2,053 results match your criteria Holoprosencephaly Imaging


Integrated clinical and omics approach to rare diseases: novel genes and oligogenic inheritance in holoprosencephaly.

Brain 2018 Nov 30. Epub 2018 Nov 30.

Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, F-35000 Rennes, France.

Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Read More

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November 2018
1 Read

mutation affects ER homeostasis, causing neurological syndrome.

J Med Genet 2018 Nov 21. Epub 2018 Nov 21.

The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

Background: Consanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. Read More

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November 2018
1 Read

Presence of Probst Bundles Indicate White Matter Remodeling in a Dog With Corpus Callosum Hypoplasia and Dysplasia.

Front Vet Sci 2018 22;5:260. Epub 2018 Oct 22.

Neurology Department, Clinic of Small Animal Surgery, Vetsuisse-Faculty Zurich, Zurich, Switzerland.

Corpus callosum abnormalities (CCA) rarely occur in dogs and are related to hypo/adypsic hypernatremia and seizures. Hypoplasia and dysplasia of the corpus callosum (CC) with concomitant lobar holoprosencephaly is the most common variant. It is currently uncertain using conventional MRI if canine CCA reflects the failure of commissural fibers to develop or the failure of the commissural fibers to cross hemispheres. Read More

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October 2018
1 Read

Duplicated distal phalanx of thumb or hallux in trisomy 13: A recurrent feature in a series of 42 fetuses.

Am J Med Genet A 2018 Nov 17;176(11):2325-2330. Epub 2018 Oct 17.

Unité fonctionnelle de fœtopathologie, Département de génétique, CHU Robert Debré, Assistance Publique - Hôpitaux de Paris, Paris, France.

Trisomy 13 or Patau syndrome (PS) is a well-known aneuploidy characterized by a polymalformative syndrome. We described a large series of fetuses with PS and compared them with cases described in the literature, most of which were live-born. In all, 42 fetuses, aged from 14 to 41 gestational weeks (GW), were examined. Read More

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November 2018
2 Reads

MRI of lobar holoprosencephaly in a cat with hypodipsic hypernatraemia.

JFMS Open Rep 2018 Jul-Dec;4(2):2055116918801602. Epub 2018 Sep 20.

Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan.

Case Summary: A 2-year-old neutered female domestic shorthair cat presented with a history of hypodipsia, recurrent hypernatraemia, pelvic limb ataxia and tremor. The serum arginine vasopressin level was low for the serum osmolality. MRI of the brain revealed a failure of separation of the cerebrum, which manifested as absence of the rostral part of the corpus callosum, fornix and septum pellucidum, thus resulting in a single fused ventricle. Read More

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September 2018
2 Reads

Subtle Changes in the Levels of BCL-2 Proteins Cause Severe Craniofacial Abnormalities.

Cell Rep 2018 Sep;24(12):3285-3295.e4

The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address:

Apoptotic cell death removes unwanted cells and is regulated by interactions between pro-survival and pro-apoptotic members of the BCL-2 protein family. The regulation of apoptosis is thought to be crucial for normal embryonic development. Accordingly, complete loss of pro-survival MCL-1 or BCL-XL (BCL2L1) causes embryonic lethality. Read More

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September 2018
1 Read

Low-level parental mosaicism affects the recurrence risk of holoprosencephaly.

Genet Med 2018 Sep 10. Epub 2018 Sep 10.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: De novo variants (DNVs) represent an important fraction of the pathogenic variant burden in holoprosencephaly (HPE). However, unexpected recurrences can occur, as evidenced by multiple affected children harboring the same apparently DNV. This study was performed to estimate the rate of parental mosaicism in a cohort of patients with HPE. Read More

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September 2018
12 Reads

Holoprosencephaly from conception to adulthood.

