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PloS One 2014Disruption of the Hedgehog signaling pathway has been implicated as an important molecular mechanism in the pathogenesis of fetal alcohol syndrome. In severe cases, the...
Disruption of the Hedgehog signaling pathway has been implicated as an important molecular mechanism in the pathogenesis of fetal alcohol syndrome. In severe cases, the abnormalities of the face and brain that result from prenatal ethanol exposure fall within the spectrum of holoprosencephaly. Single allele mutations in the Hh pathway genes Sonic Hedgehog (SHH) and GLI2 cause holoprosencephaly with extremely variable phenotypic penetrance in humans. Here, we tested whether mutations in these genes alter the frequency or severity of ethanol-induced dysmorphology in a mouse model. Timed pregnancies were established by mating Shh(+/-) or Gli2(+/-) male mice backcrossed to C57BL/6J strain, with wildtype females. On gestational day 7, dams were treated with two i.p. doses of 2.9 g/kg ethanol (or vehicle alone), administered four hrs apart. Fetuses were then genotyped and imaged, and the severity of facial dysmorphology was assessed. Following ethanol exposure, mean dysmorphology scores were increased by 3.2- and 6.6-fold in Shh(+/-) and Gli2(+/-) groups, respectively, relative to their wildtype littermates. Importantly, a cohort of heterozygous fetuses exhibited phenotypes not typically produced in this model but associated with severe holoprosencephaly, including exencephaly, median cleft lip, otocephaly, and proboscis. As expected, a correlation between the severity of facial dysmorphology and medial forebrain deficiency was observed in affected animals. While Shh(+/-) and Gli2(+/-) mice have been described as phenotypically normal, these results illustrate a functional haploinsufficiency of both genes in combination with ethanol exposure. By demonstrating an interaction between specific genetic and environmental risk factors, this study provides important insights into the multifactorial etiology and complex pathogenesis of fetal alcohol syndrome and holoprosencephaly.
Topics: Animals; Crosses, Genetic; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Genotype; Hedgehog Proteins; Holoprosencephaly; Kruppel-Like Transcription Factors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Pregnancy; Prosencephalon; Signal Transduction; Zinc Finger Protein Gli2
PubMed: 24586787
DOI: 10.1371/journal.pone.0089448 -
Molecular Syndromology Sep 2013Otocephaly-dysgnathia complex is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Mutations in the orthodenticle homeobox...
Otocephaly-dysgnathia complex is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Mutations in the orthodenticle homeobox 2 (OTX2) and paired related homeobox 1 (PRRX1) genes have recently been identified in some cases. We screened 4 otocephalic cases for these 2 genes and identified OTX2 mutations in 2 of them, thus confirming OTX2 is implicated in otocephaly. No PRRX1 mutation was identified. Interestingly, ocular involvement is not a constant feature in otocephalic cases with an OTX2 mutation. In one case, the mutation was inherited from a microphthalmic mother. The mechanism underlying this intrafamilial phenotypic variability remains unclear, but other genetic factors are likely to be necessary for the manifestation of the otocephalic phenotype.
PubMed: 24167467
DOI: 10.1159/000353727 -
Journal of Ultrasound in Medicine :... Aug 2013
Topics: Adult; Craniofacial Abnormalities; Diagnosis, Differential; Ear, External; Female; Humans; Jaw Abnormalities; Magnetic Resonance Imaging; Microstomia; Pregnancy; Ultrasonography, Prenatal
PubMed: 23887968
DOI: 10.7863/ultra.32.8.1522 -
American Journal of Medical Genetics.... Apr 2013Agnathia-otocephaly is a rare craniofacial malformation complex that is caused by de novo heterozygous and biallelic mutations in PRRX1 in two unrelated babies,...
