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1.
Exp Suppl. 2019;111:263-298. doi: 10.1007/978-3-030-25905-1_13.

Pituitary Transcription Factor Mutations Leading to Hypopituitarism.

Author information

1
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA. gergicsp@med.umich.edu.

Abstract

Congenital pituitary hormone deficiency is a disabling condition. It is part of a spectrum of disorders including craniofacial midline developmental defects ranging from holoprosencephaly through septo-optic dysplasia to combined and isolated pituitary hormone deficiency. The first genes discovered in the human disease were based on mouse models of dwarfism due to mutations in transcription factor genes. High-throughput DNA sequencing technologies enabled clinicians and researchers to find novel genetic causes of hypopituitarism for the more than three quarters of patients without a known genetic diagnosis to date. Transcription factor (TF) genes are at the forefront of the functional analysis of novel variants of unknown significance due to the relative ease in in vitro testing in a research lab. Genetic testing in hypopituitarism is of high importance to the individual and their family to predict phenotype composition, disease progression and to avoid life-threatening complications such as secondary adrenal insufficiency.This chapter aims to highlight our current understanding about (1) the contribution of TF genes to pituitary development (2) the diversity of inheritance and phenotype features in combined and select isolated pituitary hormone deficiency and (3) provide an initial assessment on how to approach variants of unknown significance in human hypopituitarism. Our better understanding on how transcription factor gene variants lead to hypopituitarism is a meaningful step to plan advanced therapies to specific genetic changes in the future.

KEYWORDS:

Genetic testing; Inheritance; Pituitary hormone deficiency; Transcription factor; Variants of unknown significance

PMID:
31588536
DOI:
10.1007/978-3-030-25905-1_13
[Indexed for MEDLINE]
2.
Surg Radiol Anat. 2019 Sep;41(9):1053-1063. doi: 10.1007/s00276-019-02284-x. Epub 2019 Jul 12.

An osteological assessment of cyclopia by micro-CT scanning.

Author information

1
School of Anatomical Sciences, Medical School, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Beverley.kramer@wits.ac.za.
2
School of Anatomical Sciences, Medical School, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Abstract

PURPOSE:

Imaging modalities such as micro-CT scanning and three-dimensional reconstruction are providing a mechanism for detailed analysis of skeletal components not only of normal specimens but also through revisitation of the abnormal. The aim of this study was to analyse the craniofacial skeleton of five human fetuses with cyclopia by means of micro-CT scanning and three-dimensional reconstruction.

MATERIALS AND METHODS:

The study consisted of five cyclopean individuals from the paediatric collection of the School of Anatomical Sciences, University of the Witwatersrand. The specimens ranged in age from 22 to 42 weeks of gestation. The osteological features of each bone of the skull were analysed with the aid of micro-CT scanning and analysis using VG studiomax software.

RESULTS:

A detailed analysis of all the bones of the skull revealed that the upper two-thirds of the viscerocranium and the anterior region of the basicranium were the most affected regions of the cyclopean fetuses. The ethmoid, nasal, inferior concha and the lacrimal bones were absent in all the cases of cyclopia. Major abnormalities were found in the premaxillary region which affected the development of the anterior dentition.

CONCLUSION:

This study supports the suggestion that the malformations of the visceral bones are secondary to defective development of the presphenoid and mesethmoid cartilages. The ethmoidal bones are important midline struts during normal development and their absence in cyclopia leads to non-laterality of facial features.

KEYWORDS:

Craniofacial development; Cyclopia; Osteology

PMID:
31300839
DOI:
10.1007/s00276-019-02284-x
[Indexed for MEDLINE]
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3.
BMJ Case Rep. 2019 May 8;12(5). pii: e228648. doi: 10.1136/bcr-2018-228648.

Holoprosencephaly or severe hydrocephalus: T1 sequence tells the story.

Author information

1
Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Abstract

Intracranial lipoma is a relatively rare benign lesion. Many are incidental findings; however, some others may present with headache, hydrocephalus or other neurological symptoms; thus, correct diagnosis of this condition is important. These lesions are of high signal intensity on T2-weighted MRI and especially those close to cerebrospinal fluid (CSF) spaces, can easily be overlooked in the background of high signal intensity of CSF. Here, we present a case of tectal lipoma, with subsequent severe hydrocephalus and absence of septum pellucidum which was initially misinterpreted as a form of holoprosencephaly, due to inadequate attention to T1-weighted images.

