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Incidence and Magnetic Resonance Imaging

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Ivana Markovic at Klinički centar Niš
Ivana Markovic
Zoran Josif Milenkovic at University of Niš
Zoran Josif Milenkovic
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Mini Review Holoprocencephaly (HPE) is a developmental anomaly featured by a failure in differentiation and cleavage of the prosencephaly resulting in incomplete separation of the two hemispheres. In almost 80% of individuals it is accompanied by specific craniofacial anomalies. Both genetic and teratogen factors are responsible for the development of HPE [1]. Rare in absolute terms, HPE is the most common brain abnormality and is seen in 1 per 8000-16,000 live births [2-4]. In an analysis of 21 HPE epidemiologic articles Orioli IM and Castilla EE [5] found that the pregnancy outcomes had relevant impact on the incident rate of HPE, being lower than 1 per 10,000 in live and stillbirth and between 40-50 per 10000 in aborted embryos. In a large series of 4,157,224 births, the same authors observed 370 infants with suspected holoprosencephaly (0,009%) stressing that isolated HPE was homogeneous among the 11 sampled countries, increasing from 0.5/10,000 births to 1/10,000 births between 1967 and 2000% [6]. The early embryonic occurrence may be even higher with prevalence of 1:250 in embryos [7] but may not be detected due to most fetuses aborting in early gestation [2]. In our small series of 4000 MRI explorations in children of different ages (from newborns to 15 years old) only three cases harboring HPE were diagnosed, accounting for almost 0.05%. Even though, the holoprosencephaly has been divided into three categories (alobar, semilobar and lobar) and a clear distinction between them does not exist. However, another two categories have been added to the previous one: the middle interhemispheric fusion variant (MIHF/MIHV or syntelencephaly [8] and a septopreoptic type [9]. Alobar HPE is a rare and the most severe congenital malformation, usually diagnosed by prenatal ultrasound, rarely postnattally by CT or MRI, because the infant is most often stillborn. There is no separation of cerebral hemisphere with only one large ventricle and failure of transverse cleavage into diencephalon and telencephalon. Semilobar HPE, less dysmorphic then alobar (HPE), has both the frontal and parietal lobes completely fused and interhemispheric fissure exist posteriorly. The concomitant anomalies might be microcephaly, macrocephaly, motor abnormalities such as choreoathetosis or lower extremity spasticity. In lobar HPE, which is less severe than the previous two subtypes, both hemispheres and lateral ventricles are clearly defined but the most rostral aspect of the frontal lobes are fused especially ventrally. Mild or moderate developmental delay, pituitary dysfunction, or visual problems may harbor the patient with above mention anomaly. Diagnosis of HPE can be established by CT or MRI .Imaging by MRI is the study of choice and can determine the clinical subtypes and associates anomalies. The presentation of the imaging characteristics of HPE’s subtypes are given below. In middle interhemispheric fusionvariant (MIHF/MIHV or syntelencephaly) there is no separation of the posterior frontal and parietal lobes, absence of the body of the corpus callosum followed by different variations in the cleavage of the basal ganglia and thalami In a septopreoptic type of HPE (vary rare anomaly) only the septal and/or preoptic regions are not separated. Other entities may include.septo-optic dysplasia, central incisor syndrome, nonspecific midline dysplasia, frontonasal dysplasia, agnathia-otocephaly
A case of lobar holoprosencephaly in neonatus one-month old who underwent MRI exam after ultrasound exploration. Almost all tomograms are degraded by motion artifacts in spite of sedation. The child is under close observation by paediatrician and neurologist. a) Sagital T1W SE tomogram shows abscense of rostrum, genum, anterior and part of posterior body of corpus callosum. Only small part of posterior body and splenium of corpus callosum are visible. b) and c) Coronal T2W SE tomograms: There is a fusion of thalami and also small part of frontal lobes around anterior commissure; frontal horns of the lateral ventricles are present, slightly dysplastic and opened laterally; the sylvian fissures look normal. e) Axial T2 FLAIR tomograms. The frontal lobes are more fully developed than in semilobar holoprosencephaly; the interhemispheric fissure and falx cerebri extend into the frontal area of the brain, although the anterior falx is hypoplastic. The septum pellucidumis absent.