Am J Med Genet C Semin Med Genet 2018 Jun;178(2):122-127

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Holoprosencephaly (HPE) consists of a spectrum of malformations related to incomplete separation of the prosencephalon. There is a wide clinical variability depending on the HPE subtype seen on imaging. Early postnatal lethality is common, however a significant fraction of newborns diagnosed with HPE will survive into childhood and even adulthood. Read More

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Further evidence for complex inheritance of holoprosencephaly: Lessons learned from pre- and postnatal diagnostic testing in Germany.

Am J Med Genet C Semin Med Genet 2018 Jun;178(2):198-205

Center for Human Genetics Regensburg, Regensburg, Germany.

Holoprosencephaly (HPE) has been defined as a distinct clinical entity with characteristic facial gestalt, which may-or may not-be associated with the true brain malformation observed postmortem in autopsy or in pre- or postnatal imaging. Affected families mainly show autosomal dominant inheritance with markedly reduced penetrance and extremely broad clinical variability even between mutation carriers within the same families. We here present advances in prenatal imaging over the last years, increasing the proportion of individuals with HPE identified prenatally including milder HPE forms and more frequently allowing to detect more severe forms already in early gestation. Read More

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June 2018
1 Read

Holoprosencephaly flashcards: An updated summary for the clinician.

Am J Med Genet C Semin Med Genet 2018 Jun;178(2):117-121

Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.

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Cytogenetics and holoprosencephaly: A chromosomal microarray study of 222 individuals with holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun;178(2):175-186

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Holoprosencephaly (HPE), a common developmental forebrain malformation, is characterized by failure of the cerebrum to completely divide into left and right hemispheres. The etiology of HPE is heterogeneous and a number of environmental and genetic factors have been identified. Cytogenetically visible alterations occur in 25% to 45% of HPE patients and cytogenetic techniques have long been used to study copy number variants (CNVs) in this disorder. Read More

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Challenging issues arising in counseling families experiencing holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun;178(2):238-245

Human Development Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

The provision of information and support to families experiencing holoprosencephaly (HPE) in a loved one is unequivocally challenging, even for the most experienced clinicians. It deserves the balance of pertinent information coupled with medical guidance that forms the basis for shared decision-making; all of which is ideally contained within a supportive environment. It requires a willingness to carefully listen to the specific concerns of the parents and family allowing them to revisit challenging issues as much as needed to encourage existing road blocks to be resolved. Read More

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Neuropathology of holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun;178(2):214-228

Department of Pathology, CHU Sainte-Justine-Chemin de la Côte Sainte-Catherine, Université de Montreal, Montreal, Québec, Canada.

Holoprosencephaly (HPE) is a primary disorder of neural induction and patterning of the rostral neural tube resulting in noncleavage of the forebrain with failure to form two separate distinct hemispheres. The spectrum of HPE is very broad and encompasses various neuropathological phenotypes of different severity. The recent literature has demonstrated that the phenotypic variability of HPE ranges from aprosencephaly-atelencephaly, at the most severe end, to milder forms such as the "middle interhemispheric variant" of HPE at the less severe end of the spectrum. Read More

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First-Trimester Diagnosis of Agnathia-Otocephaly Complex: A Series of 4 Cases and Review of the Literature.

J Ultrasound Med 2018 Aug 31. Epub 2018 Aug 31.

Fetal Imaging Unit, FETALMED-Maternal-Fetal Diagnostic Center, Santiago, Chile.

First-trimester ultrasound findings in 4 fetuses with agnathia-otocephaly complex are described. In addition, information from 3 cases reported in the literature was also reviewed, for a total of 7 cases analyzed. All 7 fetuses presented with agnathia and 6 with ventrocaudal displacement of the ears (melotia/synotia). Read More

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August 2018
9 Reads
1.530 Impact Factor

Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.

Hum Mutat 2018 Dec 24;39(12):1875-1884. Epub 2018 Sep 24.

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.

SMAD2 is a downstream effector in the TGF-β signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Read More

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December 2018
1 Read

Congenital eye anomalies: More mosaic than thought?