KEYWORDS:

neuroimaging; neurology; radiology

PMID:
31068345
DOI:
10.1136/bcr-2018-228648
[Indexed for MEDLINE]
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4.
Med Ultrason. 2019 May 2;21(2):163-169. doi: 10.11152/mu-1614.

The wide spectrum of ultrasound diagnosis of holoprosencephaly.

Author information

1
Department of Obstetrics Gynecology Carol Davila University of Medicine and Pharmacy Bucharest Romania. antoniuginec@yahoo.com.
2
Carol Davila University of Medicine and Pharmacy, Department Obstetrics, Gynecology, and Neonatology, Elias Emergency Clinical Hospital, Bucharest, Romania. simoconst69@yahoo.com.
3
University of Medicine and Pharmacy Craiova, Department of Obstetrics Gynecology, Filantropia Hospital,Craiova, Romania. stefania.tudorache@gmail.com.
4
Carol Davila University of Medicine and Pharmacy, Department of Obstetrics Gynecology, Sf Ioan Emergency Hospital , Bucharest, Romania. plesliana@gmail.com.
5
Department Obstetrics Gynecology, INSMC Polizu Hospital, Bucharest, Romania. herghelegiu.cata@gmail.com.
6
Carol Davila University of Medicine and Pharmacy, Department of Obstetrics Gynecology Sf Ioan Emergency Hospital, Bucharest, Romania. adrianneacsu2006@yahoo.com.
7
University of Medicine and Pharmacy, Victor Babes, Eftimie Murgu Place, nr 2, Timisoara, Romania. navolan@yahoo.com.
8
Department Obstetrics Gynecology, INSMC Polizu Hospital, Bucharest, Romania. dr.ioana.dragan@gmail.com.
9
Carol Davila University of Medicine and Pharmacy Department Obstetrics Gynecology, INSMC Polizu Hospital, Bucharest, Romania,. dana.oprescu@hotmail.com.

Abstract

AIM:

Holoprosencephaly (HPE) is the most common brain malformation. A wide spectrum of anatomical variants are characterized by a lack of midline separation of the cerebral hemispheres. The aim of this study was to assess the ultrasound diagnostic criteria for HPE.

MATERIAL AND METHOD:

A database of 175 fetuses with central nervous system anomalies identified by ultrasound was collected retrospectively from 2006 to 2016 in this multicenter, retrospective, observational study. Among them 18 cases (10.2%) with HPE were identified.

RESULTS:

The prevalence of HPE was 2.5:10.000 with the sex distributionmale:female of 1:1.6. Six cases were alobar subtype, 3 were semilobar, 7 were lobar and 2 were middle interhemispheric variant. In the second trimester, we consider that the abnormal fusion of the lateral ventricles and the absence of the cavum septum pellucidum are the most important landmarks for HPE. Facial abnormalities varied considerably.

CONCLUSION:

This study illustrates the heterogeneity of HPE with different cerebral and facial appearances.

PMID:
31063520
DOI:
10.11152/mu-1614
[Indexed for MEDLINE]
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5.
Indian J Pathol Microbiol. 2019 Apr-Jun;62(2):283-286. doi: 10.4103/IJPM.IJPM_275_17.

Rare association of cyclopia with craniospinal rachischisis.

Author information

1
Department of Pathology, Shri B. M. Patil Medical College, Hospital and Research Centre, Bijapur, Karnataka, India.

Abstract

Cyclopia is a severe form of holoprosencephaly which results in children being born with just one eye, absence of nose and presence of a proboscis above the median eye. Incidence of cyclopia is around 1.05 in 1, 00,000 births, including stillbirths. The association of anencephaly with spinal rachichisis varies from 17-50%. However, the existence of cyclopia with anencephaly and spinal rachischisis has been reported only in 9 cases till date. We report one more case of cyclopia with anencephaly and spinal rachischisis. Awareness of this spectrum of association with cyclopia, albeit rare, will help in early antenatal diagnosis by fetal ultrasonography. Public education and strict adherence to folic acid supplementation can prevent this unfortunate anomaly.

