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Clinical Oral Investigations Mar 2021Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This... (Review)
Review
OBJECTIVES
Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This severe anomaly of the first branchial arch is most often lethal. The estimated incidence is less than 1 in 70.000 births, with etiologies linked to both genetic and teratogenic factors. Most of the cases are sporadic. To date, two genes have been described in humans to be involved in this condition: OTX2 and PRRX1. Nevertheless, the overall proportion of mutated cases is unknown and a significant number of patients remain without molecular diagnosis. Thus, the involvement of other genes than OTX2 and PRRX1 in the agnathia-otocephaly complex is not unlikely. Heterozygous mutations in Cnbp in mice are responsible for mandibular and eye defects mimicking the agnathia-otocephaly complex in humans and appear as a good candidate. Therefore, in this study, we aimed (i) to collect patients presenting with agnathia-otocephaly complex for screening CNBP, in parallel with OTX2 and PRRX1, to check its possible implication in the human phenotype and (ii) to compare our results with the literature data to estimate the proportion of mutated cases after genetic testing.
MATERIALS AND METHODS
In this work, we describe 10 patients suffering from the agnathia-otocephaly complex. All of them benefited from array-CGH and Sanger sequencing of OTX2, PRRX1 and CNBP. A complete review of the literature was made using the Pubmed database to collect all the patients described with a phenotype of agnathia-otocephaly complex during the 20 last years (1998-2019) in order (i) to study etiology (genetic causes, iatrogenic causes…) and (ii), when genetic testing was performed, to study which genes were tested and by which type of technologies.
RESULTS
In our 10 patients' cohort, no point mutation in the three tested genes was detected by Sanger sequencing, while array-CGH has allowed identifying a 107-kb deletion encompassing OTX2 responsible for the agnathia-otocephaly complex phenotype in 1 of them. In 4 of the 70 cases described in the literature, a toxic cause was identified and 22 out the 66 remaining cases benefited from genetic testing. Among those 22 patients, 6 were carrying mutation or deletion in the OTX2 gene and 4 in the PRRX1 gene. Thus, when compiling results from our cohort and the literature, a total of 32 patients benefited from genetic testing, with only 34% (11/32) of patients having a mutation in one of the two known genes, OTX2 or PRRX1.
CONCLUSIONS
From our work and the literature review, only mutations in OTX2 and PRRX1 have been found to date in patients, explaining around one third of the etiologies after genetic testing. Thus, agnathia-otocephaly complex remains unexplained in the majority of the patients, which indicates that other factors might be involved. Although involved in first branchial arch defects, no mutation in the CNBP gene was found in this study. This suggests that mutations in CNBP might not be involved in such phenotype in humans or that, unlike in mice, a compensatory effect might exist in humans. Nevertheless, given that agnathia-otocephaly complex is a rare phenotype, more patients have to be screened for CNBP mutations before we definitively conclude about its potential implication. Therefore, this work presents the current state of knowledge on agnathia-otocephaly complex and underlines the need to expand further the understanding of the genetic bases of this disorder, which remains largely unknown.
CLINICAL RELEVANCE
We made here an update and focus on the clinical and genetic aspects of agnathia-otocephaly complex as well as a more general review of craniofacial development.
Topics: Animals; Craniofacial Abnormalities; Humans; Jaw Abnormalities; Mice; Mutation; Phenotype
PubMed: 32643087
DOI: 10.1007/s00784-020-03443-w -
Autopsy & Case Reports 2020
PubMed: 32185147
DOI: 10.4322/acr.2020.152 -
Journal of Obstetrics and Gynaecology... Aug 2022Otocephaly is a rare malformation characterized by agnathia (absence of the mandible), melotia (medially displaced ear pinna), aglossia (absence of the tongue) and...
INTRODUCTION
Otocephaly is a rare malformation characterized by agnathia (absence of the mandible), melotia (medially displaced ear pinna), aglossia (absence of the tongue) and microstomia (small oral aperture). This results due to failure of migration of the neural crest cells and is a defect of the first branchial arch. It is incompatible with life and early prenatal diagnosis is useful.
CASE REPORT
Our patient a primigravida with 19 weeks 6 days gestation was referred for micrognathia and polyhydramnios. On ultrasound examination, she had unilateral mild ventriculomegaly and posterior fossa cyst in the fetal brain. The fetus had agnathia and anophthalmia. There was an echogenic intracardiac focus and echogenic bowel. The stomach was not seen clearly. This could be due to agnathia and microstomia leading to swallowing difficulties. The patient was explained about the guarded prognosis. The pregnancy was terminated. A diagnosis of otocephaly was made.
