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Lourenço M, Curate F, Cunha E. Insights into the anatomical expressions of anencephaly in three infants from 17th to 19th- century Lisbon, Portugal. INTERNATIONAL JOURNAL OF PALEOPATHOLOGY 2025; 49:119-127. [PMID: 40262330 DOI: 10.1016/j.ijpp.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 03/28/2025] [Accepted: 04/11/2025] [Indexed: 04/24/2025]
Abstract
OBJECTIVE This study aims to analyse and compare the cranial morphological variations in three individuals, each exhibiting different severity levels of malformations. MATERIALS Three nearly complete and well-preserved skeletons of infants from the São Domingos children's necropolis in Lisbon, Portugal, dating from the 17th to early 19th centuries. METHODS Macroscopic and metric assessments were performed aimed at creating a detailed description of the skeletons. RESULTS The three infants exhibit an absence of the upper cranial vault, accompanied by several cranial bone alterations such as abnormal development and morphology of the occipital, sphenoid, temporal, and frontal bones. Additionally, two of the infants present maxillary and dental anomalies. CONCLUSIONS The three infants from the São Domingos necropolis provide crucial insights into the presence of anencephaly in an historical population, representing an exceptionally rare archaeological find. The distinct cranial abnormalities strongly support the diagnosis and highlight varying severity levels of the condition. SIGNIFICANCE These examples enhance the recognition of anencephaly in archaeological contexts and deepen the understanding of its varied bone expressions. Examining skeletal variations within the same condition also complements the broader palaeopathological discussion of rare diseases. LIMITATIONS The lack of soft tissue preservation reduces a comprehensive assessment of anencephaly in skeletal remains. The archaeological context presents challenges such as fragmentation. Additionally, determining postnatal survival is difficult due to the subtle or absent skeletal indicators that might suggest survival beyond birth. SUGGESTIONS FOR FURTHER RESEARCH Biomolecular genetics analysis could be a valuable approach for future research.
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Affiliation(s)
- Marina Lourenço
- University of Coimbra, Centre for Functional Ecology, Laboratory of Forensic Anthropology, Department of Life Sciences, Calçada Martim de Freitas, Coimbra 3000-456, Portugal; University of Coimbra, Research Centre for Anthropology and Health, Department of Life Sciences, Calçada Martim de Freitas, Coimbra 3000-456, Portugal; Era Arqueologia S.A., Calçada de Santa Catarina, 9C, Cruz Quebrada 1495-705, Portugal.
| | - Francisco Curate
- University of Coimbra, Research Centre for Anthropology and Health, Department of Life Sciences, Calçada Martim de Freitas, Coimbra 3000-456, Portugal.
| | - Eugénia Cunha
- University of Coimbra, Centre for Functional Ecology, Laboratory of Forensic Anthropology, Department of Life Sciences, Calçada Martim de Freitas, Coimbra 3000-456, Portugal; National Institute of Legal Medicine and Forensic Sciences, Rua Manuel Bento de Sousa, 3, Lisboa 1169-201, Portugal.
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Barman P, Mishra GV, Murugan G, Priyadarshee P, Wanjari M, Sood A. Lobar holoprosencephaly with associated meningocele: A rare case report of a 25-year-old patient with multiple seizures. Radiol Case Rep 2025; 20:2004-2008. [PMID: 39963386 PMCID: PMC11831739 DOI: 10.1016/j.radcr.2025.01.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/22/2024] [Accepted: 01/06/2025] [Indexed: 02/20/2025] Open
Abstract
Lobar holoprosencephaly (HPE) represents the mildest form of HPE, featuring an interhemispheric fissure extending along most of the entire midline, with the thalami remaining unfused. Lobar HPE is usually diagnosed in the prenatal stage or infancy; however, cases of adult-onset are exceedingly rare. Here, we present a 25-year-old patient who was presented with multiple episodes of seizures and was subsequently diagnosed with lobar HPE accompanied by a meningocele. By shedding light on this rare brain malformation, we hope to raise awareness among healthcare professionals and stimulate further research into the pathogenesis, clinical course, and management of adult-onset HPE.
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Affiliation(s)
- Parishmita Barman
- Department of Radiodiagnosis, Shree Balaji Medical College and Hospital, Bharath Institute of Higher Education and Research, Chromepet, Chennai, 600044, India 442001
| | - Gaurav Vedprakash Mishra
- Department of Radiodiagnosis, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha, Maharashtra, India 442001
| | - G Murugan
- Department of Radiodiagnosis, Shree Balaji Medical College and Hospital, Bharath Institute of Higher Education and Research, Chromepet, Chennai, 600044, India 442001
| | - Piyoosh Priyadarshee
- Department of Radiodiagnosis, Shree Balaji Medical College and Hospital, Bharath Institute of Higher Education and Research, Chromepet, Chennai, 600044, India 442001
| | - Mayur Wanjari
- Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha, Maharashtra, India 442001
| | - Anshul Sood
- Department of Radiodiagnosis, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha, Maharashtra, India 442001
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Scelsa B, Gano D, Hart AR, Vollmer B, Lemmon ME, Tarui T, Mulkey SB, Scher M, Pardo AC, Agarwal S, Venkatesan C. Prenatally Diagnosed Holoprosencephaly: Review of the Literature and Practical Recommendations for Pediatric Neurologists. Pediatr Neurol 2025; 162:87-96. [PMID: 39577233 DOI: 10.1016/j.pediatrneurol.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/06/2024] [Accepted: 10/19/2024] [Indexed: 11/24/2024]
Abstract
Holoprosencephaly (HPE) is one of the most common malformations in embryonic development. HPE represents a continuum spectrum that involves the midline cleavage of forebrain structures. Facial malformations of varying degrees of severity are also observed. It is probable that HPE results from a combination of genetic mutations and environmental influences during the initial weeks of pregnancy. Some patients with HPE experience early death, whereas others go on to experience neurodevelopmental impairment. Accurate fetal imaging can facilitate diagnosis and prenatal counseling, although more subtle brain abnormalities can be difficult to diagnose prenatally. Fetal counseling can be complex, given that the etiopathogenesis remains unclear and variable penetrance is prevalent in inherited genetic mutations. The aim of this narrative review is to examine the literature on HPE and to offer recommendations for pediatric neurologists for fetal counseling and postnatal care.
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Affiliation(s)
- Barbara Scelsa
- Department of Pediatric Neurology, Buzzi Children's Hospital, University of Milan, Milan, Italy.
| | - Dawn Gano
- Department of Neurology & Pediatrics, University of California San Francisco, San Francisco, California
| | - Anthony R Hart
- Department of Paediatric Neurology, King's College Hospital NHS Foundation Trust, London, UK
| | - Brigitte Vollmer
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Neonatal and Paediatric Neurology, Southampton Children's Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Monica E Lemmon
- Department of Pediatrics and Population Health Sciences, Duke University School of Medicine, Durham, North Carolina
| | - Tomo Tarui
- Division of Pediatric Neurology, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Sarah B Mulkey
- Zickler Family Prenatal Pediatrics Institute, Children's National Hospital, Washington, District of Columbia; Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Mark Scher
- Emeritus Full Professor Pediatrics and Neurology, Case Western Reserve University School of Medicine
| | - Andrea C Pardo
- Division of Neurology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago Illinois
| | - Sonika Agarwal
- Division of Neurology & Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Charu Venkatesan
- Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
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4
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Noble AR, Masek M, Hofmann C, Cuoco A, Rusterholz TDS, Özkoc H, Greter NR, Phelps IG, Vladimirov N, Kollmorgen S, Stoeckli E, Bachmann-Gagescu R. Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system. Biol Open 2024; 13:bio060421. [PMID: 39400299 PMCID: PMC11583916 DOI: 10.1242/bio.060421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 10/04/2024] [Indexed: 10/15/2024] Open
Abstract
Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. To identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510 and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain but do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation.
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Affiliation(s)
- Alexandra R. Noble
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
- University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning (AdaBD), University of Zurich, 8057 Zurich, Switzerland
| | - Markus Masek
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
| | - Claudia Hofmann
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
| | - Arianna Cuoco
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
| | | | - Hayriye Özkoc
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
| | - Nadja R. Greter
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
| | - Ian G. Phelps
- Department of Pediatrics, University of Washington, Seattle, WA 8057, USA
| | - Nikita Vladimirov
- University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning (AdaBD), University of Zurich, 8057 Zurich, Switzerland
- Brain Research Institute, University of Zurich, 98105 Zurich, Switzerland
- Center for Microscopy and Image Analysis (ZMB), University of Zurich, 8057 Zurich, Switzerland
| | - Sepp Kollmorgen
- University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning (AdaBD), University of Zurich, 8057 Zurich, Switzerland
| | - Esther Stoeckli
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
- University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning (AdaBD), University of Zurich, 8057 Zurich, Switzerland
| | - Ruxandra Bachmann-Gagescu
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
- University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning (AdaBD), University of Zurich, 8057 Zurich, Switzerland
- Institute for Medical Genetics, University of Zurich, 8952 Zurich, Switzerland
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Debnath R, Das M, Mandal B, Mukherjee S, Chatterjee U. Holoprosencephaly: Syndromic or Non-syndromic is the question. INDIAN J PATHOL MICR 2024; 67:722-724. [PMID: 38394408 DOI: 10.4103/ijpm.ijpm_183_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/27/2023] [Indexed: 02/25/2024] Open
Affiliation(s)
| | - Mou Das
- Department of Pathology, IPGME&R, Kolkata, West Bengal, India
| | - Bappa Mandal
- Department of Neonatology, IPGME&R, Kolkata, West Bengal, India
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Lena G, La Cognata D, Zanghì A, Vecchio M, Chiaramonte R, Falsaperla R, Marino F, Palmucci S, Belfiore G, Basile A, Praticò AD. Malformations of the Cerebral Commissures. JOURNAL OF PEDIATRIC NEUROLOGY 2024; 22:158-165. [DOI: 10.1055/s-0044-1786783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
AbstractMalformations of the cerebral commissures are abnormalities involving the structures which connect the brain hemispheres. The main cerebral commissures are the anterior commissure, the hippocampal commissure, and the corpus callosum, which is the largest and best known of the three and connects the neocortex of the two cerebral hemispheres. Commissures of more reduced extension are the posterior commissure and the habenular commissure. They derive embryologically from the same structure, the commensurate plate. Any interference in the embryological development of the brain commissures may cause an anomaly of all the three commissures or of a single commissure, as well as any combination of anomalies of each of them.Each of these three commissural traits may be absent, isolated, or in combination. The abnormality of the commissures, in addition, can be complete or partial, with dysplasia of the meninges, with multicystic dysplasia of the interhemispheric meninges, in the context of Aicardi syndrome or with the presence of interhemispheric lipomas.The complete agenesis of the commissures (“classic” form) is the most common form and encompasses more than a third of the cases. In complete agenesis, by definition, both the corpus callosum and the hippocampal commissure are totally absent.Anomalies of the commissural structures associated with dysplasia of the meninges include the agenesis of the corpus callosum with interhemispheric cysts (a complex spectrum of clinical and neuroradiological conditions characterized by the associated presence of an interhemispheric cyst formed by communicating cavities) and the agenesis of commissures with interhemispheric lipomas that are usually located in the subarachnoid space.Genes responsible for axonal migration to the commissural plate and those responsible for crossing and connections with the neurons of the contralateral hemisphere are multiple, so that malformations of the cerebral commissure/corpus callosum can be found in numerous malformative syndromes with other multiple associated abnormalities.