KEYWORDS:

Anencephaly; cyclopia; holoprosencephaly; spinal rachischisis.

PMID:
30971556
DOI:
10.4103/IJPM.IJPM_275_17
[Indexed for MEDLINE]
6.
Medicine (Baltimore). 2019 Mar;98(10):e14780. doi: 10.1097/MD.0000000000014780.

Case report: a novel mutation in ZIC2 in an infant with microcephaly, holoprosencephaly, and arachnoid cyst.

Author information

1
College of Basic Medical Science, Jiujiang University, Jiujiang, Jiangxi.
2
Experimental Medicine Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD.
3
Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.

Abstract

RATIONALE:

Holoprosencephaly (HPE) is a severe congenital brain malformation resulting from failed or incomplete forebrain division in early pregnancy.

PATIENT CONCERNS:

In this study, we reported a 9-month old infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst.

DIAGNOSES:

Potential genetic defects were screened directly using trio-case whole exome sequencing (WES) rather than traditional karyotype, microarray, and Sanger sequencing of select genes.

OUTCOMES:

A previous unpublished de novo missense mutation (c.1069C >G, p.H357D) in the 3rd zinc finger domain (ZFD3) of the ZIC2 gene was identified in the affected individual, but not in the parents. Sanger sequencing using specific primers verified the mutation. Extensive bioinformatics analysis confirmed the pathogenicity of this extremely rare mutation. Phenotype-genotype analysis revealed significant correlation between the 3rd zinc-finger domain with semilobor HPE.

LESSONS:

These findings expanded the spectrum of the ZIC2 gene mutations and associated clinical manifestations, which is the first identification of a mutated ZIC2 gene in a Han infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst.

PMID:
30855487
PMCID:
PMC6417543
DOI:
10.1097/MD.0000000000014780
[Indexed for MEDLINE]
Free PMC Article
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7.
Morphologie. 2019 Jun;103(341 Pt 2):122-125. doi: 10.1016/j.morpho.2019.02.001. Epub 2019 Mar 7.

External and computed tomography analysis of a strophocephalic lamb.

Author information

1
Laboratoire d'anatomie, biomécanique et organogenèse, université Libre de Bruxelles, faculté de médecine, Route de Lennik, 808 (CP 619), B 1000 Brussels, Belgium.
2
Laboratoire d'anatomie, biomécanique et organogenèse, université Libre de Bruxelles, faculté de médecine, Route de Lennik, 808 (CP 619), B 1000 Brussels, Belgium. Electronic address: slouryan@ulb.ac.be.

Abstract

CONTEXT:

The Museum of Anatomy and Embryology Louis Deroubaix attached to the Laboratory of Anatomy, Biomecanics and Organogenesis, ULB, Brussels, possesses in its liquid collections a cephalic extremity of a lamb suffering from strophocephaly. The origins have not been determined. The trunk and the limbs are resected.

MATERIAL AND METHODS:

The piece has been studied and photographed. A volumic computed tomography acquisition has been performed with a Siemens Volume Zoom. For pedagogic and museological purposes, surface reconstructions and 3D printing have been obtained.

RESULTS:

An otocephaly is observed. Both ears are located in place of the oral cavity. The mandible is welded to the braincase. The eyeballs are close together (synophtalmia) which confirms the presence of a cyclotocephaly. They are surmounted by a rudimentary snout rather than a proboscis. The presence of this muzzle allows the anomaly to be classified as a strophocephaly, a malformation already described in sheeps. CT slices of the brain show a semi-lobar holoprosencephaly with incomplete division of the cerebral hemispheres and ventricules.

DISCUSSION AND CONCLUSION:

The CT examination allows the facial anomalies to be allocated to a holoprosencephaly. The singularity of this case, compared to the human cyclotocephalies, is the presence of a differentiated muzzle rather than a simple proboscis. The holoprosencephaly is uncomplete. Such anomalies have been associated with an entire absence of cerebral differentiation but with a complete absence of the muzzle. The tridimensional printing represents an interesting educational tool easily transportable in contrast to the original specimen.