DISCUSSION
Otocephaly is a rare disorder of development of the first branchial arch. The reported incidence is 1 in 70,000. It is mostly lethal due to respiratory difficulties and may be associated with cranial and extracranial malformations. Most case reports have found that it is sporadic and could be due to mutations in the PRRX1 gene. Other anomalies that may be associated with otocephaly are neural tube defects, cephalocele, dysgenesis of corpus callosum, atresia of the third ventricle, midline probocis, hypotelorism, renal ectopia, cyclopia, vertebral and rib abnormalities, tracheo esophageal fistula, cardiac anomalies and adrenal hypoplasia. Most of the cases reported so far were diagnosed in the second or the third trimester. Facial anomaly screening has undergone a huge evolution in the recent years. In addition to the usual facial screening, we recommend mandibular arch screening in the first and early second trimester. If there is a doubt the patient may be called back at 15 to 16 weeks of gestation considering the fact that these anomalies are usually lethal and medical termination is safer earlier in pregnancy than later. MRI may be a handy tool to confirm antenatal diagnosis as it can detect the abnormal ears. Agnathia and polyhydramnios occur together in the third trimester but in the first or second trimester polyhydramnios may not be observed.
CONCLUSION
Otocephaly, though rare, poses a clinical challenge for both patient and the reporting doctor. Considering the time limitation for termination of pregnancy in our country, early prenatal diagnosis is important. A detailed face evaluation in the first trimester can help detect this defect as early as 11-14 weeks. Early diagnosis of lethal anomalies helps in completing the fetal work up and offering a safer termination. Correct diagnosis and work up of fetal anomalies allows for documentation and awareness of the presence of these conditions in our population.
PubMed: 35923505
DOI: 10.1007/s13224-021-01494-x -
BMJ Case Reports Apr 2022The case presented here shows the rare diagnosis of fetal otocephaly with lethal prognosis due to impossible airway management after birth. Otocephaly is characterised...
The case presented here shows the rare diagnosis of fetal otocephaly with lethal prognosis due to impossible airway management after birth. Otocephaly is characterised by fetal agnathia, microstomia and synotia. As in our case, otocephaly is usually not recognised until the third trimester and leads to challenging clinical situations and decision making.A woman in her 30s presented to our tertiary hospital at 27 weeks of gestation because of an unexplained polyhydramnios. 3D imaging illustrated the complex syndrome of otocephaly and helped understand the present disease patterns. After premature birth, palliative care was agreed on and the newborn was able to pass away peacefully in the arms of his parents.We recommend the implementation of 3D imaging into routine scans for the assessment of the fetal face and ears, especially in situations of unexplained polyhydramnios.
Topics: Craniofacial Abnormalities; Female; Humans; Imaging, Three-Dimensional; Infant, Newborn; Jaw Abnormalities; Polyhydramnios; Pregnancy; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 35459654
DOI: 10.1136/bcr-2022-249276 -
Journal of Human Genetics Apr 2015Agnathia-otocephaly complex is a malformation characterized by absent/hypoplastic mandible and abnormally positioned ears. Mutations in two genes, PRRX1 and OTX2, have...
Agnathia-otocephaly complex is a malformation characterized by absent/hypoplastic mandible and abnormally positioned ears. Mutations in two genes, PRRX1 and OTX2, have been described in a small number of families with this disorder. We performed clinical and genetic testing in an additional family. The proband is a healthy female with a complicated pregnancy history that includes two offspring diagnosed with agnathia-otocephaly during prenatal ultrasound scans. Exome sequencing was performed in fetal DNA from one of these two offspring revealing a heterozygous duplication in OTX2: c.271_273dupCAG, p.(Gln91dup). This change leads to the insertion of a glutamine within the OTX2 homeodomain region, and is predicted to alter this signaling molecule's ability to interact with DNA. The same variant was also identified in the proband's clinically unaffected 38-year-old husband and their 9-year-old daughter, who presented with a small mandible, normal ears and velopharyngeal insufficiency due to a short hemi-palate. This unusual presentation of OTX2-related disease suggests that OTX2 might have a role in palatal hypoplasia cases. A previously unreported OTX2 variant associated with extreme intrafamilial variability is described and the utility of exome sequencing as a tool to confirm the diagnosis of agnathia-otocephaly and to inform the reproductive decisions of affected families is highlighted.