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Affiliation(s)
- Germana Lena
- Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
| | - Daria La Cognata
- Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
| | - Antonio Zanghì
- Department of Medical and Surgical Sciences and Advanced Technologies, Research Center for Surgery of Complex Malformation Syndromes of Transition and Adulthood, University of Catania, Catania, Italy
| | - Michele Vecchio
- Department of Biomedical and Biotechnological Sciences, Rehabilitation Unit, University of Catania, Catania, Italy
| | - Rita Chiaramonte
- Department of Biomedical and Biotechnological Sciences, Rehabilitation Unit, University of Catania, Catania, Italy
| | - Raffaele Falsaperla
- Neonatal Intensive Care Unit and Neonatology, University Hospital “Policlinico Rodolico-San Marco”, Catania, Italy
| | - Francesco Marino
- Department of Medical Surgical Sciences and Advanced Technologies, University Hospital Policlinico “G. Rodolico-San Marco”, Catania, Italy
| | - Stefano Palmucci
- Department of Medical Surgical Sciences and Advanced Technologies, IPTRA Unit, University Hospital Policlinico “G. Rodolico-San Marco”, Catania, Italy
| | - Giuseppe Belfiore
- Department of Medical Surgical Sciences and Advanced Technologies, Unit of Radiology 1, University Hospital Policlinico “G. Rodolico-San Marco”, Catania, Italy
| | - Antonio Basile
- Department of Medical Surgical Sciences and Advanced Technologies, Unit of Radiology 1, University Hospital Policlinico “G. Rodolico-San Marco”, Catania, Italy
| | - Andrea D. Praticò
- Chair of Pediatrics, Department of Medicine and Surgery, Kore University, Enna, Italy
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Gergely L, Repiská V, Böhmer D, Korbeľ M, Václavová Z, McCullough L, Melišová K, Priščáková P. Post-mortem rapid aneuploidy testing for holoprosencephaly. Birth Defects Res 2024; 116:e2342. [PMID: 38632851 DOI: 10.1002/bdr2.2342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/27/2024] [Accepted: 04/08/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Abortion and fetal death are common in fetuses with holoprosencephaly, so genetic examinations often have to be made in a post-mortem setting. The efficiency of the conventional karyotyping using cultured fibroblasts in these situations is limited due to frequent culture failure. In the current study, archived cases of holoprosencephaly, where post-mortem genetic evaluation was requested and sufficient frozen material was available, were reevaluated using the quantitative fluorescence polymerase chain reaction (QF-PCR) technique. METHODS Testing for aneuploidies of chromosomes 13, 15, 16, 18, 21, 22, X, and Y with the QF-PCR technique was carried out on DNA isolated from archived frozen chorionic villi in seven cases of holoprosencephaly. RESULTS QF-PCR was successful in all seven cases. Two cases of trisomy 13, two cases of triploidy, and one case of trisomy 18 was found meaning a 71% diagnostic yield. The success rate of QF-PCR (100%, 7/7) was superior compared to conventional karyotyping (43%, 3/7). CONCLUSIONS Rapid aneuploidy testing using the QF-PCR technique is a simple, reliable, time- and cost-effective method sufficient to conclude the etiologic investigation in the majority of holoprosencephaly cases post-mortem.
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Affiliation(s)
- Lajos Gergely
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Vanda Repiská
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Daniel Böhmer
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Miroslav Korbeľ
- 1st Department of Gynaecology and Obstetrics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Zuzana Václavová
- 1st Department of Gynaecology and Obstetrics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Liam McCullough
- 1st Department of Gynaecology and Obstetrics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Katarína Melišová
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Petra Priščáková
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
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Balconara D, La Cognata D, Zanghì A, Vecchio M, Marino F, Sortino G, Belfiore G, Basile A, Falsaperla R, Praticò AD. Holoprosencephaly: The Disease and Its Related Disabilities. JOURNAL OF PEDIATRIC NEUROLOGY 2024; 22:125-131. [DOI: 10.1055/s-0044-1786773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
AbstractHoloprosencephaly (HPE), the most prevalent developmental anomaly affecting the forebrain in humans, occurs in approximately 1 in 16,000 liveborn neonates, with an incidence reaching 1 in 250 in conceptuses. This condition is distributed worldwide. HPE is etiologically heterogeneous, and its pathogenesis is variable. Environmental, teratogenic, genetic, or metabolic factors can contribute to the development of HPE. Notably, maternal insulin-dependent diabetes mellitus and maternal alcoholism are among the primary causative factors. HPE may be linked to various well-defined multiple malformation syndromes characterized by a normal karyotype, such as Smith–Lemli–Opitz's, Pallister–Hall's, or velocardiofacial syndrome. Alternatively, it can be associated with chromosomal abnormalities. (i.e., Patau's syndrome and, less frequently, Edwards' syndrome or Down's syndrome). The major genes implicated in HPE are SHH, ZIC2, SIX3, and TGIF. The range of HPE is extensive, covering diverse neuropathological phenotypes of varying severity. Three classical types of HPE can be distinguished in increasing order of severity: lobar HPE, characterized by separated right and left ventricles with some continuity across the frontal cortex; semilobar HPE, featuring a partial separation; and the most severe form, alobar HPE, where there is a single brain ventricle and the absence of an interhemispheric fissure. Additionally, there are other variations of HPE, ranging in severity, including the less severe interhemispheric median HPE (also known as middle interhemispheric variant). The phenotypic spectrum of HPE is highly extensive, encompassing severe cerebral malformations to microforms. Children with HPE often encounter numerous medical challenges; among them neurological disorders, craniofacial malformations, endocrine disorders, oral and motor dysfunction, and dysfunction of the autonomic nervous system. Neurologic problems, such as cerebral palsy and seizures, are common. The diagnosis of HPE is typically made prenatally, relying primarily on ultrasound and magnetic resonance imaging examinations. The prognosis for individuals with HPE is largely dependent on its underlying causes. Those with cytogenetic abnormalities, in particular, face a significantly poorer prognosis, with only 2% surviving beyond 1 year.
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Affiliation(s)
- Desireè Balconara
- Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
| | - Daria La Cognata
- Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
| | - Antonio Zanghì
- Department of Medical and Surgical Sciences and Advanced Technologies, Research Center for Surgery of Complex Malformation Syndromes of Transition and Adulthood, University of Catania, Catania, Italy
| | - Michele Vecchio
- Rehabilitation Unit, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Francesco Marino
- Department of Medical Surgical Sciences and Advanced Technologies “GF Ingrassia,” University Hospital Policlinico “G. Rodolico-San Marco,” Catania, Italy
| | - Giuseppe Sortino
- Unit of Diagnostic Neuroradiology, Humanitas Clinical Institute, Catania, Italy
| | - Giuseppe Belfiore
- Unit of Diagnostic Neuroradiology, Humanitas Clinical Institute, Catania, Italy
| | - Antonio Basile
- Radiology Unit 1, Department of Medical Surgical Sciences and Advanced Technologies, University Hospital Policlinico “G. Rodolico-San Marco,” Catania, Italy
| | - Raffaele Falsaperla
- Neonatal Intensive Care Unit and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
| | - Andrea D. Praticò
- Chair of Pediatrics, Department of Medicine and Surgery, Kore University, Enna, Italy
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Saumweber E, Mzoughi S, Khadra A, Werberger A, Schumann S, Guccione E, Schmeisser MJ, Kühl SJ. Prdm15 acts upstream of Wnt4 signaling in anterior neural development of Xenopus laevis. Front Cell Dev Biol 2024; 12:1316048. [PMID: 38444828 PMCID: PMC10912572 DOI: 10.3389/fcell.2024.1316048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 02/02/2024] [Indexed: 03/07/2024] Open
Abstract
Mutations in PRDM15 lead to a syndromic form of holoprosencephaly (HPE) known as the Galloway-Mowat syndrome (GAMOS). While a connection between PRDM15, a zinc finger transcription factor, and WNT/PCP signaling has been established, there is a critical need to delve deeper into their contributions to early development and GAMOS pathogenesis. We used the South African clawed frog Xenopus laevis as the vertebrate model organism and observed that prdm15 was enriched in the tissues and organs affected in GAMOS. Furthermore, we generated a morpholino oligonucleotide-mediated prdm15 knockdown model showing that the depletion of Prdm15 leads to abnormal eye, head, and brain development, effectively recapitulating the anterior neural features in GAMOS. An analysis of the underlying molecular basis revealed a reduced expression of key genes associated with eye, head, and brain development. Notably, this reduction could be rescued by the introduction of wnt4 RNA, particularly during the induction of the respective tissues. Mechanistically, our data demonstrate that Prdm15 acts upstream of both canonical and non-canonical Wnt4 signaling during anterior neural development. Our findings describe severe ocular and anterior neural abnormalities upon Prdm15 depletion and elucidate the role of Prdm15 in canonical and non-canonical Wnt4 signaling.
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Affiliation(s)
- Ernestine Saumweber
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Slim Mzoughi
- Center of OncoGenomics and Innovative Therapeutics (COGIT), Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New-York, NY, United States
| | - Arin Khadra
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Anja Werberger
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Sven Schumann
- Institute of Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Ernesto Guccione
- Center of OncoGenomics and Innovative Therapeutics (COGIT), Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New-York, NY, United States
| | - Michael J. Schmeisser
- Institute of Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Susanne J. Kühl
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
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10
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Farhud DD, Varjavand P, Zarif-Yeganeh M. CDON Mutation Related to Nose Deformity with Variable Expression in Holoprosencephaly in an Iranian Family: A Case Report. IRANIAN JOURNAL OF PUBLIC HEALTH 2024; 53:482-489. [PMID: 38894838 PMCID: PMC11182473 DOI: 10.18502/ijph.v53i2.14933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 08/07/2023] [Indexed: 06/21/2024]
Abstract
Holoprosencephaly, a complicated brain abnormality arising from incomplete prosencephalon cleavage, affects both the forebrain and the face. Holoprosencephaly Type 11, with variable expression or partial penetrance, is caused by CDON pathogenic variants associated with the disrupted Sonic Hedgehog (SHH)-pathway. Herein, we aimed to describe a family with genetic nose problems. After counselling and drawing pedigree in Farhud's Genetic Clinic, Tehran, Iran in 2021, DNA extraction of a proband and a few members of his family (patient and control) was conducted. Whole exome sequencing was utilized for detecting the gene and its variant in the proband with a nose deformity. The results were confirmed with Sanger sequencing. This variant was checked in other members by Sanger sequencing. Analysis of the Exome data showed a heterozygous splicing variant in the CDON gene (NM_016952; c.3276+1G>T) in the proband who had a nose deformity and then the results were confirmed with Sanger sequencing. Such a variant was observed in Proband's brother with a nose deformity and was not observed in Proband's cousin with no abnormal phenotype. Recent investigations, in an Iranian family, with a heterozygous splicing CDON mutation as a human candidate gene are discussed for the first time in relation to the likely pathogenesis of facial deformities, particularly nose deformity, in Holoprosencephaly.
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Affiliation(s)
- Dariush D. Farhud
- Dr. Farhud Genetic Clinic, Tehran, Iran
- Research Institute of Aging, Tehran University of Medical Sciences, Tehran, Iran
- Social Genetics Research Center, Nasim Institute, Tehran, Iran
- Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran
| | | | - Marjan Zarif-Yeganeh
- Dr. Farhud Genetic Clinic, Tehran, Iran
- Research Institute of Aging, Tehran University of Medical Sciences, Tehran, Iran
- Social Genetics Research Center, Nasim Institute, Tehran, Iran
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11
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Mori M, Takeshita S, Nakamura N, Mizuno Y, Tomita A, Aoyama M, Kakita H, Yamada Y. Efficacy of tolvaptan in an infant with syndrome of inappropriate antidiuretic hormone secretion associated with holoprosencephaly: A case report. World J Clin Cases 2023; 11:6262-6267. [PMID: 37731562 PMCID: PMC10507562 DOI: 10.12998/wjcc.v11.i26.6262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/31/2023] [Accepted: 08/15/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Holoprosencephaly (HPE) is a congenital malformation with various degrees of incomplete separation of the cerebral hemispheres due to differentiation disorders of the forebrain. Although HPE with diabetes insipidus due to associated pituitary dysfunction has been reported, HPE with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is very rare. Tolvaptan, a vasopressin V2 receptor antagonist, is effective in adults with SIADH. However, there is no report of its efficacy in infants with SIADH. The purpose of this report is to demonstrate that tolvaptan is effective for SIADH in infants and that administration of tolvaptan eliminates the need for restriction of water intake and sodium administration. CASE SUMMARY A 2414-g female infant was born at 38 wk by normal vaginal delivery. Facial anomalies and head magnetic resonance imaging indicated semilobar HPE. After birth, she had hyponatremia due to SIADH and was treated using water and sodium restriction. However, she developed an exaggerated response to the fluid restrictions, resulting in large fluctuations in serum sodium levels. Subsequent administration of tolvaptan improved the fluctuations in serum sodium levels without the need for adjustment of water or sodium administration. Serum sodium was maintained within the normal range after discontinuation of tolvaptan at 80 d of life. There were no side effects, such as hypernatremia or liver dysfunction, during the administration of tolvaptan. CONCLUSION This is the first report on the safety and efficacy of tolvaptan in an infant with SIADH associated with HPE.