KEYWORDS:

3D printing; Holoprosencephaly; Lamb; Strophocephaly; Teratogenesis

PMID:
30853367
DOI:
10.1016/j.morpho.2019.02.001
[Indexed for MEDLINE]
Icon for Elsevier Science
8.
J Craniofac Surg. 2019 Mar/Apr;30(2):532-534. doi: 10.1097/SCS.0000000000005072.

Reverse Distraction for Treatment of Hydrocephalic Macrocephaly in Late Childhood.

Author information

1
Division of Pediatric Plastic and Craniofacial Surgery and Division of Neurosurgery, Children's Mercy Hospital, Kansas City, MO.
2
Department of Plastic and Reconstructive Surgery, University of Kansas Medical Center, Kansas City, KS.

Abstract

Macrocephaly diminishes quality of life for children whose head size inhibits independent mobility and appropriate interaction with caregivers. Cranial reduction is a method of addressing these issues, historically with a high morbidity due most commonly to bleeding and shunt complications. The authors present a 9-year-old girl with holoprosencephaly and severe macrocephaly from progressive hydrocephalus who underwent cranial reduction via reverse distraction osteogenesis, a method to slowly reduce the skull volume. The patient underwent circumferential occipital temporoparietal frontal craniotomy with placement of 4 cranial distractors, followed approximately 1 month later by removal of the distractors and cranioplasty with resorbable fixation devices. The patient demonstrated significant postoperative improvement in head control and interaction in school activities. This is the oldest patient with macrocephaly treated with reverse distraction in the literature to date. The slow contraction of the cranial vault with limited bony surgery at the time of initial reduction provides an additional safety margin, and should be considered in older children presenting with profound macrocephaly.

PMID:
30789381
DOI:
10.1097/SCS.0000000000005072
[Indexed for MEDLINE]
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10.
J Genet. 2018 Dec;97(5):1315-1325.

Analysis of novel domain-specific mutations in the zebrafish ndr2/cyclops gene generated using CRISPR-Cas9 RNPs.

Author information

1
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. challa.anilkumar@gmail.com.

Abstract

Nodal-related protein (ndr2) is amember of the transforming growth factor type β superfamily of factors and is required for ventral midline patterning of the embryonic central nervous system in zebrafish. In humans, mutations in the gene encoding nodal cause holoprosencephaly and heterotaxy. Mutations in the ndr2 gene in the zebrafish (Danio rerio) lead to similar phenotypes, including loss of the medial floor plate, severe deficits in ventral forebrain development and cyclopia. Alleles of the ndr2 gene have been useful in studying patterning of ventral structures of the central nervous system. Fifteen different ndr2 alleles have been reported in zebrafish, of which eight were generated using chemical mutagenesis, four were radiation-induced and the remaining alleles were obtained via random insertion, gene targeting (TALEN) or unknown methods. Therefore, most mutation sites were random and could not be predicted a priori. Using the CRISPR-Cas9 system from Streptococcus pyogenes, we targeted distinct regions in all three exons of zebrafish ndr2 and observed cyclopia in the injected (G0) embryos.We show that the use of sgRNA-Cas9 ribonucleoprotein (RNP) complexes can cause penetrant cyclopic phenotypes in injected (G0) embryos. Targeted polymerase chain reaction amplicon analysis using Sanger sequencing showed that most of the alleles had small indels resulting in frameshifts. The sequence information correlates with the loss of ndr2 activity. In this study, we validate multiple CRISPR targets using an in vitro nuclease assay and in vivo analysis using embryos. We describe one specific mutant allele resulting in the loss of conserved terminal cysteine-coding sequences. This study is another demonstration of the utility of the CRISPR-Cas9 system in generating domain-specific mutations and provides further insights into the structure-function of the ndr2 gene.

PMID:
30555080
[Indexed for MEDLINE]
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11.
Taiwan J Obstet Gynecol. 2018 Dec;57(6):881-884. doi: 10.1016/j.tjog.2018.11.001.

Digynic triploidy in a fetus presenting with semilobar holoprosencephaly.