Topics: Abnormalities, Multiple; Adult; Child; Female; Gene Duplication; Genetic Association Studies; Heterozygote; Humans; Male; Models, Molecular; Mutation; Otx Transcription Factors; Pedigree; Phenotype; Protein Conformation; Reading Frames; Velopharyngeal Insufficiency
PubMed: 25589041
DOI: 10.1038/jhg.2014.122 -
A & a Case Reports Jul 2016Otocephaly complex is a rare and usually lethal syndrome characterized by a set of malformations consisting of microstomia, mandibular hypoplasia/agnathia, and... (Review)
Review
Otocephaly complex is a rare and usually lethal syndrome characterized by a set of malformations consisting of microstomia, mandibular hypoplasia/agnathia, and ventromedial malposition of the ears. Those cases that have been diagnosed prenatally have used an ex utero intrapartum treatment procedure to establish a definitive airway. However, prenatal diagnosis continues to be challenging, primarily because of poor diagnostic sensitivity associated with ultrasonography. We present a case of a newborn with an unanticipated otocephaly complex requiring emergent airway management. In this report, we discuss the medical and ethical issues related to the care of a newborn with this frequently fatal condition.
Topics: Craniofacial Abnormalities; Fatal Outcome; Female; Humans; Infant, Newborn; Withholding Treatment; Young Adult
PubMed: 27258179
DOI: 10.1213/XAA.0000000000000340 -
Translational Pediatrics Aug 2021Agnathia-otocephaly complex (AOC) is a rare and complex craniofacial malformation characterized by mandibular hypoplasia or agnathia, auricular fusion (synotia), and...
Agnathia-otocephaly complex (AOC) is a rare and complex craniofacial malformation characterized by mandibular hypoplasia or agnathia, auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. It can occur alone or in combination with forebrain anomalies and cardiac malformations and has an extremely poor prognosis. Here, we report a case of AOC diagnosed by systemic fetal screening at a gestational age of 25 weeks. Ultrasound revealed that the S-curve formed by the normal lower jaw and lower lip had disappeared, the lower jaw and mandible were invisible, the mouth was extremely small, and the oral fissure was "pinhole-shaped". There was a cone-shaped perioral bulge. Both ears were located in the front side of the neck, and the right foot was inverted. Excessive amniotic fluid was observed. The absence of a mandible was confirmed on X-ray examination after induced abortion. Specimen observation showed that the ear positions were extremely low, and both earlobes were connected in the front side of the neck. It was particularly challenging to identify the development of the mandible and locate auricles during prenatal ultrasound diagnosis, and the prenatal diagnosis of AOC was confirmed by combining two-dimensional and three-dimensional ultrasound in our current case.
PubMed: 34584884
DOI: 10.21037/tp-21-235 -
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 -
Medical Ultrasonography Dec 2014A case of prenatally diagnosed otocephaly is reported. Otocephaly is an extremely rare malformation characterized by absence or hypoplasia of the mandible and abnormal...
A case of prenatally diagnosed otocephaly is reported. Otocephaly is an extremely rare malformation characterized by absence or hypoplasia of the mandible and abnormal horizontal position of the ears. 2D ultrasound performed at 25 weeks of gestation revealed agnathia, proboscis and hypotelorism. 3D ultrasound (rendering mode) and magnetic resonance imaging were used to evaluate the facial features, and were essential for characterization of facial malformations in otocephaly and for the demonstration and correct prenatal counseling of the couple.
Topics: Abnormalities, Multiple; Adult; Craniofacial Abnormalities; Fatal Outcome; Female; Humans; Imaging, Three-Dimensional; Infant, Newborn; Magnetic Resonance Imaging; Pregnancy; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 25463893
DOI: 10.11152/mu.201.3.2066.164.wjh1 -
Cureus Jul 2023Otocephaly is a rare congenital abnormality characterized by the absence or underdevelopment of the mandible, misplacement of the ears towards the front, a small mouth,...
Otocephaly is a rare congenital abnormality characterized by the absence or underdevelopment of the mandible, misplacement of the ears towards the front, a small mouth, and absence or underdevelopment of the tongue. The syndrome complex of otocephaly can be categorized into four types based on associated anomalies. We present a case of this congenital anomaly in a newborn baby delivered by a 40-year-old woman who presented in active labor with premature rupture of membranes. Unfortunately, the newborn did not survive due to severe respiratory distress, which was consistent with the clinical features of this congenital anomaly. The rarity of otocephaly poses challenges for both parents and healthcare providers. Early antenatal scans are suggested for the early diagnosis of this condition. Further research and awareness are needed to better understand and manage this rare congenital disorder.
PubMed: 37575700
DOI: 10.7759/cureus.41767