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Affiliation(s)
- Mari Mori
- Department of Perinatal and Neonatal Medicine, Aichi Medical University, Nagakute 480-1195, Japan
| | - Satoru Takeshita
- Department of Perinatal and Neonatal Medicine, Aichi Medical University, Nagakute 480-1195, Japan
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya 467-8603, Japan
| | - Nami Nakamura
- Department of Perinatal and Neonatal Medicine, Aichi Medical University, Nagakute 480-1195, Japan
- Department of Pediatrics, Aichi Medical University, Nagakute 480-1195, Japan
| | - Yuki Mizuno
- Department of Pharmacy, Aichi Medical University, Nagakute 480-1195, Japan
| | - Akiko Tomita
- Department of Pharmacy, Aichi Medical University, Nagakute 480-1195, Japan
| | - Mineyoshi Aoyama
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya 467-8603, Japan
| | - Hiroki Kakita
- Department of Perinatal and Neonatal Medicine, Aichi Medical University, Nagakute 480-1195, Japan
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya 467-8603, Japan
| | - Yasumasa Yamada
- Department of Perinatal and Neonatal Medicine, Aichi Medical University, Nagakute 480-1195, Japan
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12
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Dariansyah AD, Suryaningtyas W, Parenrengi MA. Cranial vault reduction cranioplasty for severe macrocephaly due to holoprosencephaly and subdural hygroma: a case report. Childs Nerv Syst 2023; 39:2537-2541. [PMID: 37231270 DOI: 10.1007/s00381-023-06001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 05/19/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Severe macrocephaly can still be found in developing countries. This condition is usually caused by neglected hydrocephalus and can cause a lot of morbidities. Cranial vault reconstruction cranioplasty is the main treatment option for severe macrocephaly. Holoprosencephaly is often seen with features of microcephaly. Hydrocephalus should be considered as the main cause in HPE patients with features of macrocephaly. In this report, we present a rare case of cranial vault reduction cranioplasty procedure in patient with severe macrocephaly due to holoprosencephaly and subdural hygroma. CASE DESCRIPTION A 4-year-10-month-old Indonesian boy was admitted with head enlargement since birth. He had a history of VP shunt placement when he was 3 months old. But the condition was neglected. Preoperative head CT showed massive bilateral subdural hygroma that compressed brain parenchyma caudally. From the craniometric calculation, the occipital frontal circumference was 70.5 cm with prominent vertex expansion, the distance between nasion to inion was 11.91 cm and the vertical height was 25.59 cm. The preoperative cranial volume was 24.611 cc. The patient underwent subdural hygroma evacuation and cranial vault reduction cranioplasty. The postoperative cranial volume was 10.468 cc. CONCLUSION Subdural hygroma can be a rare cause of severe macrocephaly in holoprosencephaly patients. Cranial vault reduction cranioplasty and subdural hygroma evacuation is still the main treatment option. Our procedure successfully reduces significant cranial volume (57.46% volume reduction).
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Affiliation(s)
- Ahmad Data Dariansyah
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr, Soetomo General Academic Hospital, Jalan Mayjend Prof. Dr. Moestopo No. 6-8, Mojo, Gubeng, Surabaya, East Java, 60285, Indonesia
| | - Wihasto Suryaningtyas
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr, Soetomo General Academic Hospital, Jalan Mayjend Prof. Dr. Moestopo No. 6-8, Mojo, Gubeng, Surabaya, East Java, 60285, Indonesia
| | - Muhammad Arifin Parenrengi
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr, Soetomo General Academic Hospital, Jalan Mayjend Prof. Dr. Moestopo No. 6-8, Mojo, Gubeng, Surabaya, East Java, 60285, Indonesia.
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Abstract
OBJECTIVES Many serious or life-threatening neurologic conditions are first diagnosed during the fetal period, often following a routine ultrasound or sonographic evaluation after an abnormal aneuploidy screen. Such conditions represent a worrisome or unexpected finding for expectant parents, making the perinatal period a critical time point to engage and empower families encountering complex neurologic clinical scenarios. This review covers the role of perinatal palliative care in these settings. STUDY DESIGN This study is a topical review RESULTS: The prenatal identification of structural abnormalities of the brain or spinal cord, radiographic signs of hemorrhage or ischemic injury, or evidence of genetic or metabolic conditions should prompt involvement of a fetal palliative care team. The inherent prognostic uncertainty is challenging for prenatally diagnosed neurologic conditions which have difficult to predict short and long-term outcomes. While many of these conditions lead to the birth of an infant with neurodevelopmental challenges, few result in in utero demise. Palliative care beginning in the perinatal period provides an additional layer of support for families navigating complex decision-making during their pregnancy and provides continuity of care into the newborn period. Palliative care principles can help guide discussions around genetic and other diagnostic testing, fetal surgery, and birth planning. A multidisciplinary team can help support families with decision-making and through bereavement care in the setting of fetal or neonatal death. CONCLUSION Early palliative care team involvement can provide a more holistic approach to counseling, facilitate planning, and ensure that a family's goals and wishes are acknowledged throughout an infant's care trajectory. KEY POINTS · Many serious or life-threatening neurologic conditions are diagnosed during the fetal period.. · Palliative care principles should be incorporated in the fetal period for affected patients.. · Palliative care clinicians can aid parents and clinicians in shared decision-making.. · Palliative care principles should be employed by all care providers in relevant cases..
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Affiliation(s)
- Sharla Rent
- Division of Neonatology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
| | - Monica E. Lemmon
- Division of Neonatology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
- Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina
| | - Sarah Ellestad
- Department of Obstetrics and Gynecology, Maternal Fetal Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Margarita Bidegain
- Division of Neonatology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
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14
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Bian Y, Hahn H, Uhmann A. The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis. Front Endocrinol (Lausanne) 2023; 14:1219018. [PMID: 37476499 PMCID: PMC10355329 DOI: 10.3389/fendo.2023.1219018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 06/19/2023] [Indexed: 07/22/2023] Open
Abstract
Hedgehog signaling plays pivotal roles in embryonic development, adult homeostasis and tumorigenesis. However, its engagement in the pituitary gland has been long underestimated although Hedgehog signaling and pituitary embryogenic development are closely linked. Thus, deregulation of this signaling pathway during pituitary development results in malformation of the gland. Research of the last years further implicates a regulatory role of Hedgehog signaling in the function of the adult pituitary, because its activity is also interlinked with homeostasis, hormone production, and most likely also formation of neoplasms of the gland. The fact that this pathway can be efficiently targeted by validated therapeutic strategies makes it a promising candidate for treating pituitary diseases. We here summarize the current knowledge about the importance of Hedgehog signaling during pituitary development and review recent data that highlight the impact of Hedgehog signaling in the healthy and the diseased adult pituitary gland.
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Nonkulovski D, Sofijanova A, Spasovska T, Gorjan M, Muaremoska-Kanzoska L, Arsov T. Semilobar Holoprosencephaly Caused by a Novel and De Novo ZIC2 Pathogenic Variant. Balkan J Med Genet 2023; 25:71-76. [PMID: 37265970 PMCID: PMC10230831 DOI: 10.2478/bjmg-2022-0017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023] Open
Abstract
Holoprosencephaly (HPE) is the most common embryonic forebrain developmental anomaly. It involves incomplete or absent division of the prosencephalon into two distinct cerebral hemispheres during the early stages of organogenesis. HPE is etiologically heterogeneous, and its clinical presentation is very variable. We report a case of a 7 month old female infant, diagnosed with non-syndromic semilobar holoprosencephaly, caused by a novel, de novo pathogenic variant in ZIC2 - one of the most commonly mutated genes in non-syndromic HPE coding for the ZIC2 transcription factor. The patient presented with microcephaly, mild facial dysmorphic features, central hypotonia and spasticity on all four extremities. Ultrasound imaging demonstrated the absence of septum pellucidum, semilobar fusion of the hemispheres and mega cisterna magna and brain MRI with confirmed the diagnosis of HPE. Early diagnosis and management are important for the prevention and treatment of complications associated with this condition.
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Affiliation(s)
- D Nonkulovski
- Department of Pediatric Neurology, University Children’s Hospital in Skopje, Skopje, North Macedonia
| | - A Sofijanova
- Department of Pediatric Neurology, University Children’s Hospital in Skopje, Skopje, North Macedonia
| | - T Spasovska
- Department of Pediatric Neurology, University Children’s Hospital in Skopje, Skopje, North Macedonia
| | - Milanovski Gorjan
- Institute of Immunobiology and Human Genetics, Faculty of Medicine, University Sts Cyril and Methodius, Skopje, North Macedonia
| | - Lj Muaremoska-Kanzoska
- Department of Pediatric Neurology, University Children’s Hospital in Skopje, Skopje, North Macedonia
| | - T Arsov
- Institute of Immunobiology and Human Genetics, Faculty of Medicine, University Sts Cyril and Methodius, Skopje, North Macedonia
- Faculty of Medical Sciences, University Goce Delchev in Shtip, Shtip, North Macedonia
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16
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Aubert-Mucca M, Huber C, Baujat G, Michot C, Zarhrate M, Bras M, Boutaud L, Malan V, Attie-Bitach T, Cormier-Daire V. Ellis-Van Creveld Syndrome: Clinical and Molecular Analysis of 50 Individuals. J Med Genet 2023; 60:337-345. [PMID: 35927022 DOI: 10.1136/jmg-2022-108435] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 07/09/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The EVC and EVC2 genes are the major genes causative of EVC syndrome. However, an increased number of genes involved in the ciliopathy complex have been identified in EVC syndrome, leading to a better understanding of its physiopathology, namely, WDR35, GLI1, DYNC2LI1, PRKACA, PRKACB and SMO. They all code for proteins located in the primary cilia, playing a key role in signal transduction of the Hedgehog pathways. METHODS The aim of this study was the analysis of 50 clinically identified EVC cases from 45 families to further define the phenotype and molecular bases of EVC. RESULTS Our detection rate in the cohort of 45 families was of 91.11%, with variants identified in EVC/EVC2 (77.8%), DYNC2H1 (6.7%), DYNC2LI1 (2.2%), SMO (2.2%) or PRKACB (2.2%). No distinctive feature was remarkable of a specific genotype-phenotype correlation. Interestingly, we identified a high proportion of heterozygous deletions in EVC/EVC2 of variable sizes (26.92%), mostly inherited from the mother, and probably resulting from recombinations involving Alu sequences. CONCLUSION We confirmed that EVC and EVC2 are the major genes involved in the EVC phenotype and highlighted the high prevalence of previously unreported CNVs (Copy Number Variation).