A case of lobar holoprosencephaly in neonatus one-month old who underwent MRI exam after ultrasound exploration. Almost all tomograms are degraded by motion artifacts in spite of sedation. The child is under close observation by paediatrician and neurologist. a) Sagital T1W SE tomogram shows abscense of rostrum, genum, anterior and part of posterior body of corpus callosum. Only small part of posterior body and splenium of corpus callosum are visible. b) and c) Coronal T2W SE tomograms: There is a fusion of thalami and also small part of frontal lobes around anterior commissure; frontal horns of the lateral ventricles are present, slightly dysplastic and opened laterally; the sylvian fissures look normal. e) Axial T2 FLAIR tomograms. The frontal lobes are more fully developed than in semilobar holoprosencephaly; the interhemispheric fissure and falx cerebri extend into the frontal area of the brain, although the anterior falx is hypoplastic. The septum pellucidumis absent.
… 
A case of mild lobar holoprosencephaly in one month old girl with multiple congenital anomalies (Cleft hard palate and bifid uvula, retro-micrognathia, calvicular middle bone defect) MRI was performed to rule out brain malformation. There is no defined corpus callosum on sagittal T1W SE images. It is only visible posterior thin part which could be consider at least as thin splenium/posterior body but it correlates with hippocampal commissure. a) and c) axial T2W SE, and d) axial T1W SE: There is partial fusion of basal ganglia in a part of thalami and also in hypothalamic region. Frontal horns of both lateral ventricles are almost invisible, present but dysplastic, very thin and displaced laterally. The third ventricle is also present but smaller than usual. Sylvian fissures look normal. e) and f) coronal T2W SE tomograms confirm lack of frontobasal lobes separation with incomplete interhemispheric fissure and anterior falx and hallmark of examination which is partial fusion of deep gray nuclei.
A case of mild lobar holoprosencephaly in one month old girl with multiple congenital anomalies (Cleft hard palate and bifid uvula, retro-micrognathia, calvicular middle bone defect) MRI was performed to rule out brain malformation. There is no defined corpus callosum on sagittal T1W SE images. It is only visible posterior thin part which could be consider at least as thin splenium/posterior body but it correlates with hippocampal commissure. a) and c) axial T2W SE, and d) axial T1W SE: There is partial fusion of basal ganglia in a part of thalami and also in hypothalamic region. Frontal horns of both lateral ventricles are almost invisible, present but dysplastic, very thin and displaced laterally. The third ventricle is also present but smaller than usual. Sylvian fissures look normal. e) and f) coronal T2W SE tomograms confirm lack of frontobasal lobes separation with incomplete interhemispheric fissure and anterior falx and hallmark of examination which is partial fusion of deep gray nuclei.