Congenit Anom (Kyoto) 2018 Jul 24. Epub 2018 Jul 24.

Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

The eye is a sensory organ that primarily captures light and provides the sense of sight, as well as delivering non-visual light information involving biological rhythms and neurophysiological activities to the brain. Since the early 1990s, rapid advances in molecular biology have enabled the identification of developmental genes, genes responsible for human congenital diseases, and relevant genes of mutant animals with various anomalies. In this review, we first look at the development of the eye, and we highlight seminal reports regarding archetypal gene defects underlying three developmental ocular disorders in humans: (1) holoprosencephaly (HPE), with cyclopia being exhibited in the most severe cases; (2) microphthalmia, anophthalmia, and coloboma (MAC) phenotypes; and (3) anterior segment dysgenesis (ASDG), known as Peters anomaly and its related disorders. Read More

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Alobar holoprosencephaly associated with a rare chromosomal abnormality: Case report and literature review.

Medicine (Baltimore) 2018 Jul;97(29):e11521

Department of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, Sf Ioan Emergency Hospital, Bucharest, Romania.

Rationale: Holoprosencephaly is a structural malformation of the brain that results from the complete or incomplete noncleavage of the forebrain of the embryo into 2 hemispheres. We report a severe case of alobar holoprosencephaly diagnosed at 38 weeks, associated with cebocephaly, microcephaly, and craniosynostosis.

Patient Concern: The main knowledge added by this case is the late ultrasound diagnosis and chromosomal analysis that revealed a very rare abnormality (45X/46,XX/47,XX) with mosaicism at chromosome 18. Read More

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July 2018
56 Reads
5.720 Impact Factor

A Requirement for Zic2 in the Regulation of Nodal Expression Underlies the Establishment of Left-Sided Identity.

Sci Rep 2018 Jul 11;8(1):10439. Epub 2018 Jul 11.

Department of Cardiovascular Medicine, BHF Centre of Research Excellence, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, United Kingdom.

ZIC2 mutation is known to cause holoprosencephaly (HPE). A subset of ZIC2 HPE probands harbour cardiovascular and visceral anomalies suggestive of laterality defects. 3D-imaging of novel mouse Zic2 mutants uncovers, in addition to HPE, laterality defects in lungs, heart, vasculature and viscera. Read More

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July 2018
8 Reads

Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF-β, hedgehog, and FGF signaling.

Hum Mutat 2018 Oct 26;39(10):1416-1427. Epub 2018 Jul 26.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers. Read More

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October 2018
7 Reads

Semilobar holoprosencephaly with cebocephaly associated with maternal early onset preeclampsia: a case report.

J Med Case Rep 2018 Jul 7;12(1):207. Epub 2018 Jul 7.

Department of Obstetrics and Gynecology, Bahir Dar University, College of Medicine and Health Sciences, Bahir Dar, Ethiopia.

Background: The term holoprosencephaly was proposed by DeMyer and Zeman. It is a developmental defect of the embryonic forebrain with heterogeneous etiology including genetic and environmental factors. It is commonly associated with midfacial defects and has a spectrum of presentations. Read More

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July 2018
1 Read

Management Strategies for Hydrocephalus in Alobar Holoprosencephaly: A Case Report and Discussion.

Pediatr Neurosurg 2018 14;53(5):337-341. Epub 2018 Jun 14.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, School of Medicine, Adiyaman University, Adiyaman, Turkey.

Holoprosencephaly is a rare congenital malformation resulting from an impaired midline division of the prosencephalon into distinct cerebral hemispheres. Hydrocephalus is a frequent problem among the few survivors with alobar holoprosencephaly (aHPE), its most severe form. The literature about neurosurgical management of hydrocephalus in this condition is limited and dispersed, and there are still some points that need to be resolved. Read More

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December 2018

Sonic Hedgehog Is a Member of the Hh/DD-Peptidase Family That Spans the Eukaryotic and Bacterial Domains of Life.