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Affiliation(s)
- Marion Aubert-Mucca
- Centre de Référence des Maladies Osseuses Constitutionnelles, Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, Paris, France
| | - Céline Huber
- Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Genevieve Baujat
- Centre de Référence des Maladies Osseuses Constitutionnelles, Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, Paris, France
- Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Caroline Michot
- Centre de Référence des Maladies Osseuses Constitutionnelles, Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, Paris, France
- Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Mohammed Zarhrate
- Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Imagine Institute, Paris, France
| | - Marc Bras
- Bioinformatics Platform, Imagine Institute, Paris, France
| | - Lucile Boutaud
- Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
- Service de Médecine Génomique des Maladies Rares, Hopital Universitaire Necker-Enfants Malades, Paris, France
| | - Valérie Malan
- Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
- Service de Médecine Génomique des Maladies Rares, Hopital Universitaire Necker-Enfants Malades, Paris, France
| | - Tania Attie-Bitach
- Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
- Service de Médecine Génomique des Maladies Rares, Hopital Universitaire Necker-Enfants Malades, Paris, France
| | | | - Valerie Cormier-Daire
- Centre de Référence des Maladies Osseuses Constitutionnelles, Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, Paris, France
- Université Paris Cité, INSERM UMR 1163, Imagine Institute, Paris, France
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17
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Malta M, AlMutiri R, Martin CS, Srour M. Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management. CHILDREN 2023; 10:children10040647. [PMID: 37189898 DOI: 10.3390/children10040647] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/21/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
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.
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18
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Garne E, Tan J, Damkjaer M, Ballardini E, Cavero-Carbonell C, Coi A, Garcia-Villodre L, Gissler M, Given J, Heino A, Jordan S, Limb E, Loane M, Neville AJ, Pierini A, Rissmann A, Tucker D, Urhoj SK, Morris J. Hospital Length of Stay and Surgery among European Children with Rare Structural Congenital Anomalies-A Population-Based Data Linkage Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:4387. [PMID: 36901396 PMCID: PMC10002318 DOI: 10.3390/ijerph20054387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 06/18/2023]
Abstract
Little is known about morbidity for children with rare structural congenital anomalies. This European, population-based data-linkage cohort study analysed data on hospitalisations and surgical procedures for 5948 children born 1995-2014 with 18 rare structural congenital anomalies from nine EUROCAT registries in five countries. In the first year of life, the median length of stay (LOS) ranged from 3.5 days (anotia) to 53.8 days (atresia of bile ducts). Generally, children with gastrointestinal anomalies, bladder anomalies and Prune-Belly had the longest LOS. At ages 1-4, the median LOS per year was ≤3 days for most anomalies. The proportion of children having surgery before age 5 years ranged from 40% to 100%. The median number of surgical procedures for those under 5 years was two or more for 14 of the 18 anomalies and the highest for children with Prune-Belly at 7.4 (95% CI 2.5-12.3). The median age at first surgery for children with atresia of bile ducts was 8.4 weeks (95% CI 7.6-9.2) which is older than international recommendations. Results from the subset of registries with data up to 10 years of age showed that the need for hospitalisations and surgery continued. The burden of disease in early childhood is high for children with rare structural congenital anomalies.
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Affiliation(s)
- Ester Garne
- Department of Paediatrics and Adolescent Medicine, Lillebaelt Hospital, University Hospital of Southern Denmark, 6000 Kolding, Denmark
| | - Joachim Tan
- Population Health Research Institute, St George’s University of London, London SW17 0RE, UK
| | - Mads Damkjaer
- Department of Paediatrics and Adolescent Medicine, Lillebaelt Hospital, University Hospital of Southern Denmark, 6000 Kolding, Denmark
- Department of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark
| | - Elisa Ballardini
- IMER Registry, Centre for Clinical and Epidemiological Research, University of Ferrara and Azienda Ospedaliero Universitario di Ferrara, 44121 Ferrara, Italy
| | - Clara Cavero-Carbonell
- Rare Diseases Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, 46020 Valencia, Spain
| | - Alessio Coi
- Unit of Epidemiology of Rare Diseases and Congenital Anomalies, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
| | - Laura Garcia-Villodre
- Rare Diseases Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, 46020 Valencia, Spain
| | - Mika Gissler
- THL Finnish Institute for Health and Welfare, Department of Knowledge Brokers, 00271 Helsinki, Finland
- Karolinska Institutet, Department of Molecular Medicine and Surgery, 171 77 Stockholm, Sweden
| | - Joanne Given
- Faculty of Life and Health Sciences, Ulster University, Belfast BT15 1AP, UK
| | - Anna Heino
- THL Finnish Institute for Health and Welfare, Department of Knowledge Brokers, 00271 Helsinki, Finland
| | - Sue Jordan
- Faculty of Medicine, Health & Life Sciences, Swansea University, Swansea SA2 8PP, UK
| | - Elizabeth Limb
- Population Health Research Institute, St George’s University of London, London SW17 0RE, UK
| | - Maria Loane
- Faculty of Life and Health Sciences, Ulster University, Belfast BT15 1AP, UK
| | - Amanda J. Neville
- IMER Registry, Centre for Clinical and Epidemiological Research, University of Ferrara and Azienda Ospedaliero Universitario di Ferrara, 44121 Ferrara, Italy
| | - Anna Pierini
- Unit of Epidemiology of Rare Diseases and Congenital Anomalies, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
| | - Anke Rissmann
- Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty, Otto-von-Guericke-University Magdeburg, 39106 Magdeburg, Germany
| | - David Tucker
- Congenital Anomaly Register & Information Service for Wales (CARIS) Public Health Knowledge and Research, Public Health Wales, Swansea SA6 8DP, UK
| | - Stine Kjaer Urhoj
- Department of Paediatrics and Adolescent Medicine, Lillebaelt Hospital, University Hospital of Southern Denmark, 6000 Kolding, Denmark
- Section of Epidemiology, Department of Public Health, University of Copenhagen, 1353 Copenhagen, Denmark
| | - Joan Morris
- Population Health Research Institute, St George’s University of London, London SW17 0RE, UK
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Meryem B, Amine N, Houssein O, Siham EH, Nazik A, Latifa C. Antenatal and Postnatal Diagnosis of Semilobar Holoprosencephaly: Two Case Reports. Glob Pediatr Health 2023; 10:2333794X231156037. [PMID: 36814536 PMCID: PMC9940162 DOI: 10.1177/2333794x231156037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/12/2023] [Accepted: 01/22/2023] [Indexed: 02/19/2023] Open
Abstract
Holoprosencephaly (HPE) is a rare birth defect that occurs during the first few weeks of pregnancy. It results from a disturbance in the usual signaling pathways required for separation of the embryonic prosencephalon into 2 separate cerebral hemispheres. Classically four subtypes have been recognized: alobar, semilobar, lobar, and middle interhemispheric holoprosencephaly. The cause of HPE is unknown but may include genetic disorders. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip. We report 2 cases of semilobar holoprosencephaly, diagnosed in Children's Hospital of Rabat: the first one was a fetus diagnosed by ultrasonogram at 25 weeks of gestation. The second one was a newborn at 15 days of life diagnosed by brain scan.
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Affiliation(s)
- Benmoussa Meryem
- Mohammed V University, Rabat, Morocco,Benmoussa Meryem, Children’s Hospital of Rabat, Al Irfane, Rabat 10110, Morocco.
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Udaykumar N, Zaidi MAA, Rai A, Sen J. CNKSR2, a downstream mediator of retinoic acid signaling, modulates the Ras/Raf/MEK pathway to regulate patterning and invagination of the chick forebrain roof plate. Development 2023; 150:286897. [PMID: 36734326 DOI: 10.1242/dev.200857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 01/03/2023] [Indexed: 02/04/2023]
Abstract
During embryonic development, the forebrain roof plate undergoes invagination, leading to separation of the cerebral hemispheres. Any defects in this process, in humans, lead to middle interhemispheric holoprosencephaly (MIH-HPE). In this study, we have identified a previously unreported downstream mediator of retinoic acid (RA) signaling, CNKSR2, which is expressed in the forebrain roof plate in the chick embryo. Knockdown of CNKSR2 affects invagination, cell proliferation and patterning of the roof plate, similar to the phenotypes observed upon inhibition of RA signaling. We further demonstrate that CNKSR2 functions by modulating the Ras/Raf/MEK signaling. This appears to be crucial for patterning of the forebrain roof plate and its subsequent invagination, leading to the formation of the cerebral hemispheres. Thus, a set of novel molecular players have been identified that regulate the morphogenesis of the avian forebrain.
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Affiliation(s)
- Niveda Udaykumar
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016 Uttar Pradesh, India
| | - Mohd Ali Abbas Zaidi
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016 Uttar Pradesh, India
| | - Aishwarya Rai
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016 Uttar Pradesh, India
| | - Jonaki Sen
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016 Uttar Pradesh, India
- Mehta Family Center for Engineering in Medicine (MFCEM), Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
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21
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Rare manifestations of alobar holoprosencephaly and the potential causes: a report of two cases. Ann Med Surg (Lond) 2023; 85:252-256. [PMID: 36845789 PMCID: PMC9949831 DOI: 10.1097/ms9.0000000000000176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/24/2022] [Indexed: 02/28/2023] Open
Abstract
Holoprosencephaly is a rare and possibly fatal neural tube defect represented by complete or partial forebrain noncleavage. It can be classified into four types: alobar, semilobar, lobar, and middle interhemispheric fusion variant. It is usually diagnosed through prenatal ultrasound or after birth by visually observing the morphological abnormalities and/or through neurological screening. Potential causes include maternal diabetes, alcoholism, infections during pregnancy, drugs, and genetic causes. Case presentation Herein, we report two cases of holoprosencephaly's rarest manifestations, albeit cebocephaly in the first case, and cyclopia with a probocis in the second. Cebocephaly, (hypotelorism with a single nostril and a blind-ended nose) was present in the first case; a Syrian newborn girl for a 41-year-old mother who works in collecting Capparis spinosa, and cyclopia with skull vault absence and posterior encephalocele in the second case; a Syrian newborn girl for a 26-year-old mother, the parents here where second-degree relatives. Conclusions Early diagnosis through ultrasound is preferred in such cases and management options should be assessed and discussed with the parents due to poor prognosis. Adherence to pregnancy follow-up programs is essential to detect malformations and disorders as early as possible, especially when risk factors exist. Also, this paper may suggest a potential correlation between C. spinosa and holoprosencephaly. Therefore, we suggest that more research should be done.
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22
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Kollu R, Kotamraju S, Uligada S, Varunya M. Fetal Cyclopia, Proboscis, Holoprosencephaly, and Polydactyly: A Case Report With Review of Literature. Cureus 2023; 15:e34576. [PMID: 36883090 PMCID: PMC9985698 DOI: 10.7759/cureus.34576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2023] [Indexed: 02/05/2023] Open
Abstract
We present a case of holoprosencephaly (HPE) with cyclopia and proboscis. The mother was a 35-year-old, G1P1 with no known comorbid conditions, not in a consanguineous marriage, and with no history of illicit drug use. On a routine antenatal ultrasound scan, features of alobar HPE, proboscis, and other anomalies were identified. The mother was counseled about the condition and as per their consent, the pregnancy was terminated. After labor induction, she gave birth to a female neonate weighing 1,000 g. The newborn's Apgar score could not be calculated. In the initial physical examination, an eye and a 3.5-cm proboscis were seen in the middle of the forehead. The newborn had no nose, and the outer ears were normal. On postmortem examination, alobar HPE, polydactyly, ventricular septal defect, and myelomeningocele were confirmed. This case report highlights the importance of attention to these details during antenatal scans for early detection in order to reduce the maternal and neonatal health burden. The pictures presented in this article were taken after obtaining parental consent.
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Affiliation(s)
- Raja Kollu
- Radiodiagnosis, Narayana Mallareddy hospital , Malla Reddy Medical College for Women, Hyderabad, IND
| | - Sai Kotamraju
- Radiodiagnosis, Malla Reddy Medical College for Women, Hyderabad, IND
| | - Seema Uligada
- Radiology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, IND
| | - Mary Varunya
- Radiology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, IND
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23
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Bando H, Brinkmeier ML, Castinetti F, Fang Q, Lee MS, Saveanu A, Albarel F, Dupuis C, Brue T, Camper SA. Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man. Hum Mol Genet 2023; 32:367-385. [PMID: 35951005 PMCID: PMC9851746 DOI: 10.1093/hmg/ddac192] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/22/2022] [Accepted: 08/09/2022] [Indexed: 01/24/2023] Open
Abstract
Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss-of-function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/-; Pou1f1+/dw double heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked the development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for the activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.