Author information

1
Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan.
2
Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan; School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: cpc_mmh@yahoo.com.
3
Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan; MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan; MacKay Medical College, New Taipei City, Taiwan.
4
Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
5
Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; Department of Bioengineering, Tatung University, Taipei, Taiwan.

Abstract

OBJECTIVE:

We present digynic triploidy in a fetus with semilobar holoprosencephaly (HPE).

CASE REPORT:

A 32-year-old, gravid 1, para 0, woman underwent prenatal ultrasound examination at 12 weeks of gestation, and the ultrasound showed relative macrocephaly, a small non-cystic placenta, and a fetus with absent nasal bone and semilobar HPE. The pregnancy was terminated subsequently, and a 50-g fetus was delivered with a relatively enlarged head and premaxillary agenesis. The placenta was small and non-cystic. Postnatal cytogenetic analysis of the umbilical cord revealed a karyotype of 69, XXX. Postnatal DNA marker analysis using quantitative fluorescent polymerase chain reaction assays and the polymorphic short tandem repeat markers for chromosome 18 and 20 on the placental tissues showed a diallelic pattern with a dosage of 1:2 (paternal allele to maternal allele ratio), indicating a maternal origin of the triploidy.

CONCLUSION:

Fetuses with digynic triploidy may present relative macrocephaly, semilobar HPE and a small placenta on prenatal ultrasound.

KEYWORDS:

Digynic triploidy; Semilobar holoprosencephaly

PMID:
30545546
DOI:
10.1016/j.tjog.2018.11.001
[Indexed for MEDLINE]
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12.
Brain. 2019 Jan 1;142(1):35-49. doi: 10.1093/brain/awy290.

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

Author information

1
Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, F-35000 Rennes, France.
2
Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.
3
Service de Génétique Clinique, CHU, Rennes, France.
4
Laboratoire de Cytogénétique, Cytologie et Histologie Quantitative, Hôpital de Hautepierre, HUS, Strasbourg, France.
5
Service de Génétique et Embryologie Médicales, Hôpital Armand Trousseau, Paris, France.
6
Service de Génétique, CHU, Nantes, France.
7
Service de Génétique, CHU, Lille, France.
8
Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants-Malades, Université Paris Descartes, 149, rue de Sèvres, Paris, France.
9
Department of Clinical Genetics, Centre de Référence “AnDDI Rares”, Poissy Hospital GHU PIFO, Poissy, France.

Abstract

Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10-9). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.

PMID:
30508070
DOI:
10.1093/brain/awy290
[Indexed for MEDLINE]
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13.
Genet Med. 2019 Apr;21(4):1015-1020. doi: 10.1038/s41436-018-0261-8. Epub 2018 Sep 10.

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

Author information

1
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
2
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. mamuenke@mail.nih.gov.

Abstract

PURPOSE:

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

METHODS:

We developed a targeted capture next-generation sequencing (NGS) panel of 153 genes with potential implication in HPE. Sequencing data from a cohort of 136 HPE family trios were analyzed to identify probands with apparently DNVs. DNVs were examined in the proband and their parents to detect any deviations from the expected ~50/50 allele ratio of true heterozygosity. Selected variants were confirmed by Droplet Digital™ polymerase chain reaction (ddPCR).

RESULTS:

We identified 28 high-confidence DNVs, 20 of which occurred in known HPE genes. Nineteen of the 20 variants (95%) were pathogenic or likely pathogenic. Sequence data analysis showed evidence of parental mosaicism in five cases, for an overall mosaicism rate of 26%. In addition, we found evidence for likely postzygotic events in four cases (50%).

CONCLUSIONS:

High sensitivity methods, such as high-depth NGS and ddPCR, are essential to providing an accurate assessment of recurrence risk in HPE families with apparently DNVs.

KEYWORDS:

droplet digital PCR; genetic counseling; holoprosencephaly; next-generation sequencing; somato-gonadal mosaicism

PMID:
30197418
DOI:
10.1038/s41436-018-0261-8
[Indexed for MEDLINE]
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14.
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):122-127. doi: 10.1002/ajmg.c.31624.