Authors:
Henk Roelink

J Dev Biol 2018 Jun 8;6(2). Epub 2018 Jun 8.

Department of Molecular and Cell Biology, University of California, 16 Barker Hall, 3204, Berkeley, CA 94720, USA.

Sonic Hedgehog (Shh) coordinates Zn in a manner that resembles that of peptidases. The ability of Shh to undergo autoproteolytic processing is impaired in mutants that affect the Zn coordination, while mutating residues essential for catalytic activity results in more stable forms of Shh. The residues involved in Zn coordination in Shh are found to be mutated in some individuals with the congenital birth defect holoprosencephaly, demonstrating their importance in development. Read More

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June 2018
1 Read

Recent advances in understanding inheritance of holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun 22;178(2):258-269. Epub 2018 May 22.

Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, F - 35000, Rennes, France.

Holoprosencephaly (HPE) is a complex genetic disorder of the developing forebrain characterized by high phenotypic and genetic heterogeneity. HPE was initially defined as an autosomal dominant disease, but recent research has shown that its mode of transmission is more complex. The past decade has witnessed rapid development of novel genetic technologies and significant progresses in clinical studies of HPE. Read More

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June 2018
11 Reads

Molecular testing in holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun 17;178(2):187-193. Epub 2018 May 17.

Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, Maryland.

Holoprosencephaly (HPE) is a structural brain anomaly characterized by failure of the forebrain to separate during early embryogenesis. Both genetic and environmental etiologies of HPE have been discovered over the last three decades. Traditionally, the genetic workup for HPE has been a karyotype, chromosomal microarray, and/or Sanger sequencing of select genes. Read More

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Prenatal diagnosis of holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun 17;178(2):206-213. Epub 2018 May 17.

Division of Radiology, Children's National Health System, Washington, DC.

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. Read More

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Syndromes associated with holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun 17;178(2):229-237. Epub 2018 May 17.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Holoprosencephaly (HPE) is partial or complete failure of the forebrain to divide into hemispheres and can be an isolated finding or associated with a syndrome. Most cases of HPE are associated with a syndrome and roughly 40%-60% of fetuses with HPE have trisomy 13 which is the most common etiology of HPE. Other syndromes associated with HPE include additional aneuploidies like trisomy 18 and single gene disorders such as Smith-Lemli-Opitz syndrome. Read More

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Holoprosencephaly in the genomics era.

Am J Med Genet C Semin Med Genet 2018 Jun 17;178(2):165-174. Epub 2018 May 17.

Medical Genetics Branch, National Human, Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Holoprosencephaly (HPE) is the direct consequence of specific genetic and/or environmental insults interrupting the midline specification of the nascent forebrain. Such disturbances can lead to a broad range of phenotypic consequences for the brain and face in humans. This malformation sequence is remarkably common in utero (1 in 250 human fetuses), but 97% typically do not survive to birth. Read More

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Nongenetic risk factors for holoprosencephaly: An updated review of the epidemiologic literature.

Am J Med Genet C Semin Med Genet 2018 Jun 15;178(2):151-164. Epub 2018 May 15.

Office of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

Holoprosencephaly (HPE) is a major structural birth defect of the brain that occurs in approximately 1 in 10,000 live births. Although some genetic causes of HPE are known, a substantial proportion of cases have an unknown etiology. Due to the low birth prevalence and rarity of exposure to many potential risk factors for HPE, few epidemiologic studies have had sufficient sample size to examine risk factors. Read More

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Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun 15;178(2):246-257. Epub 2018 May 15.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Nonchromosomal, nonsyndromic holoprosencephaly (NCNS-HPE) has traditionally been considered as a condition of brain and craniofacial maldevelopment. In this review, we present the results of a comprehensive literature search supporting a wide spectrum of extracephalic manifestations identified in patients with NCNS-HPE. These manifestations have been described in case reports and in large cohorts of patients with "single-gene" mutations, suggesting that the NCNS-HPE phenotype can be more complex than traditionally thought. Read More

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Modeling the complex etiology of holoprosencephaly in mice.