… 
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Mini Review Open Access
Journal of Neonatal Biology
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ISSN: 2167-0897
Markovic and Milenkovic, J Neonatal Biol 2016, 6:1
DOI: 10.4172/2167-0897.1000250
Volume 6 • Issue 1 • 1000250
J Neonatal Biol, an open access journal
ISSN: 2167-0897
Mini Review
Holoprocencephaly (HPE) is a developmental anomaly featured by
a failure in dierentiation and cleavage of the prosencephaly resulting
in incomplete separation of the two hemispheres. In almost 80% of
individuals it is accompanied by specic craniofacial anomalies. Both
genetic and teratogen factors are responsible for the development of HPE
[1]. Rare in absolute terms, HPE is the most common brain abnormality
and is seen in 1 per 8000-16,000 live births [2-4]. In an analysis of 21
HPE epidemiologic articles Orioli IM and Castilla EE [5] found that the
pregnancy outcomes had relevant impact on the incident rate of HPE,
being lower than 1 per 10,000 in live and stillbirth and between 40-50
per 10000 in aborted embryos. In a large series of 4,157,224 births, the
same authors observed 370 infants with suspected holoprosencephaly
(0,009%) stressing that isolated HPE was homogeneous among the 11
sampled countries, increasing from 0.5/10,000 births to 1/10,000 births
between 1967 and 2000% [6]. e early embryonic occurrence may be
even higher with prevalence of 1:250 in embryos [7] but may not be
detected due to most fetuses aborting in early gestation [2]. In our small
series of 4000 MRI explorations in children of dierent ages (from new-
borns to 15 years old) only three cases harboring HPE were diagnosed,
accounting for almost 0.05%. Even though, the holoprosencephaly has
been divided into three categories (alobar, semilobar and lobar) and
a clear distinction between them does not exist. However, another
two categories have been added to the previous one: the middle
interhemispheric fusion variant (MIHF/MIHV or syntelencephaly [8]
and a septopreoptic type [9]. Alobar HPE is a rare and the most severe
congenital malformation, usually diagnosed by prenatal ultrasound,
rarely postnattally by CT or MRI, because the infant is most oen
stillborn. ere is no separation of cerebral hemisphere with only one
large ventricle and failure of transverse cleavage into diencephalon
and telencephalon. Semilobar HPE, less dysmorphic then alobar
(HPE), has both the frontal and parietal lobes completely fused and
interhemispheric ssure exist posteriorly. e concomitant anomalies
might be microcephaly, macrocephaly, motor abnormalities such as
choreoathetosis or lower extremity spasticity.
In lobar HPE, which is less severe than the previous two subtypes,
both hemispheres and lateral ventricles are clearly dened but the
most rostral aspect of the frontal lobes are fused especially ventrally.
Mild or moderate developmental delay, pituitary dysfunction, or
visual problems may harbor the patient with above mention anomaly.
Diagnosis of HPE can be established by CT or MRI .Imaging by MRI
is the study of choice and can determine the clinical subtypes and
associates anomalies. e presentation of the imaging characteristics
of HPE’s subtypes are given below. In middle interhemispheric fusion
Incidence and Magnetic Resonance Imaging
Ivana Markovic1 and Zoran Milenkovic2*
1Institute of Radiology, Clinical Center Nis, Serbia .Bvl.Zoran Djindjic 48, 18000 Nis, Serbia
2General Hospital “Sava Surgery”, Bvl.dr. Zoran Djindjic 91, Nis, Serbia
*Corresponding author: Zoran Milenkovic, General Hospital “Sava Surgery”, Bvl.
dr. Zoran Djindjic, Tel: +381 18 537-907; E-mail: zoran@junis.ni.ac.rs
Received February 07, 2017; Accepted February 22, 2017; Published February
28, 2017
Citation: Markovic I, Milenkovic Z (2017) Incidence and Magnetic Resonance
Imaging. J Neonatal Biol 6: 250. doi:10.4172/2167-0897.1000250
Copyright: © 2017 Markovic I, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Figure 1: A case of semilobar holoprosencephaly (a 12 year old girl who
underwent MRI examination after the rst episode of seizures. She has been
under antiepileptic drugs up to now. a) Sagital T1W SE tomogram shows
abscense of rostrum, genum, anterior and part of posterior body of corpus
callosum. Only small part of posterior body and splenium of corpus callosum
are visible. b) and c) Coronal T2W SE tomograms: There is a fusion of thalami
and also small part of frontal lobes around anterior commissure; frontal horns
of the lateral ventricles are present, slightly dysplastic and opened laterally;
the sylvian ssures look normal. e) Axial T2 FLAIR tomograms, the frontal
lobes are more fully developed than in semilobar holoprosencephaly; the
interhemispheric ssure and falx cerebri extend into the frontal area of the
brain, although the anterior falx is hypoplastic. The septum pellucidum is
absent.
variant (MIHF/MIHV or syntelencephaly) there is no separation of the
posterior frontal and parietal lobes, absence of the body of the corpus
callosum followed by dierent variations in the cleavage of the basal
ganglia and thalami In a septopreoptic type of HPE (vary rare anomaly)
only the septal and/or preoptic regions are not separated. Other entities
may include.septo-optic dysplasia, central incisor syndrome, non-
specic midline dysplasia, frontonasal dysplasia, agnathia-otocephaly
(Figures 1-3).
