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Autopsy & Case Reports 2020
PubMed: 32185147
DOI: 10.4322/acr.2020.152 -
Molecular Genetics & Genomic Medicine Apr 2020Agnathia-otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia,...
BACKGROUND
Agnathia-otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia, aglossia, and abnormally positioned auricles with or without associated anomalies. Variants affecting function of OTX2 and PRRX1, which together regulate the neural crest cells and the patterning of the first pharyngeal arch as well as skeletal and limb development, were identified to be causal for the anomaly in a few patients.
METHODS
Family-based exome sequencing (ES) on a fetus with severe agnathia-otocephaly, cheilognathopalatoschisis, laryngeal hypoplasia, fused lung lobes and other organ abnormalities and mRNA expression analysis were performed.
RESULTS
Exome sequencing detected a de novo SMAD3 missense variant in exon 6 (c.860G>A) associated with decreased mRNA expression. Variants in SMAD3 cause Loeys-Dietz syndrome 3 presenting with craniofacial anomalies such as mandibular hypoplasia, micro- or retro-gnathia, bifid uvula and cleft palate as well as skeletal anomalies and arterial tortuosity. The SMAD3 protein acts as a transcriptional regulator in the transforming growth factor β (TGFB) and bone morphogenetic (BMP) signaling pathways, which play a key role in the development of craniofacial structures originating from the pharyngeal arches.
CONCLUSION
Agnathia-otocephaly with or without associated anomalies may represent the severe end of a phenotypic spectrum related to variants in genes in the interacting SMAD/TGFB/BMP/SHH/FGF developmental pathways.
Topics: Craniofacial Abnormalities; Fetus; Genetic Testing; Humans; Loss of Function Mutation; Phenotype; Smad3 Protein; Ultrasonography, Prenatal; Exome Sequencing
PubMed: 32100971
DOI: 10.1002/mgg3.1178 -
Acta Veterinaria Scandinavica Jan 2020Otocephaly is a rare lethal malformation of the first branchial arch. While the knowledge on the causes of otocephaly in animals is limited, different syndromic forms in...
BACKGROUND
Otocephaly is a rare lethal malformation of the first branchial arch. While the knowledge on the causes of otocephaly in animals is limited, different syndromic forms in man are associated with variants of the PRRX1 and OTX2 genes.
CASE PRESENTATION
A stillborn male lamb of the Istrian Pramenka sheep breed showed several congenital craniofacial anomalies including microstomia, agnathia, aglossia, and synotia. In addition, the lamb had a cleft palate, a small opening in the ventral neck region, a cystic oesophagus and two hepatic cysts. The brain was normally developed despite the deformed shape of the head. Taken together the findings led to a diagnosis of otocephaly. Whole-genome sequencing was performed from DNA of the affected lamb and both parents revealing a heterozygous single nucleotide variant in the OTX2 gene (Chr7: 71478714G > A). The variant was absent in both parents and therefore due to a de novo mutation event. It was a nonsense variant, XM_015097088.2:c.265C > T; which leads to an early premature stop codon and is predicted to truncate more than 70% of the OTX2 open reading frame (p.Arg89*).
CONCLUSIONS
The genetic findings were consistent with the diagnosis of the otocephaly and provide strong evidence that the identified loss-of-function variant is pathogenic due to OTX2 haploinsufficiency. The benefits of trio-based whole-genome sequencing as an emerging tool in veterinary pathology to confirm diagnosis are highlighted.
Topics: Animals; Craniofacial Abnormalities; Genetic Variation; Mutation; Otx Transcription Factors; Sheep; Sheep Diseases
PubMed: 31969185
DOI: 10.1186/s13028-020-0503-z -
Prenatal Diagnosis Apr 2020The objective of this study is to evaluate the prenatal diagnosis, postnatal characteristics, and the spectrum of associated findings in fetuses with holoprosencephaly...
OBJECTIVE
The objective of this study is to evaluate the prenatal diagnosis, postnatal characteristics, and the spectrum of associated findings in fetuses with holoprosencephaly (HPE).
METHODS
Fetal neurosonograms, postnatal assessment, and chromosomal analysis were performed in a cohort of 25 fetuses with HPE.
RESULTS
The prevalence of HPE in high-risk pregnancies was 4.4:10 000. The alobar subtype was the most frequently encountered, with 17 cases (68%). Interestingly, among them, four cases (16%) presented with the rare agnathia-otocephaly complex. Chromosomal abnormalities were detected in 11 cases (44%), the most frequent being trisomy 13 in seven cases (five alobar, one semilobar, and one lobar HPE), followed by trisomy 18 in two cases with semilobar HPE. One case of alobar HPE had 45, XX, t(18;22) (q10;q10), -18p karyotyping, and one case of semilobar HPE was associated with triploidy. Facial malformations in HPE spectrum ranged from cyclopia, proboscis, and arrhinia that were associated with the alobar subtype to hypotelorism and median cleft that were frequent among the semilobar and lobar subtypes. Associated neural tube defects were identified in 12% of cases.
CONCLUSION
Our study illustrates the clinical and genetic heterogeneity of HPE and describes different chromosomal abnormalities associated with HPE.
Topics: Abortion, Induced; Adolescent; Adult; Chromosome Disorders; Chromosomes, Human, Pair 18; Chromosomes, Human, Pair 22; Consanguinity; Craniofacial Abnormalities; Egypt; Encephalocele; Female; Fetal Death; Hernia, Umbilical; Holoprosencephaly; Humans; Male; Neural Tube Defects; Pregnancy; Pregnancy in Diabetics; Prevalence; Translocation, Genetic; Triploidy; Trisomy 13 Syndrome; Trisomy 18 Syndrome; Ultrasonography, Prenatal; Young Adult
PubMed: 31955448
DOI: 10.1002/pd.5649 -
The Journal of Craniofacial Surgery 2020Agnathia-otocephaly complex (AOC) is a rare malformation complex of the first pharyngeal arch that is characterized by agnathia/dysgnathia, microstomia,...
Agnathia-otocephaly complex (AOC) is a rare malformation complex of the first pharyngeal arch that is characterized by agnathia/dysgnathia, microstomia, aglossia/hypoglossia and variable displacement of the ears. Only 11 post-infancy patients with severe AOC have been described in the literature, and the incidence of this malformation complex is estimated to be 1 per 70,000 births. In this brief clinical study, the authors describe the case of an 18-year-old female diagnosed with AOC who underwent a 3-step mandibular distraction protocol with an external distraction device. The surgical protocol the authors used was unique in that we first placed a tissue expander in the submental area to enlarge the skin envelope in an effort to mitigate skeletal relapse from soft tissue forces. Furthermore, the way in which the authors slowed the activation of the distraction device to allow for soft tissue healing behind the pins was a novel component of the patient's treatment. The 3-step mandibular distraction protocol the authors present in this study increased the length of the mandible by 20 mm, and nearly doubled the size of the patient's mandible from an initial volume of 3.62 cm to a post-operative volume of 6.89 cm. Future surgeries will aim to improve the function of our patient's expanded mandible. Most important of all, the surgical treatment authors are presenting led to a significant improvement in our patient's physical appearance and 3d quality of life.
Topics: Adolescent; Craniofacial Abnormalities; Female; Humans; Jaw Abnormalities; Mandible; Osteogenesis, Distraction; Quality of Life
PubMed: 31634311
DOI: 10.1097/SCS.0000000000005945