Holoprosencephaly from conception to adulthood.

Author information

1
Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
2
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
3
Health Services for Children with Special Needs, Inc., Washington, DC.

Abstract

Holoprosencephaly (HPE) consists of a spectrum of malformations related to incomplete separation of the prosencephalon. There is a wide clinical variability depending on the HPE subtype seen on imaging. Early postnatal lethality is common, however a significant fraction of newborns diagnosed with HPE will survive into childhood and even adulthood. Here we will review the clinical management of HPE during different ages from the prenatal period to adulthood.

KEYWORDS:

holoprosencephaly adult child management

PMID:
30182446
DOI:
10.1002/ajmg.c.31624
[Indexed for MEDLINE]
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15.
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):198-205. doi: 10.1002/ajmg.c.31625.

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

Author information

1
Center for Human Genetics Regensburg, Regensburg, Germany.
2
Medical Faculty, Institute of Human Genetics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
3
Department of Medical Genetics, Children's Hospital Chemnitz, Chemnitz, Germany.
4
Center for Prenatal Diagnosis and Human Genetics, Berlin, Germany.
5
Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen, Germany.

Abstract

Holoprosencephaly (HPE) has been defined as a distinct clinical entity with characteristic facial gestalt, which may-or may not-be associated with the true brain malformation observed postmortem in autopsy or in pre- or postnatal imaging. Affected families mainly show autosomal dominant inheritance with markedly reduced penetrance and extremely broad clinical variability even between mutation carriers within the same families. We here present advances in prenatal imaging over the last years, increasing the proportion of individuals with HPE identified prenatally including milder HPE forms and more frequently allowing to detect more severe forms already in early gestation. We report the results of diagnostic genetic testing of 344 unrelated patients for HPE at our lab in Germany since the year 2000, which currently with the application of next generation sequencing (NGS) panel sequencing identifies causal mutations for about 31% (12/38) of unrelated individuals with normal chromosomes when compared to about 15% (46/306) using conventional Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). More comprehensive genetic testing by our in house NGS panel sequencing of 10 HPE associated genes (MiSeq™ and NextSeq™500, Illumina, Inc., San Diego, CA) not only allowed to include genes with smaller contribution to the phenotype, but may also unravel additional low frequency or more common genetic variants potentially contributing to the observed large intrafamiliar variability and may ultimately guide our understanding of the individual clinical manifestation of this complex developmental disorder.

PMID:
30182445
DOI:
10.1002/ajmg.c.31625
[Indexed for MEDLINE]
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16.
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):117-121. doi: 10.1002/ajmg.c.31621.

Holoprosencephaly flashcards: An updated summary for the clinician.

Author information

1
GeneDx, Gaithersburg, Maryland.
2
Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
PMID:
30182444
DOI:
10.1002/ajmg.c.31621
[Indexed for MEDLINE]
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17.
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):113-116. doi: 10.1002/ajmg.c.31626.

Introduction.

Author information

1
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
2
GeneDx, Gaithersburg, Maryland.
PMID:
30182443
DOI:
10.1002/ajmg.c.31626
[Indexed for MEDLINE]
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18.
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):175-186. doi: 10.1002/ajmg.c.31622.

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

Author information

1
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
2
Division of Human Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
3
Division of Developmental and Behavioral Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
4
General Pediatrics Services Shriners for Children Medical Center, Pasadena, California.
5
General Pediatrics Services Children's Hospital Los Angeles, Los Angeles, California.
6
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
7
Invitae Corporation, San Francisco, California.

