal gradient of expression (SHH, SIX3, and TGIF) and one a dorsoventral gradient (ZIC2). But, in addition to the vertical axis, genes expressed in the neural tube also may have rostrocaudal and mediolateral gradients in the other axes. These other gradients may be equally as important as the vertical. If the rostrocaudal gradient extends as far as the mesencephalic neuromere, it may interfere with the formation, migration, or apoptosis of the mesencephalic neural crest, which forms membranous bones of the face, orbits, nose, and parts of the eyes, and may explain the midfacial hypoplasia seen in many, but not all, children with holoprosencephaly. This rostrocaudal gradient also causes noncleavage of the caudate nucleus, thalamus, and hypothalamus and contributes to the formation of the dorsal cyst of holoprosencephaly, which is probably derived from an expanded suprapineal recess of the 3rd ventricle with secondary dilation of the telencephalic monoventricle and at times may produce a unique transfontanellar encephalocele. The extent of the mediolateral gradient may explain the severe disorganization of cerebral cortical architecture in medial parts of the forebrain and normal cortex in lateral parts, including the radial glial fibers. This preserved lateral cortex may explain why some children with holoprosencephaly have better intellectual function than expected and may also be important in the pathogenesis of epilepsy, by contrast with malformations such as lissencephaly, in which the entire cerebral cortex is involved. Epilepsy in some, but not all, cases also may be related to the sequential maturation of axonal terminals in relation to the neurons they innervate. Diabetes insipidus is a complication in a majority of patients; other neuroendocrinopathies occur less frequently. Secondary down-regulation of the OTP gene or of downstream genes such as BRN2 or SIM1 may result in failure of terminal differentiation of magnocellular neurons of the supraoptic and paraventricular hypothalamic nuclei. Disoriented radial glial fibers or abnormal ependyma may allow aberrant migration of neuroepithelial cells into the ventricle. A new classification of holoprosencephaly is needed to integrate morphologic and genetic criteria.
Despite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described.
To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function.
The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation.
In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01).
Patients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.
Two patients with orbital hypotelorism, flat nose, and bilateral lateral cleft of lip and palate with a hypoplastic philtrumpremaxilla Anlage are described. Both patients had holoprosencephaly (arhinencephaly), a brain defect characterized by an arrest in prosencephalic cleavage with no or incomplete proplasia of frontal poles and olfactory bulbs. The two patients are an intermediate stage in a graded series of median facio-cerebral malformations which begins with cyclopia, and then, as face and brain transform toward normality, extends through ethmocephaly, cebocephaly, median cleft lip, and the two patients presented here. The facies of these patients are diagnostic of the type of brain malformation. Careful attention to face-brain relationships will significantly extend the number oif diagnostic facies which currently can be recognized. Physiological defects include poikilothermia, apnea, seizures, rigidity, and lack of psychomotor development.
Useful diagnostic studies include skull roentgenograms to show orbital hypotelorism and absent crista galli, electroencephalography, dermatoglyphics, chromosome studies, and sometimes pneumoencephalography.
Some holoprosencephalic patients, such as our first patient, who have few or no extracephalic malformations, have a 46 chromosome karyotype. Others, such as Patient 2, have many extracephalic anomalies. The literature suggests that the latter patients are apt to have 13-15 trisomy. The face predicts the holoprosencephalic brain irrespective of extracephalic anomalies or karyotype.
Flanders Interuniversity Institute of Biotechnology, Born–Bunge Foundation
- Drs
- Nelis
- De Van Broeckhoven
- Jonghe
- V Timmerman
- Van Gerwen
From the Molecular Genetics Department (Drs. Nelis, Van Broeckhoven, De Jonghe, and Timmerman, V. Van Gerwen), Flanders Interuniversity Institute of
Biotechnology, Born–Bunge Foundation, University of Antwerp, Laboratory of Neuropathology (Dr. Ceuterick), Born–Bunge Foundation, University of
Antwerp, and Department of Neurology (Dr. De Jonghe), University Hospital Antwerp, Antwerpen, and Centre de Référence Neuromusculaire (Drs. Van den
Bergh and Belpaire–Dethiou), Cliniques Universitaires St.-Luc, Université Catholique de Louvain, and Unité de Génétique Médicale (Dr. Verellen),
Pediatric neuroimaging 3rd ed
- A J Barkovich
Barkovich AJ. Pediatric neuroimaging, 3rd ed. Philadelphia:
Lippincott Williams & Wilkins 2000:218 –324.
Hacettepe Children's Hospital
- Dr
- A Palau
- L Cuesta
- Pedrola
Université Catholique de Louvain, Brussels, Belgium; Department of Neurology and Neuromuscular Diseases Research Laboratory (Drs. Erdem, Tan, and
Demirci), Hacettepe University, and Department of Pediatric Neurology (Dr. Topaloglu), Hacettepe Children's Hospital, Ankara, Turkey; Laboratory of
Genetics and Molecular Medicine (Dr. Palau, A. Cuesta and L. Pedrola), Instituto de Biomedicina, CSIC, Valencia, and Department of Genetics (Dr. Palau),
Universitat de Valencia, Burjassot, Spain; and Institute of Neurology (Dr. Gabreëls–Festen), University Hospital Nijmegen, the Netherlands.
Supported in part by the Fund for Scientific Research (FWO-Flanders), a concerted action of the University of Antwerp (UIA), the Interuniversity Attraction
Poles (IUAP) Program P5/19 of the Federal Office for Scientific, Technical and Cultural Affairs (OSTC), and the Geneeskundige Stichting Koningin Elisabeth
(GSKE), Belgium. E.N. and V.T. are postdoctoral fellows of the FWO. H.T. has been supported by the Association Française contre les Myopathies (AFM,
France). F.P. has been supported by the Comision Interministerial de Ciencia y Tecnologia (CICYT) and the Fondo de Investigacion Sanitaria (FIS), Spain.
Received May 24, 2002. Accepted in final form August 9, 2002.
Peripheral Neuropathy Group Universiteitsplein 1, B-2610 Antwerpen, Belgium; e-mail: vincent.timmerman@ua.ac
- Address Correspondence
- Reprint Requests To Prof
- Dr
- Vincent Timmerman
Address correspondence and reprint requests to Prof. Dr. Vincent Timmerman, Molecular Genetics Laboratory (VIB8), Peripheral Neuropathy Group,
University of Antwerpen, Universiteitsplein 1, B-2610 Antwerpen, Belgium; e-mail: vincent.timmerman@ua.ac.be
Copyright © 2002 by AAN Enterprises, Inc. 1865