Agnathia-otocephaly is a rare craniofacial malformation complex that is caused by de novo heterozygous and biallelic mutations in PRRX1 in two unrelated babies, respectively. We studied the PRRX1 gene in a non-consanguineous Indonesian female infant who was diagnosed prenatally with severe retrognathia (bilateral Pruzansky type III). Her older affected brother died shortly after birth and had agnathia-otocephaly. A c.266_269dupAAAA frameshift mutation in the poly A tract in PRRX1 was identified in the proband while her father only had an inframe duplication (c.267_269dupAAA) of the adenosine trinucleotide residue. Expression of both mutations in COS7 cells showed loss of function of the frame shift mutation only. Results of SNP genotyping coupled with recurrence of this novel mutation in this family are consistent with a paternally derived germline mosaicism rather than autosomal recessive inheritance as predicted by the family history. Severe retrognathia (bilateral Pruzansky III) and agnathia-otocephaly represent a spectrum of craniofacial malformations in this family.
Topics: Animals; Autopsy; COS Cells; Chlorocebus aethiops; Craniofacial Abnormalities; DNA Replication; Fatal Outcome; Female; Frameshift Mutation; Gene Expression; Genes, Reporter; Heterozygote; Homeodomain Proteins; Humans; Infant, Newborn; Jaw Abnormalities; Mosaicism; Open Reading Frames
PubMed: 23444262
DOI: 10.1002/ajmg.a.35879 -
Prenatal Diagnosis Sep 2012
Topics: Animals; COS Cells; Chlorocebus aethiops; Craniofacial Abnormalities; DNA Mutational Analysis; Fatal Outcome; Female; Frameshift Mutation; Heterozygote; Homeodomain Proteins; Humans; Infant, Newborn; Jaw Abnormalities; Pregnancy; Ultrasonography, Prenatal
PubMed: 22674740
DOI: 10.1002/pd.3910 -
Journal of Medical Genetics Jun 2012Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this...
BACKGROUND
Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans.
METHODS AND RESULTS
This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly, suggesting a genetic relationship between anophthalmia and otocephaly. OTX2, a known microphthalmia locus, was screened in this family and a frameshifting mutation was found. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation. Because OTX2 mutations may not be sufficient to cause otocephaly, the study assayed the potential of otx2 to modify craniofacial phenotypes in the context of known otocephaly gene suppression in vivo. It was found that otx2 can interact genetically with pgap1, prrx1, and msx1 to exacerbate mandibular and midline defects during zebrafish development. However, sequencing of these loci in the OTX2-positive families did not unearth likely pathogenic lesions, suggesting further genetic heterogeneity and complexity.
CONCLUSION
Identification of OTX2 involvement in otocephaly/dysgnathia in humans, even if loss of function mutations at this locus does not sufficiently explain the complex anatomical defects of these patients, suggests the requirement for a second genetic hit. Consistent with this notion, trans suppression of otx2 and other developmentally related genes recapitulate aspects of the otocephaly phenotype in zebrafish. This study highlights the combined utility of genetics and functional approaches to dissect both the regulatory pathways that govern craniofacial development and the genetics of this disease group.
Topics: Animals; Base Sequence; Disease Models, Animal; Embryo, Nonmammalian; Female; Holoprosencephaly; Humans; Jaw Abnormalities; Molecular Sequence Data; Otx Transcription Factors; Pedigree; Sequence Analysis, DNA; Zebrafish
PubMed: 22577225
DOI: 10.1136/jmedgenet-2012-100892 -
Veterinary Pathology Nov 2012Aprosencephaly is a rare condition in veterinary and human medicine characterized by the complete absence of telencephalon and diencephalon. Some cases are accompanied...
