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Cyclopia-otocephaly association: A new case of the most severe variant of agnathia-holoprosencephaly complex
Abstract
This report describes a new case of true cyclopia with otocephaly and additional brain malformations (alobar holoprosencephaly). This is a very rare occurrence involving lack of cleavage of the prosencephalon and disturbed development of the first branchial arch. An inductive defect of the prechordal mesoderm is considered as the cause for this malformation, which is a part of agnathia-holoprosencephaly complex.
... Extracranial anomalies can also be observed. Arhinencephaly is regarded as a minor clinical expression of holoprosencephaly which is a midline anomaly defined as absence or incomplete cleavage and rotation of the forebrain of various etiologies [6][7][8]. We report here a fetopathologic examination of a fetus having an arhinencephaly, synophthalmia associated with holoprosencephaly. ...
... In typical form, it is accompanied with the absence of all structures present between the ocular globes. We have a single median eye in single ocular globe [8,9]. Therefore, synophthalmia (Figure 2a), is a variant form of cyclopia that associates a single median eye with two ocular globes partially fused in median position [5]. ...
... It is always combined with severe midline facial defect like arhinencephaly, synophtalmia observed in our case. The degree of severity of the facial abnormalities is correlated with the forebrain deficiency type [8]. That leads DeMyer [14] to write: "The face predicts the brain" in 80% of cases. ...
We report here a macroscopic analysis of one fetus conserved in Bouin then in formol having an arhinencephaly, synophthalmia associated with holoprosencephaly. We aimed to relate the various etiologies of observed anomalies in conjunction with the literature review. To perform the study, a fetopathologic examination including autopsy and radiologic analysis were done. Assay of FISH and OncoScan were made. Fetopathologic examination showed severe craniofacial malformations associated with extracranial defects including persistent troncus arteriosus communis, abnormal lung lobulation, extremities deformities and single umbilical artery. FISH and OncoSan had given unsuccessful results, because nucleic acids were highly degraded. The macroscopic examination of the fetus having arhinencephaly and synophthalmia highlights asymptomatology association with holoprosencephaly sequence and visceral defects.
... It normally leads to the development of maxillary and mandibular prominences and starts to develop at the 4th and 5th weeks of gestation. Holoprosencephaly [1][2][3][4][5][6][7][8][9][10][11] is the most commonly associated feature with AGOTC, but various systemic anomalies have also been reported as associated findings: anencephaly and meningomyelocele [12], situs inversus, and anomalies affecting lung [13], eyes (micro/ anophthalmia) [14], adrenal and genito-urinary systems [15,16], and cardiovascular and skeletal systems [17,18]. This disorder is usually lethal because of the resulting pulmonary hypoplasia and its associated severe respiratory problems, with only very few living birth cases [19][20][21][22]. ...
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 methodsIn 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.ResultsIn 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 relevanceWe 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.
... The baby had a single eye, midline fused ears (synotia), astomia, and absent proboscis. [23] A case with AOC, AOC (agnathia-microstomia-synotia) syndrome was reported by Wai and Chandran. They reported a baby with agnathia, melotia (anteromedial malposition of ears), microstomia, aglossia, or microglossia (absent or rudimentary tongue). ...
Agnathia is an extremely rare lethal neurocristopathy. The disorder has also been termed agnathia-holoprosencephaly spectrum, agnathia-otocephaly complex, agnathia-astomia-synotia, or cyclopia-otocephaly association. The incidence is estimated to be 1 in 70,000 infants (Schiffer et al. 2002).
Agnathia is an extremely rare lethal neurocristopathy. The disorder has also been termed agnathia-holoprosencephaly spectrum, agnathia-otocephaly complex, agnathia-astomia-synotia, or cyclopia-otocephaly association. The incidence is estimated to be 1 in 70,000 infants (Schiffer et al. 2002).
Records of the facial deformities associated with holoprosencephaly go back to medieval times (Frutiger 1969). Early descriptions of morbid anatomy were published in the 19th century, but identification of the characteristic features is based on the comprehensive treatise of Kundrat (1882). The older literature on cyclopia and arhinencephaly in man and domesticated animals was reviewed by Köhn (1952). Series of cases were studied by Yakovlev (1959), DeMyer et al. (1964), Robain and Gorce (1972), and Jellinger and Groß (1973).
Many birth defects, although rare individually, are encountered in clinical practice and have now become treatable if properly diagnosed. In the Atlas of Genetic Diagnosis and Counseling, Harold Chen, MD, shares his almost 40 years of clinical genetics practice in a comprehensive pictorial atlas of 203 genetic disorders, malformations, and malformation syndromes. The author provides a detailed outline for each disorder, describing its genetics, basic defects, clinical features, diagnostic tests, and counseling issues, including recurrence risk, prenatal diagnosis, and management. Numerous color photographs of prenatal ultrasounds, imagings, cytogenetics, and postmortem findings illustrate the clinical features of patients at different ages, patients with varying degrees of severity, and the optimal diagnostic strategies. The disorders cited are supplemented by case histories and diagnostic confirmation by cytogenetics, biochemical, and molecular techniques, when available. Also available in a CD-ROM edition (ISBN: 1-58829-974-5).
Authoritative and up-to-date, the Atlas of Genetic Diagnosis and Counseling will help all physicians to understand and recognize genetic diseases and malformation syndromes, and consequently better evaluate, counsel, and manage affected patients.
Objetivo: Presentar dos casos de otocefalia.
Congenital defects are common in animals but there is only one report of crossbred (Iranian nativexHolstein) calf has been recorded in Iran. There were severe congenital deformities in the brain of a cyclopia calf. Forebrain structures include olfactory bulb (arrhinocephaly) and cerebral hemispheres (inepisencephaly) have not been formed. Epiphysis and hypophysis have not been formed. There was only a single optic nerve. © 2012 Academic Journals Inc.
We have examined eleven cases of holoprosencephaly with special emphasis on the frontal proboscis. Although the nostril appears blind ended grossly, the proboscis has a single slender midline nostril lined with squamous mucosa containing numerous sebaceous glands. It is actually connected to a poorly formed but definite nasal cavity microscopically. The inner portion of the nostril tunnel is lined by olfactory mucosa containing numerous subjacent secretary glands. Despite the absence of olfactory bulbs and tracts the cartilaginous nasal capsule is identified along with abnormal nasal cavity. However, the nasal capsule is hypoplastic, and has an aberrant nasal septum and no concha. In severe form of holoprosencephaly, i.e., cyclopia, the nasal capsule is noted above the level of the ethmoid plate, in which case the nasal cavity dose not communicate with nasopharynx because it is too distant from the hypoplastic maxilla. Therefore, choanal atresia is resulted. Although unique maxillary bone comprises the whole upper jaw, the failure of fusion between vomeronasal septum and palatal processes in holoprosencephaly results in abnormal maxillary bone which is characterized by a narrow palate without palatal arch form. Nevertheless, through serial microscopic sections we could find a space between the posterior maxilla and the sphenoid bone, which is composed of adipose tissue and is similar in shape to the nasal capsule. This space is thought to be made for the nasal capsule during early developmental period. The present study suggests that the frontal proboscis in holoprosencephaly is an undescended nose. In most cases it is connected to the aberrant nasal cavity which is located beneath the proboscis. The level of proboscis descends gradually toward normal nose position as the severity of holoprosencephaly decreased from cyclopia, ethmocephaly, cebocephaly, to premaxillary agenesis. Key words: frontal proboscis, holoprosencephaly, craniofacial dysmorphia
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