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Affiliation(s)
- Hironori Bando
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | | | - Frederic Castinetti
- Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille, Maladies Rares (MarMaRa), Marseille, France
| | - Qing Fang
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Mi-Sun Lee
- Michigan Neuroscience Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA
| | - Alexandru Saveanu
- Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille, Maladies Rares (MarMaRa), Marseille, France
| | - Frédérique Albarel
- Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille, Maladies Rares (MarMaRa), Marseille, France
| | - Clémentine Dupuis
- Department of Pediatrics, Centre Hospitalier Universitaire de Grenoble-Alpes, site Nord, Hôpital Couple Enfants, Grenoble, France
| | - Thierry Brue
- Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille, Maladies Rares (MarMaRa), Marseille, France
| | - Sally A Camper
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
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24
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Douceau S, Deutsch Guerrero T, Ferent J. Establishing Hedgehog Gradients during Neural Development. Cells 2023; 12:225. [PMID: 36672161 PMCID: PMC9856818 DOI: 10.3390/cells12020225] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 01/07/2023] Open
Abstract
A morphogen is a signaling molecule that induces specific cellular responses depending on its local concentration. The concept of morphogenic gradients has been a central paradigm of developmental biology for decades. Sonic Hedgehog (Shh) is one of the most important morphogens that displays pleiotropic functions during embryonic development, ranging from neuronal patterning to axon guidance. It is commonly accepted that Shh is distributed in a gradient in several tissues from different origins during development; however, how these gradients are formed and maintained at the cellular and molecular levels is still the center of a great deal of research. In this review, we first explored all of the different sources of Shh during the development of the nervous system. Then, we detailed how these sources can distribute Shh in the surrounding tissues via a variety of mechanisms. Finally, we addressed how disrupting Shh distribution and gradients can induce severe neurodevelopmental disorders and cancers. Although the concept of gradient has been central in the field of neurodevelopment since the fifties, we also describe how contemporary leading-edge techniques, such as organoids, can revisit this classical model.
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Affiliation(s)
- Sara Douceau
- INSERM UMR-S 1270, F-75005 Paris, France
- Institut du Fer à Moulin, INSERM, Sorbonne Univeristy, F-75005 Paris, France
| | - Tanya Deutsch Guerrero
- INSERM UMR-S 1270, F-75005 Paris, France
- Institut du Fer à Moulin, INSERM, Sorbonne Univeristy, F-75005 Paris, France
| | - Julien Ferent
- INSERM UMR-S 1270, F-75005 Paris, France
- Institut du Fer à Moulin, INSERM, Sorbonne Univeristy, F-75005 Paris, France
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25
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Mazengia Andualem A, Gebeyehu Shiferaw F. Aventriculy with Holoprosencephaly and Chiari 3 Malformation: A Rare Case Report from Resource limited set up; Ethiopian Report. INTERDISCIPLINARY NEUROSURGERY 2023. [DOI: 10.1016/j.inat.2023.101730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
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26
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Doyle-Meyers L, Dong C, Xu EQ, Vallender EJ, Blair RV, Didier P, He F, Wang X. Cyclopia in a newborn rhesus macaque born to a dam infected with SIV and receiving antiretroviral therapy during pregnancy. CURRENT TRENDS IN IMMUNOLOGY 2023; 24:91-103. [PMID: 39640529 PMCID: PMC11620240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Cyclopia, a rare genetic anomaly and birth defect, was recently observed in our nonhuman primate study. A newborn rhesus macaque, delivered via cesarean section, exhibited facial abnormalities, including a single eye in the middle of the forehead. This macaque was born to a dam who had been inoculated with SIV in the first trimester and received antiretroviral therapy (ART) in the early third trimester of pregnancy. Prenatal ultrasound detected fetal defects, including the fusion of the thalami and absence of third ventricle during the third trimester of fetal development. Remarkably, the newborn macaque was diagnosed with severe alobar holoprosencephaly, characterized by a single eye located on the facial midline and proboscises positioned above and below the eye. This condition was accompanied by the absence of a nose, mouth, mandible, maxilla, nasal and oral cavities, tongue, as well as the esophagus. Subsequent genetic screening identified a significant down-regulation of craniofacial development-associated genes, although genetic mutations in the sonic hedgehog gene (SHH) were not present. As the fetal defects were identified prior to the initiation of antiretroviral therapy, it is possible that other environmental factors may have contributed to the development of cyclopia in this rhesus case. However, the etiology of this congenital HPE case remains essentially unknown.
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Affiliation(s)
- Lara Doyle-Meyers
- Division of Veterinary Medicine, Tulane National Primate
Research Center, 18703 Three Rivers Road, Covington, LA, 70433, USA
| | - Chunming Dong
- Department of Cell and Molecular Biology, School of Science
and Engineering, Tulane University, 6823 St. Charles Avenue, New Orleans, LA, 70118,
USA
| | - Eddie Qidi Xu
- Department of Cell and Molecular Biology, School of Science
and Engineering, Tulane University, 6823 St. Charles Avenue, New Orleans, LA, 70118,
USA
- Tulane University School of Public Health and Tropical
Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA
| | - Eric J. Vallender
- Division of Veterinary Medicine, Tulane National Primate
Research Center, 18703 Three Rivers Road, Covington, LA, 70433, USA
- Department of Psychiatry and Human Behavior, Division of
Neurobiology and Behavior Research, University of Mississippi Medical Center,
Jackson, MS, 39216, USA
| | - Robert V. Blair
- Pathology & Laboratory Medicine, Tulane University
School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
- Division of Comparative Pathology, Tulane National Primate
Research Center, 18703 Three Rivers Road, Covington, LA, 70433, USA
| | - Peter Didier
- Pathology & Laboratory Medicine, Tulane University
School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
- Division of Comparative Pathology, Tulane National Primate
Research Center, 18703 Three Rivers Road, Covington, LA, 70433, USA
| | - Fenglei He
- Department of Cell and Molecular Biology, School of Science
and Engineering, Tulane University, 6823 St. Charles Avenue, New Orleans, LA, 70118,
USA
| | - Xiaolei Wang
- Pathology & Laboratory Medicine, Tulane University
School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
- Division of Comparative Pathology, Tulane National Primate
Research Center, 18703 Three Rivers Road, Covington, LA, 70433, USA
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27
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Schlosser ADS, Costa GJC, Silva HSD, Mello JLMD, Gomes LDO, Onoyama MMO, Costa TMC. Holoprosencephaly in Patau Syndrome. REVISTA PAULISTA DE PEDIATRIA : ORGAO OFICIAL DA SOCIEDADE DE PEDIATRIA DE SAO PAULO 2023; 41:e2022027. [PMID: 36921175 PMCID: PMC10013991 DOI: 10.1590/1984-0462/2023/41/2022027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/26/2022] [Indexed: 03/18/2023]
Abstract
OBJECTIVE To evaluate radiological (gestational and perinatal) and neonatal signs of patients with Patau syndrome and semilobar holoprosencephaly, as well as to report the association of both pathologies. CASE DESCRIPTION This case report is about a female infant, born at term with trisomy of the chromosome 13 and semilobar holoprosencephaly, with thalamic fusion and a single cerebral ventricle, in addition to several other changes that worsened the patient's prognosis. COMMENTS Chromosome 13 trisomy is a genetic alteration that leads to the symptoms that determines Patau syndrome. In this syndrome, cardiovascular, urogenital, central nervous system, facial structure and intellectual impairment are common, in addition to problems in limb formation, such as decreased humerus and femur length, polydactyly, hypotelorism and low ear implantation. It is estimated, however, that holoprosencephaly is present in only 24 to 45% of the patients with trisomy 13.
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28
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Ece B, Aydın S, Kantarci M. Antenatal imaging: A pictorial review. World J Clin Cases 2022; 10:12854-12874. [PMID: 36569012 PMCID: PMC9782949 DOI: 10.12998/wjcc.v10.i35.12854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/17/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Today, in parallel with the use of imaging modalities increases in all fields, the use of imaging methods in pregnant women is increasing. Imaging has become an integral component of routine pregnancy follow-up. Imaging provides parents with an early opportunity to learn about the current situation, including prenatal detection of anomalies or diseases, etiology, prognosis, and the availability of prenatal or postnatal treatments. Various imaging modalities, especially ultrasonography, are frequently used for imaging both maternal and fetal imaging. The goal of this review was to address imaging modalities in terms of usefulness and safety, as well as to provide demonstrative examples for disorders. And this review provides current information on selecting a safe imaging modality to evaluate the pregnant and the fetus, the safety of contrast medium use, and summarizes major pathological situations with demonstrative sonographic images to assist radiologists and obstetricians in everyday practice.
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Affiliation(s)
- Bunyamin Ece
- Department of Radiology, Kastamonu University, Kastamonu 37150, Turkey
| | - Sonay Aydın
- Department of Radiology, Erzincan University, Erzincan 24142, Turkey
| | - Mecit Kantarci
- Department of Radiology, Erzincan University, Erzincan 24142, Turkey
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29
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Monsalve T, Londoño OC, Pais-Brito JL, Buikstra J. Ecce Homo: Moving past labels to lives. INTERNATIONAL JOURNAL OF PALEOPATHOLOGY 2022; 39:85-92. [PMID: 36332400 DOI: 10.1016/j.ijpp.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/26/2022] [Accepted: 10/04/2022] [Indexed: 06/16/2023]
Abstract
OBJECTIVES We report a contemporary individual who died with advanced holoprosencephaly (HPE) to encourage recognition of rare diseases (RDs), especially congenital conditions in archaeological samples. We also explore the range of conditions associated with hydrocephalus in support of nuanced interpretations of this disease. MATERIALS The skeleton of a 17-year-old male who died with clinically diagnosed HPE, along with an age and sex matched comparative sample of 6 individuals who suffered accidental death and who were normal. METHODS We observed and measured all remains using standard osteological methods. The clinical records for Ecce Homo were scrutinized; his family was interviewed, and his skull was X-rayed. RESULTS The morphology and morphometry of Ecce Homo's skeleton display irregularities along the cranial midline and the postcranial skeleton consistent with anomalies derived from HPE as well as related congenital disorders and physical anomalies. CONCLUSIONS We have reported HPE here and developed a differential diagnosis with closely related conditions. Likewise we relate the information generated in the clinical history and interviews with the family of Ecce Homo to facilitate an understanding of the social context. SIGNIFICANCE This case is exceptional in providing information from the life context of a contemporary individual who suffered from a rare disease (HPE), with skeletal remains could be studied extensively. The differential diagnosis is useful in identifying HPE and other closely related conditions. LIMITATIONS This is a single example with clinical intervention. SUGGESTIONS FOR FURTHER RESEARCH Future osteological research should occur on other cases of HPE; molecular studies may offer further clarity.
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Affiliation(s)
- Timisay Monsalve
- Departamento de Antropología-FCSH, Universidad de Antioquia, Medellín, Colombia.
| | - Olga Cecilia Londoño
- Departamento de Antropología-FCSH, Universidad de Antioquia, Medellín, Colombia.
| | - Jose Luis Pais-Brito
- Orthopaedic Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Canary Islands, Spain; University of La Laguna, Tenerife, Canary Islands, Spain.