We are presenting MRI characteristics of our cases below.
Citation: Markovic I, Milenkovic Z (2017) Incidence and Magnetic Resonance Imaging. J Neonatal Biol 6: 250. doi:10.4172/2167-0897.1000250
Page 2 of 3
Volume 6 • Issue 1 • 1000250
J Neonatal Biol, an open access journal
ISSN: 2167-0897
Figure 2: A case of lobar holoprosencephaly in neonatus one- month old who underwent MRI exam after ultrasound exploration. Almost all tomograms are degraded
by motion artifacts in spite of sedation. The child is under close observation by paediatrician and neurologist. a) Sagital T1W SE tomogram shows abscense of
rostrum, genum, anterior and part of posterior body of corpus callosum. Only small part of posterior body and splenium of corpus callosum are visible. b) and c)
Coronal T2W SE tomograms: There is a fusion of thalami and also small part of frontal lobes around anterior commissure; frontal horns of the lateral ventricles are
present, slightly dysplastic and opened laterally; the sylvian ssures look normal. e) Axial T2 FLAIR tomograms. The frontal lobes are more fully developed than in
semilobar holoprosencephaly; the interhemispheric ssure and falx cerebri extend into the frontal area of the brain, although the anterior falx is hypoplastic. The
septum pellucidumis absent.
Figure 3: A case of mild lobar holoprosencephaly in one month old girl with multiple congenital anomalies (Cleft hard palate and bid uvula, retro-micrognathia,
calvicular middle bone defect) MRI was performed to rule out brain malformation. There is no dened corpus callosum on sagittal T1W SE images. It is only visible
posterior thin part which could be consider at least as thin splenium/posterior body but it correlates with hippocampal commissure. a) and c) axial T2W SE, and d)
axial T1W SE: There is partial fusion of basal ganglia in a part of thalami and also in hypothalamic region. Frontal horns of both lateral ventricles are almost invisible,
present but dysplastic, very thin and displaced laterally. The third ventricle is also present but smaller than usual. Sylvian ssures look normal. e) and f) coronal T2W
SE tomograms conrm lack of frontobasal lobes separation with incomplete interhemispheric ssure and anterior falx and hallmark of examination which is partial
fusion of deep gray nuclei.
Citation: Markovic I, Milenkovic Z (2017) Incidence and Magnetic Resonance Imaging. J Neonatal Biol 6: 250. doi:10.4172/2167-0897.1000250
Page 3 of 3
Volume 6 • Issue 1 • 1000250
J Neonatal Biol, an open access journal
ISSN: 2167-0897
References
1. Barkovich AJ (2005) Pediatric Neuroimaging. (4th edn), LippincottWilliams and
Wilkins, USA.
2. Raam MS, Solomon BD, Muenke M (2011) Holoprosencephaly: A guide to
diagnosis and clinical management. Indian Pediatr 48: 457-466.
3. Dubourg C, Bendavid C, Pasquier L (2007) Holoprosencephaly. Orphanet J
Rare Dis 2: 1-8.
4. Winter TC, Kennedy AM, Woodward PJ (2015) Holoprosencephaly: A survey
of the entity, with embryology and fetal imaging. Radiographics 35: 275-290.
5. Orioli IM, Castilla EE (2010) Epidemiology of holoprosencephaly: Prevalence
and risk factors. Am J Med Genet C Semin Med Genet 154C: 13-21.
6. Orioli IM, Castilla EE (2007) Clinical epidemiologic study of holoprosencephaly
in South America. Am J Med Genet A 143A: 3088-3099.
7. Matsunaga E, Shiota K (1977) Holoprosencephaly in human embryos:
Epidemiologic studies of 150 cases. Teratology 16: 261-272.
8. Barkovich AJ, Quint DJ (1993) Middle interhemispheric fusion: an unusual
variant of holoprosencephaly. AJNR Am J Neuroradiol 14: 431-440.