Abstract

Holoprosencephaly (HPE), a common developmental forebrain malformation, is characterized by failure of the cerebrum to completely divide into left and right hemispheres. The etiology of HPE is heterogeneous and a number of environmental and genetic factors have been identified. Cytogenetically visible alterations occur in 25% to 45% of HPE patients and cytogenetic techniques have long been used to study copy number variants (CNVs) in this disorder. The karyotype approach initially demonstrated several recurrent chromosomal anomalies, which led to the identification of HPE-specific loci and, eventually, several major HPE genes. More recently, higher-resolution cytogenetic techniques such as subtelomeric multiplex ligation-dependent probe amplification and chromosomal microarray have been used to analyze chromosomal anomalies. By using chromosomal microarray, we sought to identify submicroscopic chromosomal deletions and duplications in patients with HPE. In an analysis of 222 individuals with HPE, a deletion or duplication was detected in 107 individuals. Of these 107 individuals, 23 (21%) had variants that were classified as pathogenic or likely pathogenic by board-certified medical geneticists. We identified multiple patients with deletions in established HPE loci as well as three patients with deletions encompassed by 6q12-q14.3, a CNV previously reported by Bendavid et al. In addition, we identified a new locus, 16p13.2 that warrants further investigation for HPE association. Incidentally, we also found a case of Potocki-Lupski syndrome, a case of Phelan-McDermid syndrome, and multiple cases of 22q11.2 deletion syndrome within our cohort. These data confirm the genetically heterogeneous nature of HPE, and also demonstrate clinical utility of chromosomal microarray in diagnosing patients affected by HPE.

KEYWORDS:

CNV; array CGH; chromosomal microarray; copy number variant; holoprosencephaly

PMID:
30182442
PMCID:
PMC6127867
DOI:
10.1002/ajmg.c.31622
[Indexed for MEDLINE]
Free PMC Article
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19.
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):238-245. doi: 10.1002/ajmg.c.31627.

Challenging issues arising in counseling families experiencing holoprosencephaly.

Author information

1
Human Development Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Abstract

The provision of information and support to families experiencing holoprosencephaly (HPE) in a loved one is unequivocally challenging, even for the most experienced clinicians. It deserves the balance of pertinent information coupled with medical guidance that forms the basis for shared decision-making; all of which is ideally contained within a supportive environment. It requires a willingness to carefully listen to the specific concerns of the parents and family allowing them to revisit challenging issues as much as needed to encourage existing road blocks to be resolved. It necessitates that professionals see each and every family as unique, without preconceived notions about what is or is not important and being prepared to accept thoughts and decisions that may not fit with the professional's own beliefs. To some, this may sound impractical, inefficient, or even impossible within the time constrained models of modern day clinical services. However, in practice, this patient-focused approach is arguably the most essential step in providing "personalized medicine" to the populations we encounter. This manuscript is intended to provide a brief review of relevant literature and case discussions to highlight issues for families learning of the diagnosis of HPE during a pregnancy, at birth, during childhood or more rarely, in adolescence.

KEYWORDS:

genetic counseling; holoprosencephaly

PMID:
30182441
DOI:
10.1002/ajmg.c.31627
[Indexed for MEDLINE]
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20.
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):214-228. doi: 10.1002/ajmg.c.31623.

Neuropathology of holoprosencephaly.

Author information

1
Department of Pathology, CHU Sainte-Justine-Chemin de la Côte Sainte-Catherine, Université de Montreal, Montreal, Québec, Canada.

Abstract

Holoprosencephaly (HPE) is a primary disorder of neural induction and patterning of the rostral neural tube resulting in noncleavage of the forebrain with failure to form two separate distinct hemispheres. The spectrum of HPE is very broad and encompasses various neuropathological phenotypes of different severity. The recent literature has demonstrated that the phenotypic variability of HPE ranges from aprosencephaly-atelencephaly, at the most severe end, to milder forms such as the "middle interhemispheric variant" of HPE at the less severe end of the spectrum. Between them, different intermediate forms demonstrate a continuum in a wide phenotypic spectrum rather than well-defined categories. Although the term "HPE" suggests a disorder affecting only the prosencephalon, other brain structures are involved, underlining the complexity of the malformation. Because of close spatiotemporal interactions and common signaling pathways contributing to the development of both brain and face, concomitant facial and ocular anomalies are associated with brain malformation. In this review, the characteristic neuropathological features of the various forms of HPE are described as well as their associated brain, face, and ocular malformations, to delineate the different phenotypes.

KEYWORDS:

aprosencephaly/atelencephaly; eye anomalies; forebrain anomalies; hindbrain anomalies; holoprosencephaly; midfacial defect; syntelencephaly

PMID:
30182440
DOI:
10.1002/ajmg.c.31623
[Indexed for MEDLINE]
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