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30
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Fleury V. Dynamics of early stages of nose morphogenesis. THE EUROPEAN PHYSICAL JOURNAL. E, SOFT MATTER 2022; 45:93. [PMID: 36401057 PMCID: PMC9674774 DOI: 10.1140/epje/s10189-022-00245-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 11/03/2022] [Indexed: 06/16/2023]
Abstract
The formation of sensory organs is an important developmental and evolutionary question. In the context of regenerative medicine also, it is important to know as accurately as possible how sensory organs form. The formation of ears, eyes or nose stems presumably from tissue thickenings called placodes Graham and Shimeld (J Anat 222(1):32-40, 2013), Horie et al. (Nature 560:228-232, 2018) which become these organs after processes termed inductions. However, the origin of the placodes, the mechanism of induction and the overall face organization are not understood. Recently, it has been suggested that there is a physical principle to face organization. Indeed, it has been shown that there exists a pattern of rings and rays in the early blastula which defines the position of face landmarks, especially the ears and eyes Fleury et al. (Second order division in sectors as a prepattern for sensory organs in vertebrate development, 2021), Fleury and Abourachid (Eu Phys J E 45:31, 2022). Tensions in the sectors defined by the intersections of the said rings and rays create the actual face features. I report here that a similar situation exists for the nose. This explains the robustness of face formation in the chordates phylum. By studying nasal pit formation in the chicken embryo by time-lapse (T-L) video microscopy, I show that the nasal placode originates in a narrow sector deformed by tension forces following the biaxial pattern of rings and rays mentioned above. Cells align in the pattern and exert organized forces. Further contractions of the pattern contribute to inducing the nasal pit. The observation of the early pre-pattern of lines which locks the facial features explains readily a number of facts regarding sensory organs. Especially the existence of a lacrimal canal between the eye and the nose Lefevre and Freitag (Semin Ophthalmo l 27(5-6):175-86, 2012), or of a slit connecting the nose to the mouth, the correlation between nose, mouth and eye morphogenesis Dubourg et al. (J Rare Dis 2(8), 2007), the presence of shallow valleys on the nasal and optic vesicles, the medio-lateral asymmetry of nostrils with often a bent slit Liu et al. (PLoS ONE 12: e0181928, 2017), the uneven number of nostrils in many fish Cox (J R Soc Interf 5(23):575-593, 2008) and possibly the transition between agnatha and gnathostomes Gai and Zhu (Chinese Sci Bull 57(31), 2012): all appear under this light, geometrically straightforward. The nasal pit forms in a sector of tissue which was present on the blastodic (early embryonic stage), and which is projected onto the nasal vesicle during neurulation. The nasal pit forms along a hairpin of tissue. The top part of the hairpin forms the nares, and the bottom part a groove often visible in many animals.
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Affiliation(s)
- Vincent Fleury
- Laboratoire Matière et Systèmes Complexes, Université de Paris Cité/CNRS UMR 7057, 10 Rue Alice Domont et Léonie Duquet, 75013, Paris, France.
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31
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Transcriptional Profile of the Developing Subthalamic Nucleus. eNeuro 2022; 9:9/5/ENEURO.0193-22.2022. [PMID: 36257692 PMCID: PMC9581575 DOI: 10.1523/eneuro.0193-22.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 12/15/2022] Open
Abstract
The subthalamic nucleus (STN) is a small, excitatory nucleus that regulates the output of basal ganglia motor circuits. The functions of the STN and its role in the pathophysiology of Parkinson's disease are now well established. However, some basic characteristics like the developmental origin and molecular phenotype of neuronal subpopulations are still being debated. The classical model of forebrain development attributed the origin of STN within the diencephalon. Recent studies of gene expression patterns exposed shortcomings of the classical model. To accommodate these findings, the prosomeric model was developed. In this concept, STN develops within the hypothalamic primordium, which is no longer a part of the diencephalic primordium. This concept is further supported by the expression patterns of many transcription factors. It is interesting to note that many transcription factors involved in the development of the STN are also involved in the pathogenesis of neurodevelopmental disorders. Thus, the study of neurodevelopmental disorders could provide us with valuable information on the roles of these transcription factors in the development and maintenance of STN phenotype. In this review, we summarize historical theories about the developmental origin of the STN and interpret the gene expression data within the prosomeric conceptual framework. Finally, we discuss the importance of neurodevelopmental disorders for the development of the STN and its potential role in the pathophysiology of neurodevelopmental disorders.
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32
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Bihamba Bira L, Sikakulya FK, Mumbere M, Mathe J. Synophtalmia on a newborn. SAGE Open Med Case Rep 2022; 10:2050313X221131651. [PMID: 36267337 PMCID: PMC9577069 DOI: 10.1177/2050313x221131651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Synophtalmia or cyclopia is a rare presentation of alobar holoprosencephaly. Cases which have been reported are stillborn or dead in post-delivery period. We are presenting a 3000-g live full-term newborn girl delivered by caesarean section with a well-marked cyclopia, but who died 30 min post-delivery. The case did not present with other abnormalities. The literature showed that genetic disorders are associated with cyclopia. A prenatal anomaly scan can help in the early detection of the condition and timely termination of the pregnancy can be conducted.
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Affiliation(s)
- Laetitia Bihamba Bira
- Hopital de Mutwanga, Territoire de
Beni, Nord-Kivu, Democratic Republic of the Congo
| | - Franck Katembo Sikakulya
- Faculty of Medicine, Université
Catholique du Graben, Butembo, Democratic Republic of the Congo,Department of Surgery, Faculty of
Clinical Medicine and Dentistry, Kampala International University Western Campus,
Ishaka-Bushenyi, Uganda,Franck Katembo Sikakulya, Department of
Surgery, Faculty of Clinical Medicine and Dentistry, Kampala International
University Western Campus, Ishaka-Bushenyi, PO.Box 70, Uganda.
| | - Mupenzi Mumbere
- Faculty of Medicine, Université
Catholique du Graben, Butembo, Democratic Republic of the Congo
| | - Jeff Mathe
- Faculty of Medicine, Université
Catholique du Graben, Butembo, Democratic Republic of the Congo
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33
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Cospain A, Faoucher M, Cauchois A, Carre W, Quelin C, Dubourg C. Fetal Description of the Pancreatic Agenesis and Holoprosencephaly Syndrome Associated to a Specific CNOT1 Variant. Pediatr Dev Pathol 2022; 25:548-552. [PMID: 35481434 DOI: 10.1177/10935266221095305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Holoprosencephaly (HPE) is a clinically and genetically heterogeneous disease, which can be associated with various prenatal comorbidities not always detectable on prenatal ultrasound. We report on the case of a foetus carrying a semi-lobar HPE diagnosed at ultrasound, for which a fetal autopsy and a whole exome sequencing were performed following a medical termination of pregnancy. Neuropathological examination confirmed the semi-lobar HPE and general autopsy disclosed a total pancreas agenesis. Whole exome sequencing found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo in the foetus. The same variant was previously reported in 5 unrelated children. All individuals had HPE, and 4 out of 5 presented endo- and exocrine pancreatic insufficiency or total pancreas agenesis. CNOT1 encodes a subunit of the CCRN4-NOT complex, expressed at the early stage of embryonic development. This report is the first fetal description of the phenotype associating HPE and pancreatic agenesis linked to the recurrent CNOT1 missense c.1603C>T, p.(Arg535Cys). This finding strengthens the hypothesis of a specific recurrent variant associated with a particular phenotype of HPE and pancreas agenesis. The fetal autopsy that revealed the pancreas agenesis was crucial in guiding the genetic diagnosis and enabling accurate genetic counselling.
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Affiliation(s)
- Auriane Cospain
- Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, 36684CHU Rennes, Rennes, France.,Service de Génétique Moléculaire et Génomique, 36684CHU, Rennes, France
| | - Marie Faoucher
- Service de Génétique Moléculaire et Génomique, 36684CHU, Rennes, France.,CNRS, IGDR, UMR 6290, Univ Rennes, Rennes, France
| | - Aurélie Cauchois
- Anatomie et cytologie pathologiques, CHU de Rennes, Rennes, France
| | - Wilfrid Carre
- Service de Génétique Moléculaire et Génomique, 36684CHU, Rennes, France.,CNRS, IGDR, UMR 6290, Univ Rennes, Rennes, France
| | - Chloé Quelin
- Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, 36684CHU Rennes, Rennes, France.,Anatomie et cytologie pathologiques, CHU de Rennes, Rennes, France
| | - Christèle Dubourg
- Service de Génétique Moléculaire et Génomique, 36684CHU, Rennes, France.,CNRS, IGDR, UMR 6290, Univ Rennes, Rennes, France
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Watanabe T, Yokoyama A, Shimizu S, Bessho K. A plunging ranula in a child with holoprosencephaly: a case of unique pathophysiology and difficult airway management. J Korean Assoc Oral Maxillofac Surg 2022; 48:232-236. [PMID: 36043254 PMCID: PMC9433862 DOI: 10.5125/jkaoms.2022.48.4.232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/13/2021] [Indexed: 11/18/2022] Open
Abstract
A ranula is a pseudocyst that originates from the sublingual gland after trauma. Acute cases of ranulas that progress rapidly and cause respiratory distress are rare. Holoprosencephaly is a complex brain malformation caused by incomplete cleavage of the prosencephalon. Children with holoprosencephaly may experience upper airway obstruction due to the associated dentoalveolar malformations and oromotor dysfunctions. We present the case of an eight-year-old female patient with holoprosencephaly and a plunging ranula that manifested as an acute course due to difficult airway management. She required gastrostomy for oromotor dysfunctions related to feeding and swallowing and difficulty managing oral secretions. The sublingual gland and ranula were removed under general anesthesia. Postoperatively, urgent reintubation and close monitoring in the intensive care unit were required due to upper airway obstruction. We successfully managed the patient with close cooperation of a pediatrician and an anesthetist, and no recurrence was observed at the one-year follow-up. A ranula can be caused by trauma to the floor of the mouth in association with lingually inclined mandibular teeth, a type of dentoalveolar compensation seen in maxillary hypoplasia associated with holoprosencephaly. Careful consideration is needed in such cases since airway management can be difficult due to postoperative swelling and oromotor dysfunctions.
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Affiliation(s)
| | - Atsushi Yokoyama
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Shimizu
- Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan
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Fujino S, Enokizono M, Ihara S, Kono T, Miyama S. Sinus pericranii associated with syntelencephaly: a case report. BMC Neurol 2022; 22:316. [PMID: 36008788 PMCID: PMC9404582 DOI: 10.1186/s12883-022-02764-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/21/2022] [Indexed: 11/22/2022] Open
Abstract
Background Sinus pericranii is a rare cranial venous malformation resulting in a subcutaneous mass due to abnormal communication between intracranial and subperiosteal/interperiosteal veins. To date, to the best of our knowledge, there are no reports of sinus pericranii associated with syntelencephaly, a subtype of lobar holoprosencephaly. We herein report a case of sinus pericranii associated with syntelencephaly. This report can provide us better understanding of the etiology of sinus pericranii, the potential risks, and the treatment options for these patients. Case presentation A 2-year-4-month old female patient who received the diagnosis of syntelencephaly as a neonate presented with a subcutaneous mass in the parietal region. The mass was soft, nonpulsatile, 3 × 2 cm in size, and showed enlargement in the lying position. Color cranial Doppler ultrasound, head magnetic resonance imaging (MRI), and cerebral angiography revealed a dilated vessel passing through the parietal bone and forming a communication between the superior sagittal sinus and scalp veins. Based on these findings, sinus pericranii was diagnosed. The head MRI also showed coronal craniosynostosis, a tight posterior fossa. At age 2 years and 7 months, the patient underwent a transection of the sinus pericranii and the mass resolved without any complications or recurrences for more than 2.5 years to date. Conclusion Sinus pericranii is a rare cranial and venous malformation sometimes accompanied by brain malformations or craniosynostosis that may become more apparent as the brain and skull develop. Since this condition can be complicated by intracranial hemorrhage and sinus thrombosis, early detection is necessary to determine the treatment options. Physicians should be alert to the possibility of this condition if they observe a soft cranial mass that appears to decrease in size in the sitting position and bulge in the lying position.