Aprosencephaly is a rare condition in veterinary and human medicine characterized by the complete absence of telencephalon and diencephalon. Some cases are accompanied by a facial dysmorphism designated as otocephaly. A stillborn lamb had splanchnocranial anomalies that were classified by computed tomography, magnetic resonance imaging, and pathologic examination as aprosencephaly and otocephaly. The brain included parts of the cerebellum and brainstem but no telencephalon, diencephalon, or mesencephalon. The cerebellum had a structurally normal cortex with expression of neuronal nuclear antigen in the inner and doublecortin in the outer granular cell layers, as well as an irregularly situated nucleus dentatus. Aprosencephaly with otocephaly has been described in mice with heterozygous mutations in the Otx2 gene; however, no causative polymorphisms were detected in the Otx2 gene region of this lamb.
Topics: Anencephaly; Animals; Brain Stem; Cerebellum; Craniofacial Abnormalities; DNA; Female; Immunohistochemistry; Magnetic Resonance Imaging; Male; Otx Transcription Factors; Phenotype; Pregnancy; Sequence Analysis, DNA; Sheep; Sheep Diseases; Skull; Stillbirth; Tomography, X-Ray Computed
PubMed: 22431914
DOI: 10.1177/0300985812439722 -
Gene Feb 2012Agnathia-otocephaly is a rare, often lethal malformation characterized by absence or hypoplasia of the mandible, microstomia, hypoglossia/aglossia, and variable anterior...
Agnathia-otocephaly is a rare, often lethal malformation characterized by absence or hypoplasia of the mandible, microstomia, hypoglossia/aglossia, and variable anterior midline fusion of the ears (melotia, synotia). Etiologies have been linked to both genetic and teratogenic factors and to date, a definitive, commonly identifiable cause has not been recognized. Mouse and human genetic studies have implicated OTX2 and PRRX1 as potential candidate genes for agnathia-otocephaly. In this study we report a sporadic case of agnathia-otocephaly complex with associated features of maldevelopment and examine the roles of OTX2 and PRRX1. The proband, a male born at 31 weeks, displayed severe micrognathia, microstomia, posteriorly-rotated and low set ears, and downward slanting palpebral fissures. Mutation analysis was performed after sequencing the entire coding regions of OTX2 and PRRX1 genes isolated from the proband and his parents. After thorough analysis, no DNA variations were detected. This suggests that mutations in different genes or environmental causes are responsible.
Topics: Ear; Holoprosencephaly; Homeodomain Proteins; Humans; Infant, Newborn; Jaw Abnormalities; Otx Transcription Factors
PubMed: 22198066
DOI: 10.1016/j.gene.2011.11.033 -
Journal of Pediatric Neurosciences Jan 2011
PubMed: 21977107
DOI: 10.4103/1817-1745.84426 -
Ginecologia Y Obstetricia de Mexico Aug 2011Otocephaly is a rare and lethal congenital malformation characterized by the presence of agnathia, microstomia, aglossia and synotia. Despite its frequent association...
Otocephaly is a rare and lethal congenital malformation characterized by the presence of agnathia, microstomia, aglossia and synotia. Despite its frequent association with severe malformations, diagnosis in the few published cases is usually made at III trimester. In this case, three-dimensional ultrasound scan was performed in a Chinese primigravida with no remarkable personal nor familiar history since mandible was difficulty visualized with two-dimensional sonography at 21 weeks of gestation. Multiplanar and rendering mode showed the typical cervicofacial features of otocephaly without associated malformations. After parental counselling, they opted for termination of pregnancy and necropsy confirmed our prenatal findings. Our case shows the usefulness of three-dimensional ultrasound in assessing fetal cervicofacial pathology. Volumetric capture allows a delayed study of fetal anatomy and multiplanar mode offers the reconstruction of views whose achivement is difficult with conventional 2D ultrasound. Surface rendering provides excellent spatial vision and enables parents to understand the severity of the malformation thus helping with their decisions.
Topics: Abortion, Eugenic; Branchial Region; China; Craniofacial Abnormalities; Female; Humans; Imaging, Three-Dimensional; Infant, Newborn; Pregnancy; Pregnancy Trimester, Second; Ultrasonography, Prenatal; Young Adult
PubMed: 21966847
DOI: No ID Found