Am J Med Genet C Semin Med Genet 2018 Jun 11;178(2):140-150. Epub 2018 May 11.

Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York.

Holoprosencephaly (HPE) is a common developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in Nodal and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations interact with more common modifiers, genetic and/or environmental, to produce severe patterning defects. Read More

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Holoprosencephaly: A clinical genomics perspective.

Am J Med Genet C Semin Med Genet 2018 Jun 11;178(2):194-197. Epub 2018 May 11.

GeneDx, Gaithersburg, Maryland.

New and rapidly evolving technologies have dramatically impacted the practice of clinical genetics as well as broader areas of medicine. To illustrate this trend from the perspective of a clinical molecular laboratory, we briefly summarize our general experience conducting exome testing for patients with holoprosencephaly (HPE). Though these cases are not representative of HPE more generally (i. Read More

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Functions of TGIF homeodomain proteins and their roles in normal brain development and holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 Jun 11;178(2):128-139. Epub 2018 May 11.

Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan.

Holoprosencephaly (HPE) is a frequent human forebrain developmental disorder with both genetic and environmental causes. Multiple loci have been associated with HPE in humans, and potential causative genes at 14 of these loci have been identified. Although TGIF1 (originally TGIF, for Thymine Guanine-Interacting Factor) is among the most frequently screened genes in HPE patients, an understanding of how mutations in this gene contribute to the pathogenesis of HPE has remained elusive. Read More

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A novel fetal sequence patogenesis resulting in oral meningoencephalocele.

Bratisl Lek Listy 2018 ;119(5):272-274

Objectives: To analyze a rare triad of intracranial fetal pathologies and clinical study of the novel defined sequence pathogenesis based on prenatal and postmortem findings.

Methods: Complex multidisciplinary clinical analysis and review of up-to-date literature.

Results: In an 18-gestational-week fetus the screening ultrasound scan resembled the semilobar type of holoprosencephaly and oral tumor. Read More

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January 2018
2 Reads

Study of Normal and Abnormal Prenatal Development Using the Kyoto Collection of Human Embryos.

Authors:
Kohei Shiota

Anat Rec (Hoboken) 2018 Jun 16;301(6):955-959. Epub 2018 Apr 16.

Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.

Four topics on normal and abnormal human prenatal development are briefly reviewed. These studies were made possible by using the Kyoto Collection of Human Embryos, the largest collection of human embryo specimens procured after therapeutic abortion. The topics discussed include: (1) variability of human embryo development and implications for clinical teratology, (2) abnormal development in human embryos and intrauterine fate of human conceptuses, (3) holoprosencephaly, and (4) maternal hyperthermia in early pregnancy and birth defects. Read More

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Clinical and Demographic Evaluation of a Holoprosencephaly Cohort From the Kyoto Collection of Human Embryos.

Anat Rec (Hoboken) 2018 Jun 16;301(6):973-986. Epub 2018 Apr 16.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Holoprosencephaly (HPE) is a genetically and phenotypically heterogeneous disorder involving developmental defects. HPE is a rare condition (1/10,000-20,000 newborns) but can be found as frequently as 1/250 among conceptions, suggesting that most HPE embryos are incompatible with postnatal life and result in spontaneous abortions during the first trimester of gestation. Beginning in 1961, the Kyoto University in Japan collected over 44,000 human conceptuses in collaboration with several hundred domestic obstetricians. Read More

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June 2018
2 Reads

[Alobar holoprosencephaly associated with diabetes insipidus and hypothyroidism in a 10-month old infant].

Pan Afr Med J 2017 1;28:193. Epub 2017 Nov 1.