9. Hahn JS, Barnes PD, Clegg NJ, Stashinko EE. (2010) Septopreoptic
holoprosencephaly: A mild subtype associated with midline craniofacial
anomalies. AJNR Am J Neuroradiol 31: 1596-601.
ResearchGate has not been able to resolve any citations for this publication.
Holoprosencephaly: A Survey of the Entity, with Embryology and Fetal Imaging
Article
Full-text available
  • Jan 2015
Structural malformations of the brain are an important cause of childhood mortality and morbidity, with the latter having long-term financial and psychosocial implications for the affected child and family. Holoprosencephaly (HPE) is a severe brain malformation characterized by abnormal cleavage of the prosencephalon in the 5th gestational week. Aprosencephaly and atelencephaly occur earlier because of failure in the formation of the prosencephalon and telencephalon, respectively. The HPE spectrum classically includes alobar, semilobar, and lobar forms, although there are no clear-cut defining features. The middle interhemispheric variant (MIH), also known as syntelencephaly, is classified as a variant of HPE with midline interhemispheric fusion. Other conditions sometimes included in the spectrum of HPE include septo-optic dysplasia (SOD); "minimal" HPE, which is associated with subtle craniofacial malformations and mild developmental delay; and microform HPE, which by definition excludes brain involvement. The focus of this article will be on the spectrum of findings visible in fetal manifestation of the HPE spectrum. Brain embryology; the imaging characteristics, epidemiology, and embryology of HPE; and the more common associated anomalies, particularly those of the face ("the face predicts the brain") are reviewed. Recognition of these anomalies is important for accurate parental counseling, since the prognosis is poor but not invariably lethal; children with the milder forms may live well into their teens with severe developmental delays, endocrine dysfunction, and disrupted homeostasis. Available data on outcome in surviving children are summarized. Illustrative fetal ultrasonographic and magnetic resonance images are presented with clinical, autopsy, and postnatal imaging correlation. (C) RSNA, 2015
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Holoprosencephaly
Article
Full-text available
  • Feb 2007
  • ORPHANET J RARE DIS
Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH, ZIC2, SIX3 and TGIF. Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life.
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Modern Pediatric Neuroimaging
Conference Paper
  • Dec 2008
LEARNING OBJECTIVES 1) Understand when fetal MRI will be a useful adjunct to fetal ultrasound. 2) Learn the techniques to perform high quality fetal MRI. 3) Learn to interpret fetal MRI scans. 4) Understand when diffusion imaging is useful in pediatric neuroradiology. 5) Learn the specific techniques that tailor diffusion imaging to the neonatal and pediatric brain. 6) Learn how the results of diffusion tensor imaging can help to understand the pathology and pathophysiology in pediatric neurological disease. 7) Learn the best techniques for detecting malformations of the brain. 8) Learn how the findings in brain malformations reflect the disruption of underlying events in brain development. ABSTRACT Imaging of the developing brain and interpreting these images are extremely challenging tasks for the radiologist. The immature brain differs greatly from the mature brain: it has fewer, shallower sulci, less white matter volume, higher water content, and different signal intensity of the white matter. As a result, different MR imaging sequences must be used. In addition, the immaturity of the brain causes disease processes to affect it differently than the adult brain; infection or injury to the developing brain may result in malformation rather than destruction. This course will look at three different aspects of disorders of brain development: MRI of the Fetal CNS; Diffusion Imaging in the Pediatric CNS; and Imaging of Brain Malformations. MRI of the Fetal CNS will discuss the indications for MRI of the fetus with suspected CNS abnormalities. Clearly, sonography is the initial study that should be obtained, but MRI can add a great deal of supplemental information if performed and interpreted properly. How to select patients who will benefit most from fetal MRI will be discussed, as will techniques for obtaining high quality fetal MR imaging. Many examples of fetal pathology as demonstrated by MRI will be shown. Diffusion Imaging in the Pediatric CNS will discuss how diffusion techniques can be used to assess brain maturity and how it can be optimally modified to show disorders of brain formation and subtle brain injuries. Utility of diffusion imaging in neonatal brain injury, brain infections, CNS trauma, and hypoxia-ischemia will be discussed. Techniques for assessment of white matter pathology will be introduced. Brain malformations are a difficult topic for radiologists but are extremely important, both for prognosis and for genetic implications. This lecture will show optimal techniques for detecting malformations, will show techniques for detecting subtle malformations, and will show how MRI reflects the disruption of normal development.
