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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 -
Journal of the Chinese Medical... Jul 2007Otocephaly is a rare lethal syndrome of microstomia, aglossia, agnathia, and synotia. This male infant was born to a 19-year-old, gravida 1, para 0, woman who received...
Otocephaly is a rare lethal syndrome of microstomia, aglossia, agnathia, and synotia. This male infant was born to a 19-year-old, gravida 1, para 0, woman who received routine prenatal check-up. Polyhydramnios, low-lying ears, and proboscis were noted by sonography at 29 weeks of gestation. Amniocentesis showed a normal karyotype of 46, XY. Premature rupture of membranes and preterm labor were noted at 32 weeks of gestation. A male infant was delivered preterm and died shortly after birth. The infant showed midline proboscis and absence of mandible. The simple, soft ears were extremely low-set and were near the midline of the neck. Otocephaly is regarded as the most severe form of first arch anomalies. Prenatal diagnosis should be dependent on ultrasound analysis. In the face of polyhydramnios, otocephaly is one of the possible fetal anomalies.
Topics: Abnormalities, Multiple; Adult; Ear; Female; Humans; Infant, Newborn; Male; Microstomia; Pregnancy; Syndrome; Ultrasonography, Prenatal
PubMed: 17631468
DOI: 10.1016/S1726-4901(07)70009-6 -
Autopsy & Case Reports 2020
PubMed: 32185147
DOI: 10.4322/acr.2020.152 -
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 -
American Journal of Medical Genetics Oct 1989Otocephaly ("agnathia") is a developmental field complex with structural defects limited to the craniofacial region. Previously, two infants with otocephaly, situs... (Comparative Study)
Comparative Study
Otocephaly ("agnathia") is a developmental field complex with structural defects limited to the craniofacial region. Previously, two infants with otocephaly, situs inversus totalis, renal defects, and vertebral and rib abnormalities were reported by Pauli et al. [Teratology 23:85-93, 1981]. We describe a similarly affected infant male, supporting the existence of this midline malformation association. A generalized disturbance in cell migration from the primitive streak may be its pathogenesis. A search for additional patients among cases of otocephaly may establish its prevalence, patterns of associated anomalies, and cause.
Topics: Facial Bones; Humans; Infant, Newborn; Male; Ribs; Situs Inversus; Skull; Syndrome
PubMed: 2817004
DOI: 10.1002/ajmg.1320340223 -
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 -
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 -
European Journal of Medical Genetics 2010Agnathia-otocephaly, a rare, sporadic and lethal malformation, is characterized by microstomia (small mouth), aglossia (absence of the tongue), agnathia (absence of the... (Review)
Review
Agnathia-otocephaly, a rare, sporadic and lethal malformation, is characterized by microstomia (small mouth), aglossia (absence of the tongue), agnathia (absence of the lower jaw) and abnormally positioned ears. It is a principal anomaly derived from the first pharyngeal arch as a consequence of failed mesenchymal migration of the maxillary prominence and atrophy in the development of the mandibular prominences. Unfortunately, these patients have poor prognoses and may succumb to death shortly after birth due to respiratory problems if appropriate airway management is not implemented. Difficulties persist in the prenatal diagnosis of agnathia-otocephalic patients. However, two- and three-dimensional ultrasonography, computed tomography and magnetic resonance imaging technologies now offer significant improvements in refining the resolution of distinctive facial anomalies. This complex disorder can be attributed to both genetic and teratogenic causes, in addition to other unidentifiable factors. Furthermore, studies in model organisms, in particular mice, have unraveled potential genetic pathways that may contribute to the etiology. This article highlights current perspectives on agnathia-otocephaly with a focus on the etiological causes and issues concerning prenatal diagnosis, differential diagnosis, prognosis and genetic counseling. Finally, studies using animal models especially genetically engineered mice are described to comprehend the molecular genetic interactions that may occur during the genesis of this intriguing craniofacial birth defect.
Topics: Abnormalities, Multiple; Airway Management; Animals; Branchial Region; Ear; Face; Female; Fetal Diseases; Humans; Magnetic Resonance Imaging; Mandible; Maxillofacial Abnormalities; Mice; Mice, Transgenic; Microstomia; Pregnancy; Prenatal Diagnosis; Syndrome; Tomography, X-Ray Computed; Tongue; Ultrasonography, Prenatal
PubMed: 20849990
DOI: 10.1016/j.ejmg.2010.09.002 -
Journal of Ultrasound in Medicine :... Mar 2019First-trimester ultrasound findings in 4 fetuses with agnathia-otocephaly complex are described. In addition, information from 3 cases reported in the literature was... (Review)
Review
First-trimester ultrasound findings in 4 fetuses with agnathia-otocephaly complex are described. In addition, information from 3 cases reported in the literature was also reviewed, for a total of 7 cases analyzed. All 7 fetuses presented with agnathia and 6 with ventrocaudal displacement of the ears (melotia/synotia). Four fetuses had holoprosencephaly. In 6 cases, the parents opted for termination of pregnancy. The remaining case resulted in premature delivery at 26 weeks due to severe polyhydramnios and early neonatal death. This report highlights the important role of ultrasound in the identification of agnathia-otocephaly complex in the first trimester of pregnancy.
Topics: Abortion, Eugenic; Adult; Craniofacial Abnormalities; Female; Holoprosencephaly; Humans; Imaging, Three-Dimensional; Infant; Infant Death; Infant, Newborn; Pregnancy; Pregnancy Trimester, First; Retrospective Studies; Ultrasonography, Prenatal; Young Adult
PubMed: 30171631
DOI: 10.1002/jum.14759 -
Birth Defects Research Oct 2020Agnathia otocephaly is a rare craniofacial malformation complex characterised by absent/hypoplastic mandible, abnormally positioned ears meeting at level of neck....
BACKGROUND
Agnathia otocephaly is a rare craniofacial malformation complex characterised by absent/hypoplastic mandible, abnormally positioned ears meeting at level of neck. Besides mutations in two genes, PRRX1 and OTX2, a teratogenic cause has been suggested. A higher risk of congenital malformations has been associated with paternal work in mining in the Democratic Republic of the Congo's part of the Copperbelt.
CASE
We studied a female neonate with a clinical diagnosis of agnathia otocephaly, stillborn in Lubumbashi in 2019. The child's father had been working as an artisanal mineworker at the time of conception.
RESULTS
Genetic analysis did not reveal a causal mutation. The concentrations of cobalt, arsenic cadmium, and uranium in cord blood of the infant were much higher than those of normal neonates from a previous study.
CONCLUSION
In the absence of identified genetic causes, we hypothesize this case of agnathia otocephaly was related to an exogenous cause, possibly the father's mining-related job.
Topics: Child; Craniofacial Abnormalities; Democratic Republic of the Congo; Female; Homeodomain Proteins; Humans; Infant; Infant, Newborn; Jaw Abnormalities; Zambia
PubMed: 32639113
DOI: 10.1002/bdr2.1758