Service de Pédiatrie, UFR des Sciences de la Santé, Université Gaston Berger de Saint-Louis, Sénégal.

Holoprosencephaly (HPE) is a serious brain malformation due to a failure of medial forebrain cleavage. This is an abnormality which is more often associated with craniofacial malformations, psychomotor development delay, diabetes insipidus and variable endocrine disorders. It is due to different causes including chromosomal abnormalities (trisomy 13, 18)and polymalformative syndromes (CHARGE Syndrome). Read More

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April 2018
6 Reads

"Twig-like" cerebral vessels are not pathognomonic for ACTA A2 mutations: A case report.

Interv Neuroradiol 2018 Aug 28;24(4):463-468. Epub 2018 Mar 28.

3 Toronto Western Hospital & University Health Network, University of Toronto, Toronto, Canada.

ACTA2 mutations are recently described genetically defined abnormalities of blood vessels in various organs of the body with specific abnormalities in cerebral vessels in the form of straightening of all cerebral arteries ("twig-like" pattern), stenosis/occlusions, proximal dilatation, and absent "moyamoya" type of collaterals. We describe a one-and-a half year-old girl child who presented with mild motor developmental delay and on neuroimaging showed septo-preoptic holoprosencephaly, diffuse radial polymicrogyria, and pontine hypoplasia along with magnetic resonance angiographic features suggestive of ACTA2 mutation type of cerebral vessels. However, genetic studies revealed no evidence of ACTA2 mutation, indicating that the "twig-like" pattern may not only be a pathognomonic feature of ACTA2 mutations. Read More

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August 2018
18 Reads

Loss-of-function mutations in FGF8 can be independent risk factors for holoprosencephaly.

Hum Mol Genet 2018 06;27(11):1989-1998

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.

The utilization of next generation sequencing has been shown to accelerate gene discovery in human disease. However, our confidence in the correct disease-associations of rare variants continues to depend on functional analysis. Here, we employ a sensitive assay of human FGF8 variants in zebrafish to demonstrate that the spectrum of isoforms of FGF8 produced by alternative splicing can provide key insights into the genetic susceptibility to human malformations. Read More

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June 2018
1 Read

New mutations and an updated database for the patched-1 (PTCH1) gene.

Mol Genet Genomic Med 2018 05 25;6(3):409-415. Epub 2018 Mar 25.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

Background: Basal cell nevus syndrome (BCNS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), maxillary keratocysts, and cerebral calcifications. BCNS most commonly is caused by a germline mutation in the patched-1 (PTCH1) gene. PTCH1 mutations are also described in patients with holoprosencephaly. Read More

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May 2018
1 Read

Multiple roles of Sonic Hedgehog in the developing human cortex are suggested by its widespread distribution.

Brain Struct Funct 2018 Jun 28;223(5):2361-2375. Epub 2018 Feb 28.

Department of Psychiatry, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA.

Sonic Hedgehog (Shh) plays an instrumental role in brain development, fine-tuning processes such as cell proliferation, patterning, and fate specification. Although, mutations in the SHH pathway in humans are associated with various neurodevelopmental disorders, ranging from holoprosencephaly to schizophrenia, its expression pattern in the developing human brain is not well established. We now determined the previously not reported wide expression of SHH in the human fetal cerebral cortex during most of the gestation period (10-40 gestational weeks). Read More

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June 2018
2 Reads

Hikers poisoned: Veratrum steroidal alkaloid toxicity following ingestion of foraged Veratrum parviflorum.

Clin Toxicol (Phila) 2018 Sep 28;56(9):841-845. Epub 2018 Feb 28.

f Emory University School of Medicine , Atlanta , GA , USA.