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Holoprosencephaly: A Guide to Diagnosis and Clinical Management
Article
  • Jun 2011
  • Indian Pediatr
Holoprosencephaly affects 1 in 8,000 live births and is the most common structural anomaly of the developing forebrain, resulting in facial dysmorphism, neurologic impairment, and additional clinical sequelae. Given the increasing relative contribution of genetic diseases to perinatal morbidity and mortality in India, proper recognition and management of holoprosencephaly can improve care for a significant number of affected Indian children. We used the PubMed database (search terms: "holoprosencephaly," "HPE," "holoprosencephaly India") and cross-referenced articles regarding holoprosencephaly, using our research group's extensive experience as a guide for identifying seminal papers in the field. Holoprosencephaly is classified into four types based on the nature of the brain malformations as seen on neuroimaging and/or pathologic examination, with typically recognizable craniofacial phenotypes. Despite the identification of several genetic loci and other etiologic agents involved in pathogenesis, additional causes are elusive. Moreover, satisfactory explanations for phenomena such as incomplete penetrance and variable expressivity are lacking. For each patient, pediatricians should follow a diagnostic protocol including dysmorphology examination, complete family history and ascertainment of risk factors, and neuroimaging. Many medical issues, including hypothalamic dysfunction, endocrinologic dysfunction, motor impairment, respiratory issues, seizures, and hydrocephalus should be prioritized in management. Pediatricians should work with genetic specialists to identify syndromic forms and to perform cytogenetic investigation, molecular screening, and genetic counseling in order to fully characterize prognosis and recurrence risk.
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Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies
Article
  • Oct 2010
  • AM J NEURORADIOL
SUMMARY: HPE is a congenital brain malformation characterized by failure of the prosencephalon to divide into 2 hemispheres. We have identified 7 patients who have a mild subtype of HPE in which the midline fusion was restricted to the septal region or preoptic region of the telencephalon. This subtype, which we call septopreoptic HPE, falls in the spectrum of lobar HPE, but lacks significant frontal neocortical fusion seen in lobar HPE. Other imaging characteristics include thickened or dysplastic fornix, absent or hypoplastic anterior CC, and single unpaired ACA. The SP was fully formed in 4, partially formed in 2, and absent in 1. Mild midline craniofacial malformation, such as SMMCI and CNPAS were found in 86% and 71%, respectively. Patients outside of infancy often manifested language delay, learning disabilities, or behavioral disturbances, while motor function was relatively spared.
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Epidemiology of holoprosencephaly: prevalence and risk factors. Am J Med Genet C Semin Med Genet 154C:13-21
Article
  • Feb 2010
  • AM J MED GENET C
The wide variation in cerebral and facial phenotypes and the recognized etiologic heterogeneity of holoprosencephaly (HPE) contribute to the observed inter-study heterogeneity. High lethality during the early stages of embryonic and fetal development makes HPE detection age dependent. By reviewing 21 HPE epidemiologic articles, the observed prevalence rate differences can be largely explained by the pregnancy outcome status of the studied cohort: livebirth, stillbirth, and terminations of pregnancy (TOPs): lower than 1 per 10,000 when live and still births were included, higher when TOPs were included, and between 40 and 50 per 10,000 in two classical Japanese studies on aborted embryos. The increasing secular trend observed in some studies probably resulted from an increasing use of prenatal sonography. Ethnic variations in birth prevalence rates (BPRs) could occur in HPE, but the available data are not very convincing. Higher BPRs were generally observed in the less favored minorities (Blacks, Hispanics, Pakistanis), suggesting a bias caused by a lower prenatal detection rate of HPE, and consequently less TOPs. Severe ear defects, as well as microstomia, were part of the spectrum of HPE. Non-craniofacial anomalies, more frequently associated with HPE than expected, were genital anomalies (24%), postaxial polydactyly (8%), vertebral defects (5%), limb reduction defects (4%), and transposition of great arteries (4%). The variable female predominance, found in different HPE studies, could also depend on the proportion of early conceptions in each study sample, as males are more likely to be lost through spontaneous abortions.