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Affiliation(s)
- Shuhei Fujino
- Department of Neurology, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8561, Japan.
| | - Mikako Enokizono
- Department of Radiology, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8561, Japan
| | - Satoshi Ihara
- Department of Neurosurgery, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8561, Japan
| | - Tatsuo Kono
- Department of Radiology, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8561, Japan
| | - Sahoko Miyama
- Department of Neurology, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8561, Japan
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36
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Ghanta PR, Phatak S, Bhansali PJ, Unadkat BS, Goyal N. Antenatal Ultrasonographic Diagnosis of a Constellation of Alobar Holoprosencephaly, Ethmocephaly, and Hydronephrosis in a Case of Early-Onset Intrauterine Growth Retardation: A Case Report. Cureus 2022; 14:e27375. [PMID: 36046320 PMCID: PMC9418636 DOI: 10.7759/cureus.27375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2022] [Indexed: 11/19/2022] Open
Abstract
Alobar holoprosencephaly is a congenital malformation that results from failure of the forebrain/prosencephalon to divide into right and left halves. Despite the literature on the genetic and chromosomal abnormalities associated with this condition, information on additional causes and explanations for variability in phenotypic expressivity are lacking. We report a case of early-onset intrauterine growth retardation with alobar holoprosencephaly, ethmocephaly, and hydronephrosis diagnosed on antenatal ultrasonography in a 27-year-old primigravida with no known risk factors or family history. The combination of holoprosencephaly with associated midline facial anomalies and the genitourinary abnormality, in this case, constitutes a rare phenotypic presentation. This case emphasizes the importance of antenatal ultrasonography in the early detection of lethal anomalies like alobar holoprosencephaly. The pregnancy was safely terminated in accordance with the mother’s decision.
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Spadari F, Pulicari F, Pellegrini M, Scribante A, Garagiola U. Multidisciplinary approach to Gorlin-Goltz syndrome: from diagnosis to surgical treatment of jawbones. Maxillofac Plast Reconstr Surg 2022; 44:25. [PMID: 35843976 PMCID: PMC9288940 DOI: 10.1186/s40902-022-00355-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/06/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Gorlin syndrome, also known as Gorlin-Goltz syndrome (GGS) or basal cell nevus syndrome (BCNS) or nevoid basal cell carcinoma syndrome (NBCCS), is an autosomal dominant familial cancer syndrome. It is characterized by the presence of numerous basal cell carcinomas (BCCs), along with skeletal, ophthalmic, and neurological abnormalities. It is essential to anticipate the diagnosis by identifying the pathology through the available diagnostic tests, clinical signs, and radiological manifestations, setting up an adequate treatment plan. MAIN BODY In the first part, we searched recent databases including MEDLINE (PubMed), Embase, and the Cochrane Library by analyzing the etiopathogenesis of the disease, identifying the genetic alterations underlying them. Subsequently, we defined what are, to date, the major and minor clinical diagnostic criteria, the possible genetic tests to be performed, and the pathologies with which to perform differential diagnosis. The radiological investigations were reviewed based on the most recent literature, and in the second part, we performed a review regarding the existing jawbone protocols, treating simple enucleation, enucleation with bone curettage in association or not with topical use of cytotoxic chemicals, and "en bloc" resection followed by possible bone reconstruction, marsupialization, decompression, and cryotherapy. CONCLUSION To promote the most efficient and accurate management of GGS, this article summarizes the clinical features of the disease, pathogenesis, diagnostic criteria, differential diagnosis, and surgical protocols. To arrive at an early diagnosis of the syndrome, it would be advisable to perform radiographic and clinical examinations from the young age of the patient. The management of the patient with GGS requires a multidisciplinary approach ensuring an adequate quality of life and effective treatment of symptoms.
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Affiliation(s)
- Francesco Spadari
- Department of Biomedical Surgical and Dental Sciences, Maxillo-Facial and Odontostomatology Unit, School of Orthodontics, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Federica Pulicari
- Department of Biomedical Surgical and Dental Sciences, Maxillo-Facial and Odontostomatology Unit, School of Orthodontics, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Matteo Pellegrini
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences Section of Dentistry, University of Pavia, Pavia, Italy
| | - Andrea Scribante
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences Section of Dentistry, University of Pavia, Pavia, Italy
| | - Umberto Garagiola
- Department of Biomedical Surgical and Dental Sciences, Maxillo-Facial and Odontostomatology Unit, School of Orthodontics, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
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38
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Young TL, Whisenhunt KN, LaMartina SM, Hewitt AW, Mackey DA, Tompson SW. Sonic Hedgehog Intron Variant Associated With an Unusual Pediatric Cortical Cataract. Invest Ophthalmol Vis Sci 2022; 63:25. [PMID: 35749127 PMCID: PMC9234370 DOI: 10.1167/iovs.63.6.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose To identify the genetic basis of an unusual pediatric cortical cataract demonstrating autosomal dominant inheritance in a large European–Australian pedigree. Methods DNA from four affected individuals were exome sequenced utilizing a NimbleGen SeqCap EZ Exome V3 kit and HiSeq 2500. DNA from 12 affected and four unaffected individuals were genotyped using Human OmniExpress-24 BeadChips. Multipoint linkage and haplotyping were performed (Superlink-Online SNP). DNA from one affected individual and his unaffected father were whole-genome sequenced on a HiSeq X Ten system. Rare small insertions/deletions and single-nucleotide variants (SNVs) were identified in the disease-linked region (Golden Helix SVS). Combined Annotation Dependent Depletion (CADD) analysis predicted variant deleteriousness. Putative enhancer function and variant effects were determined using the Dual-Glo Luciferase Assay system. Results Linkage mapping identified a 6.23-centimorgan support interval at chromosome 7q36. A co-segregating haplotype refined the critical region to 6.03 Mbp containing 21 protein-coding genes. Whole-genome sequencing uncovered 114 noncoding variants from which CADD predicted one was highly deleterious, a novel substitution within intron-1 of the sonic hedgehog signaling molecule (SHH) gene. ENCODE data suggested this site was a putative enhancer, subsequently confirmed by luciferase reporter assays with variant-associated gene overexpression. Conclusions In a large pedigree, we have identified a SHH intron variant that co-segregates with an unusual pediatric cortical cataract phenotype. SHH is important for lens formation, and mutations in its receptor (PTCH1) cause syndromic cataract. Our data implicate increased function of an enhancer important for SHH expression primarily within developing eye tissues.
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Affiliation(s)
- Terri L Young
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
| | - Kristina N Whisenhunt
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
| | - Sarah M LaMartina
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
| | - Alex W Hewitt
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.,Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia.,Eye Department, Royal Hobart Hospital, University of Tasmania, Hobart, Tasmania, Australia
| | - David A Mackey
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.,Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia.,Eye Department, Royal Hobart Hospital, University of Tasmania, Hobart, Tasmania, Australia
| | - Stuart W Tompson
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
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Rodriguez-Acevedo AJ, Antonsson A, Liyanage UE, Hughes MC, Gordon S, van der Pols J, Green AC. Associations of keratinocyte cancers with snp variants in the sonic hedgehog pathway. BMC Cancer 2022; 22:490. [PMID: 35505292 PMCID: PMC9063108 DOI: 10.1186/s12885-022-09565-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 04/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Sonic Hedgehog (SHH) pathway dysregulation is implicated in basal cell carcinoma (BCC) development. To evaluate the possible wider role of SHH gene variants in skin carcinogenesis, we assessed associations of genes in the SHH pathway with lifetime development of any keratinocyte cancer (KC), and with developing either BCCs or squamous cell carcinomas (SCCs) exclusively, in a 25-year prospective, population-based study of 1,621 Australians. METHODS We genotyped 795 unrelated adults with available blood samples: 311 cases with any KC (186 developing BCCs-only, 55 SCCs-only, 70 BCCs and SCCs) and 484 controls. We compared allele frequencies of 158 independent SNPs across 43 SHH genes between cases and controls, and performed a gene-based analysis. RESULTS We found associations between SNP rs4848627 (GLI2) (related to DNA synthesis in keratinocytes) and development of any KC (OR = 1.53; 95% CI = 1.06-2.13, P < 0.01) and SCCs exclusively (OR = 2.12; 95%CI = 1.39-3.23, P < 0.01). SNP rs3217882 located in CCND2 was associated with exclusive BCC development (OR = 1.43, CI = 1.12-1.82, P < 0.01). The gene-based analysis suggested an association of PRKACG (protein kinase cAMP-activated catalytic subunit gamma) with any KC (P = 0.013). CONCLUSION We conclude that variants located in genes in the SHH pathway may are involved in SCC as well as BCC development.
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Affiliation(s)
- Astrid J Rodriguez-Acevedo
- The University of Queensland Diamantina Institute, The University of Queensland, Dermatology Research Centre, Brisbane, QLD, Australia
| | - Annika Antonsson
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Upekha E Liyanage
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4006, Australia
| | - Maria Celia Hughes
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4006, Australia
| | - Scott Gordon
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4006, Australia
| | - Jolieke van der Pols
- Faculty of Health, School of Exercise and Nutrition Sciences, Queensland University of Technology (QUT), Brisbane, Australia
| | - Adele C Green
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4006, Australia. .,CRUK Manchester Institute and Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
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40
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Montaguti E, Cariello L, Brunelli E, Youssef A, Livi A, Salsi G, Pilu G. Sonography of fetal holoprosencephaly: a guide to recognize the lesser varieties. J Matern Fetal Neonatal Med 2022; 35:9717-9723. [PMID: 35272544 DOI: 10.1080/14767058.2022.2050900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
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.
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Affiliation(s)
- Elisa Montaguti
- Obstetric Unit, Department of Medical and Surgical Sciences, University of Bologna and IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
| | - Luisa Cariello
- Obstetric Unit, Department of Medical and Surgical Sciences, University of Bologna and IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
| | - Elena Brunelli
- Obstetric Unit, Department of Medical and Surgical Sciences, University of Bologna and IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
| | - Aly Youssef
- Obstetric Unit, Department of Medical and Surgical Sciences, University of Bologna and IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
| | - Alessandra Livi
- Obstetric Unit, Department of Medical and Surgical Sciences, University of Bologna and IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
| | - Ginevra Salsi
- Obstetric Unit, Department of Medical and Surgical Sciences, University of Bologna and IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
| | - Gianluigi Pilu
- Obstetric Unit, Department of Medical and Surgical Sciences, University of Bologna and IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
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Obanife O, Adekanye AG, Ekpo RG, Okonkwo NS, Gbaji EJ, Akaba K, Ashindoitiang J, Asuquo J, Ogunleye O. Management of alobar holoprosencephaly associated with fronto-nasal encephalocoele and type I (closed-lips) schizencephaly at the university of calabar teaching Hospital: A case report and literature review. INTERDISCIPLINARY NEUROSURGERY 2022. [DOI: 10.1016/j.inat.2021.101410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Henker LC, Lorenzett MP, Piva MM, Wronski JG, de Andrade DGA, Borges AS, Driemeier D, Oliveira-Filho JP, Pavarini SP. Alobar holoprosencephaly in an aborted American Quarter Horse fetus. J Equine Vet Sci 2022; 112:103898. [PMID: 35150851 DOI: 10.1016/j.jevs.2022.103898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/06/2022] [Accepted: 02/07/2022] [Indexed: 11/24/2022]
Abstract
Holoprosencephaly is a central nervous system malformation, characterized by incomplete or total lack of division of prosencephalon hemispheres, which is commonly accompanied by craniofacial malformations. A 9-month-gestation aborted American Quarter Horse fetus was submitted for postmortem examination. The fetus lacked haircoat and had severe facial malformations including marked shortening/absence of the maxillary, incisive and nasal bones, bilateral anophthalmia, and pre-maxillary agenesis. The prosencephalon was small and nearly spherical, represented by a single lobe, with no visible separation between cerebral hemispheres. The olfactory bulbs, piriform lobes, and the optic chiasm were absent. At cross-sectioning of the prosencephalon, the inner structures of the brain were completely absent, and replaced by a monoventricle lined by the remaining compressed cortex, and the thalami were fused. Since mutations in the sonic hedgehog (SHH) gene have been associated with human holoprosencephaly, the three coding SHH exons were sequenced using liver DNA of the aborted foal. The obtained SHH sequence was similar to the Equus caballus SHH mRNA sequence deposited in GenbankTM (XM_023640069.1); therefore, no polymorphism in the coding region of this gene justifying the phenotype was observed. This is the first report of alobar holoprosencephaly in horses.