Introduction: Steroidal alkaloids are found in plants of the genus Veratrum. Their toxicity manifests as gastrointestinal symptoms followed by a Bezold-Jarisch reflex: hypopnea, hypotension, and bradycardia. Some Veratrum steroidal alkaloids are also teratogens interfering with the hedgehog-2 signaling pathway, which causes cyclopsia and holoprosencephaly. Read More

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September 2018
4 Reads

7q Deletion/12q Duplication Is the Possible Cause of an Alobar Holoprosencephaly Case.

Mol Syndromol 2017 Dec 24;9(1):52-57. Epub 2017 Nov 24.

Access to genome (ATG P.C.), Clinical Laboratory Genetics, University of Athens, Athens, Greece.

Holoprosencephaly (HPE) spectrum disorder is the most common congenital malformation of the human brain with absence of or incomplete midline cleavage. Its cause is heterogenic, making genetic counseling a challenge. In this case report, a pregnancy affected by alobar HPE is described. Read More

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December 2017
6 Reads

ZIC2 in Holoprosencephaly.

Adv Exp Med Biol 2018 ;1046:269-299

Early Mammalian Development Laboratory, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.

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. Read More

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History and highlights of the teratological collection in the Museum Anatomicum of Leiden University, The Netherlands.

Am J Med Genet A 2018 03 5;176(3):618-637. Epub 2018 Feb 5.

Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno-Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. Read More

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March 2018
3 Reads

Importance of complete phenotyping in prenatal whole exome sequencing.

Hum Genet 2018 Feb 1;137(2):175-181. Epub 2018 Feb 1.

Medical Genetics and Genomics Laboratories, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.

Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. Read More

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February 2018
2 Reads

Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression.

Sci Rep 2018 02 1;8(1):2140. Epub 2018 Feb 1.

Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama, 351-0198, Japan.

One of the causal genes for holoprosencephaly (HPE) is ZIC2 (HPE5). It belongs to the zinc finger protein of the cerebellum (Zic) family of genes that share a C2H2-type zinc finger domain, similar to the GLI family of genes. In order to clarify the role of Zic2 in gene regulation, we searched for its direct target genes using chromatin immunoprecipitation (ChIP). Read More

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February 2018
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Stillborn Infants: Associated Malformations.

Birth Defects Res 2018 01;110(2):114-121

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Stillbirth, defined as death of a fetus in utero after 20 weeks of gestation, occurs in 1 to 2% of pregnancies in the United States. Many of these stillborn infants have associated malformations, including chromosome abnormalities, neural tube defects, and malformation syndromes. Other causes are abnormalities of the placenta and maternal conditions, such as pre-eclampsia and obesity. Read More

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January 2018
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Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain.

Biochem Biophys Res Commun 2018 02;496(2):575-581

State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China. Electronic address:

Human protein TGIF1 is an essential regulator of cell fate with broad roles in different tissues, and has been implicated in holoprosencephaly (HPE) and many cancers. The function of TGIF1 in transcriptional regulation depends on its three-amino acid loop extension (TALE) type of homeodomain (HD). Two missense mutations that led to P192A and R219C substitutions in TGIF1-HD were previously found in HPE patients and suggested to be the causes for these cases. Read More

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February 2018
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Solitary median maxillary central incisor, holoprosencephaly and congenital nasal pyriform aperture stenosis in a premature infant: case report.

Arch Argent Pediatr 2018 Feb;116(1):e130-e134

Tepecik Training and Research Hospital, Department of Neonatology, Izmir,Turkey.

Solitary median maxillary central incisor syndrome is a rare disorder involving midline abnormalities such as holoprosencephaly, nasal cavity anomalies, cleft palate-lip, hypotelorism, microcephaly, and panhypopituitarism. Congenital nasal pyriform aperture stenosis is a lethal cause of neonatal respiratory distress due to narrowing of the pyriform aperture anteriorly and it can be confused with choanal atresia. In this report, we present a newborn infant with solitary median maxillary central incisor syndrome accompanied by other abnormalities including holoprosencephaly, nasal pyriform aperture stenosis, microcephaly and panhypopituitarism. Read More

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February 2018
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