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Holoprosencephaly in human embryos: Epidemiologic studies of 150 cases
Article
  • Dec 1977
One hundred fifty embryos with holoprosencephaly were found among the total of 36,380 conceptuses obtained through induced abortion in the period from 1962 to 1974, giving an overall incidence of 0.4 percent. The occurrence was period from 1962 to 1974, giving an overall incidence of 0.4 percent. The occurrence was largely at random through time, and no "epidemic" was noted in particular years or months, but there appeared more cases derived from conceptions in winter than in summer months. The mean maternal age did not differ significantly from that of the general embryonic population, indicating that, although none of our cases were karyotyped, chromosome aberrations such as trisomies 13 and 18 that are closely associated with maternal age may not constitute a major part as causes of holoprosencephaly in human embryos. Materal age did not differ by the presence or absence of associated external anomalies. No association was found with paternal age, parental consanguinity nor with maternal medical history, including irregularity of menstrual cycles, and smoking and drinking habits. There was an indication that the mothers were prone to have repeated miscarriages, supporting the view that some kind of maternal predisposition is responsible for the causation of holoprosencephaly. Argument was made that, apart from various chromosome aberrations well documented as causes of this malformation, polygenic mechanism probably accounts for the majority of the cases with normal karyotype.
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Middle interhemispheric fusion: An unusual variant of holoprosencephaly
Article
  • Mar 1993
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.
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Clinical Epidemiology of Holoprosencephaly in South America
Article
  • Dec 2007
  • AM J MED GENET A
ECLAMC: Latin American Study of Congenital Malformations examined 4,157,224 births (1967-2000), detecting 370 newborns with suspected holoprosencephaly (HPE): 182 (49.2%) had only craniofacial defects; 99 (26.8%) had defects in other systems; (15.1%) had chromosomal anomalies; 5 (1.4%) had recognized syndromes; and 28 (7.6%) had isolated median cleft lip. The latter group was excluded from subsequent analyses because of epidemiological differences from the other groups. The birth prevalence rate (BPR) of isolated HPE was homogeneous among the 11 sampled countries, increasing from 0.5/10,000 births to 1/10,000 births between 1967 and 2000, suggesting improved ascertainment, mainly after 1996. Microtia, cleft lip/palate, and microstomia were preferentially associated with HPE, but cleft palate only was not. Maternal diabetes was more prevalent in HPE than in controls when adding the isolated and associated groups (OR: 3.5; 95% CI: 0.9-16.2). Maternal flu was more prevalent in isolated HPE (OR: 3.6; 0.9-16.6) and in isolated plus associated HPE (OR: 2.8; 1.0-7.9) than in controls. A second series of better documented HPE cases, 179 in number (2.2/10,000), ascertained from 827,968 births occurring from 2000 to 2003, was used for phenotypic definition of cerebral and facial anomalies. In 83 of 174 HPE cases with specified cerebral defects, 40% were alobar, 43% were semilobar, and 17% were lobar. All cases of cyclopia, ethmocephaly, and cebocephaly were of the alobar or semilobar types. Female excess occurred in the total sample, but not within the subgroups themselves because of their small sample sizes. Neither alobar HPE nor cyclopia was associated with female predilection. Among the 174 HPE cases, 39% had neither oral clefting nor a severe dysmorphic face. Of facial phenotypes, 26% had cyclopia, ethmocephaly, or cebocephaly; 25% had premaxillary agenesis; and 10% had cleft lip and palate or cleft palate only. Cyclopia was not associated with oral clefts; 6 of 8 cases of ethmocephaly had cleft palate; 6 of 20 cases of cebocephaly had oral clefts; 4 of 20 cases had premaxillary agenesis; and 2 of 20 cases had cleft palate.
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