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Affiliation(s)
- Luan Cleber Henker
- Setor de Patologia Veterinária, Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9090, Bairro Agronomia, Porto Alegre, RS 91540-000, Brazil.
| | - Marina Paula Lorenzett
- Setor de Patologia Veterinária, Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9090, Bairro Agronomia, Porto Alegre, RS 91540-000, Brazil
| | - Manoela Marchezan Piva
- Setor de Patologia Veterinária, Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9090, Bairro Agronomia, Porto Alegre, RS 91540-000, Brazil
| | - Júlia Gabriela Wronski
- Setor de Patologia Veterinária, Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9090, Bairro Agronomia, Porto Alegre, RS 91540-000, Brazil
| | - Danilo Giorgi Abranches de Andrade
- São Paulo State University (Unesp), School of Veterinary Medicine and Animal Science, Department of Veterinary Clinical Science,18618-681 Botucatu, Brazil
| | - Alexandre Secorun Borges
- São Paulo State University (Unesp), School of Veterinary Medicine and Animal Science, Department of Veterinary Clinical Science,18618-681 Botucatu, Brazil
| | - David Driemeier
- Setor de Patologia Veterinária, Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9090, Bairro Agronomia, Porto Alegre, RS 91540-000, Brazil
| | - José Paes Oliveira-Filho
- São Paulo State University (Unesp), School of Veterinary Medicine and Animal Science, Department of Veterinary Clinical Science,18618-681 Botucatu, Brazil
| | - Saulo Petinatti Pavarini
- Setor de Patologia Veterinária, Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9090, Bairro Agronomia, Porto Alegre, RS 91540-000, Brazil
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Barratt KS, Drover KA, Thomas ZM, Arkell RM. Patterning of the antero-ventral mammalian brain: Lessons from holoprosencephaly comparative biology in man and mouse. WIREs Mech Dis 2022; 14:e1552. [PMID: 35137563 DOI: 10.1002/wsbm.1552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/30/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- Kristen S Barratt
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Kyle A Drover
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Zoe M Thomas
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Ruth M Arkell
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
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Nessler J, Wunderlich C, Eikelberg D, Beineke A, Raue J, Runge M, Tipold A, Ganter M, Rehage J. Holoprosencephalia, hypoplasia of corpus callosum and cerebral heterotopia in a male belted Galloway heifer with adipsia. BMC Vet Res 2022; 18:51. [PMID: 35057802 PMCID: PMC8772152 DOI: 10.1186/s12917-022-03152-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/10/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Specialized neurons in the diencephalon detect blood hypernatremia in dehydrated animals. These neurons are connected with the pituitary gland, subsequently producing antidiuretic hormone to reabsorb water from urine in the kidneys, and to the forebrain to generate thirst and trigger drinking behavior. CASE PRESENTATION This is the first case report describing clinical findings, magnetic resonance imaging (MRI) and necropsy results of a Belted Galloway heifer with severe clinical signs of dehydration and hypernatremia, but concurrent adipsia and isosthenuria. Due to insufficient recovery with symptomatic treatment, owners elected euthanasia. Postmortem MRI and necropsy revealed a complex forebrain malformation: mild abnormal gyrification of the forebrain cortex, lobar holoprosencephaly, and corpus callosum hypoplasia. The affected brain structures are well known to be involved in osmoregulation and generation of thirst in dogs, humans and rodents. CONCLUSIONS Complex forebrain malformation can be involved in the pathogenesis of hypernatremia and adipsia in bovines.
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Affiliation(s)
- Jasmin Nessler
- Department for Small Animal Internal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, Buenteweg 9, 30559, Hannover, Germany.
| | - Christian Wunderlich
- Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany
| | - Deborah Eikelberg
- Institute for Pathology, University of Veterinary Medicine Hannover, Foundation, Buenteweg 17, 30559, Hannover, Germany
| | - Andreas Beineke
- Institute for Pathology, University of Veterinary Medicine Hannover, Foundation, Buenteweg 17, 30559, Hannover, Germany
| | - Jonathan Raue
- Department for Small Animal Internal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, Buenteweg 9, 30559, Hannover, Germany
| | - Martin Runge
- Lower Saxony State Office for Consumer Protection and Food Safety Food and Veterinary Institute Braunschweig/Hannover, Eintrachtweg 17, 30173, Hannover, Germany
| | - Andrea Tipold
- Department for Small Animal Internal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, Buenteweg 9, 30559, Hannover, Germany
| | - Martin Ganter
- Clinic for Swine, Small Ruminants and Forensic Medicine, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany
| | - Jürgen Rehage
- Clinic for Cattle, University of Veterinary Medicine Vienna (Vetmeduni Vienna), Veterinaerplatz 1, A-1210, Vienna, Austria
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Zug R. Developmental disorders caused by haploinsufficiency of transcriptional regulators: a perspective based on cell fate determination. Biol Open 2022; 11:bio058896. [PMID: 35089335 PMCID: PMC8801891 DOI: 10.1242/bio.058896] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease. This article has an associated Future Leader to Watch interview with the author of the paper.
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Affiliation(s)
- Roman Zug
- Department of Biology, Lund University, 22362 Lund, Sweden
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Patel TN, Dhanyamraju PK. Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies. J Biomed Res 2021; 36:1-9. [PMID: 34963676 PMCID: PMC8894283 DOI: 10.7555/jbr.35.20210139] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Development is a sophisticated process maintained by various signal transduction pathways, including the Hedgehog (Hh) pathway. Several important functions are executed by the Hh signaling cascade such as organogenesis, tissue regeneration, and tissue homeostasis, among various others. Considering the multiple functions carried out by this pathway, any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers. In the present review article, we explored a wide range of diseases caused by aberrant Hh signaling, including developmental defects and cancers. Finally, we concluded this mini-review with various treatment strategies for Hh-induced diseases.
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Affiliation(s)
- Trupti N Patel
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Vellore, Tamil Nadu 632014, India
| | - Pavan Kumar Dhanyamraju
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.,Penn State Cancer Institute, Hershey, PA 17033, USA
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Molecular Bases of Human Malformation Syndromes Involving the SHH Pathway: GLIA/R Balance and Cardinal Phenotypes. Int J Mol Sci 2021; 22:ijms222313060. [PMID: 34884862 PMCID: PMC8657641 DOI: 10.3390/ijms222313060] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 11/27/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022] Open
Abstract
Human hereditary malformation syndromes are caused by mutations in the genes of the signal transduction molecules involved in fetal development. Among them, the Sonic hedgehog (SHH) signaling pathway is the most important, and many syndromes result from its disruption. In this review, we summarize the molecular mechanisms and role in embryonic morphogenesis of the SHH pathway, then classify the phenotype of each malformation syndrome associated with mutations of major molecules in the pathway. The output of the SHH pathway is shown as GLI activity, which is generated by SHH in a concentration-dependent manner, i.e., the sum of activating form of GLI (GLIA) and repressive form of GLI (GLIR). Which gene is mutated and whether the mutation is loss-of-function or gain-of-function determine in which concentration range of SHH the imbalance occurs. In human malformation syndromes, too much or too little GLI activity produces symmetric phenotypes affecting brain size, craniofacial (midface) dysmorphism, and orientation of polydactyly with respect to the axis of the limb. The symptoms of each syndrome can be explained by the GLIA/R balance model.
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Alobar Holoprosencephaly with Cebocephaly in a Neonate Born to an HIV-Positive Mother in Eastern Uganda. Case Rep Otolaryngol 2021; 2021:7282283. [PMID: 34733564 PMCID: PMC8560288 DOI: 10.1155/2021/7282283] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 10/16/2021] [Indexed: 11/24/2022] Open
Abstract
Background Holoprosencephaly (HPE) is a rare cerebrofacial abnormality resulting from the complete or partial failure of the diverticulation and cleavage of the primitive forebrain. It has an incidence at birth of 1:16000. Case Presentation. We report a case of a 2600 g newborn female delivered by an HIV-infected mother in whom an antenatal ultrasound scan at 34 weeks' gestation reported features of fetal alobar holoprosencephaly. The neonate was born with cebocephaly, a monkey-like head, and did not survive for more than 30 minutes following delivery by caesarian section despite oxygen therapy. Conclusion Alobar HPE with cebocephaly remains incompatible with life. In this resource-limited setting, the diagnosis was made clinically, and only an ultrasound scan was performed to confirm the diagnosis. Chromosomal analysis could have given more information.
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Sandoval Karamian AG, Mercimek-Andrews S, Mohammad K, Molloy EJ, Chang T, Chau V, Murray DM, Wusthoff CJ. Neonatal encephalopathy: Etiologies other than hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med 2021; 26:101272. [PMID: 34417137 DOI: 10.1016/j.siny.2021.101272] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Neonatal encephalopathy (NE) describes the clinical syndrome of a newborn with abnormal brain function that may result from a variety of etiologies. HIE should be distinguished from neonatal encephalopathy due to other causes using data gathered from the history, physical and neurological exam, and further investigations. Identifying the underlying cause of encephalopathy has important treatment implications. This review outlines conditions that cause NE and may be mistaken for HIE, along with their distinguishing clinical features, pathophysiology, investigations, and treatments. NE due to brain malformations, vascular causes, neuromuscular causes, genetic conditions, neurogenetic disorders and inborn errors of metabolism, central nervous system (CNS) and systemic infections, and toxic/metabolic disturbances are discussed.
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Affiliation(s)
- A G Sandoval Karamian
- Children's Hospital of Philadelphia, Division of Neurology, 3501 Civic Center Blvd Office 1200.12, Philadelphia, PA, 19104, USA.
| | - S Mercimek-Andrews
- Biochemical Geneticist, Department of Medical Genetics, University of Alberta, 8-39 Medical Sciences Building, 8613 - 144 Street, Edmonton, T6G 2H7, Alberta, Canada.
| | - K Mohammad
- Cumming School of Medicine, University of Calgary, Alberta Children's Hospital, Room B4-286, 28 Oki drive NW, Calgary, AB, T3B 6A8, Canada.
| | - E J Molloy
- Trinity College, the University of Dublin, Trinity Translational Medicine Institute, Dublin, Ireland; Children's Health Ireland at Tallaght and Crumlin & and Coombe Women's and Infants University Hospital, Dublin, Ireland; Trinity Research in Childhood Centre (TRiCC), Trinity Academic Centre, Tallaght University Hospital, Dublin 24, Ireland.
| | - T Chang
- George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USA; Neonatal Neurology Program, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.
| | - Vann Chau
- Neurology, Neonatal Neurology Program, The Hospital for Sick Children, 555 University Avenue, Toronto ON, M5G 1X8, Canada.
| | - D M Murray
- Deptartment of Paediatric and Child Health, University College Cork, ARm 2.32, Paediatric Academic Unit, Floor 2, Seahorse Unit, Cork University Hospital, Wilton, Cork, T12 DCA4, Ireland.
| | - Courtney J Wusthoff
- Division of Child Neurology, Division of Pediatrics- Neonatal and Developmental Medicine, Stanford Children's Health, 750 Welch Road, Suite 317, Palo Alto, CA, 94304 USA.
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50
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Loo CKC, Pearen MA, Ramm GA. The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes. Int J Mol Sci 2021; 22:ijms22189854. [PMID: 34576017 PMCID: PMC8468456 DOI: 10.3390/ijms22189854] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/03/2021] [Accepted: 09/09/2021] [Indexed: 12/18/2022] Open
Abstract
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. SHH mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.
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Affiliation(s)
- Christine K. C. Loo
- South Eastern Area Laboratory Services, Department of Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Correspondence: ; Tel.: +61-2-93829015
| | - Michael A. Pearen
- Hepatic Fibrosis Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (M.A.P.); (G.A.R.)
| | - Grant A. Ramm
- Hepatic Fibrosis Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (M.A.P.); (G.A.R.)
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia
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