A collection of disease information resources and questions answered by our Genetic and Rare Diseases Information Specialists for Microtia-Anotia. In this paper, the term “microtia” includes anotia as the most severe end .. Several cases reports of mosaicism 46,X,der(Y)t(Y;1)(q12;q21)/ Microtia-anotia is a spectrum of congenital anomalies of the auricle ranging from mild [PubMed]; Okajima H, Takeichi Y, Umeda K, et al.
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Mexico has a prevalence of microtia of 7.
Microtia is defined as a congenital malformation of the external ear characterized by a small auricular lobe with an abnormal shape. It is more often unilateral and on the right side. Males are more frequently affected than females. It can occur as an isolated defect or can be associated with other abnormalities such as stenosis of the external auditory canal.
In three of the main pediatric hospitals in Mexico, microtia is among the most important causes of attendance in the Genetics Department. Microtia-atresia must be considered as a major malformation with important repercussions in hearing function requiring multidisciplinary medical care in order to limit the disability associated and to provide genetic counseling. Its etiology is complex. Only in a minor number of cases it has been possible to identify a main genetic component as in monogenic presentations or a main environmental cause as in fetal alcohol syndrome or pregestational diabetes.
In most cases this malformation is multifactorial. Due to the relevance that the frequency of microtia atresia has in different health services in Mexico, it is important that all medical professionals are aware of its clinical, molecular and inherited characteristics. This malformation mocrotia a wide spectrum of clinical abnormalities of the ear, which differ with regard to its severity, qnotia minor anomalies to the complete absence of the ear or anotia.
Population studies in some European countries and in the U. In tertiary-level care hospitals, this malformation is found among the first reasons for outpatient consults. Between and there were at least 19 familial cases identified. To contextualize these figures in relation to the high frequency of consultation for microtia-atresia in our microtiz, they can be compared anotoa the frequency reported in the Hungarian Registry of Congenital Abnormalities, 11 which identified a total of cases during a year periodwith a prevalence of 0.
Some authors consider microtia to be the minimal expression of this disorder. Different studies indicate that Mendelian inheritance is more common in syndromic and familial cases, whereas polygenic or multifactorial causes are more probable in sporadic cases.
Different risk factors have been described such as the effect of the disorders micdotia the glucose levels in poorly controlled gestational diabetes. There is also evidence that exposure to certain medications such as mycophenolate retinoids and thalidomide cause microtia. InHermann Marx published the first classification system for congenital anomalies of the external ear, which is one of the most used currently. Figure 1 Types of microtia-atresia. A Type III with auricular skin tag arrow.
B Type I with preauricular appendices arrow. Small ear that retains all of its anatomic components, but the length is 2 standard deviations SD below the mean. Residual tissue of vertical cartilage with presence of some structures of the ear and a length 2 SD below the mean.
Irregular tissue mass without resemblance to the ear. This classification is used by the different specialists who provide care to patients as part of the clinical approach of microtia. Each case is individual and will have its own requirements for care depending on the type of lesion and if it is uni- or bilateral or if it is believed that it can be isolated or is syndromic.
According to the judgment of the physician, disorders need to be ruled out at the vertebral, renal and ophthalmological level as well as to carry out hearing tests.
Microtia-Anotia: A Global Review of Prevalence Rates
Also, in mifrotia cases and if there is a healthy earindications must be carefully followed so that the ear remains without damage. It is also important to decrease the risks of frequent infections or exposure to ear toxins caused by some antibiotics that can cause hearing damage that would have been preserved.
Once the patient has an optimal health status and growth conditions, a surgical procedure may be considered that would reconstruct the ear. However, we must insist that this is dependent on the case. If it has also been established that there is a hereditary family history or if there was exposure to possible teratogens, etc.
For these reasons, in these cases the coordinated efforts of pediatricians, geneticists, plastic surgeons, audiologists, ear-nose-throat specialists ENTsophthalmologists and psychologists, anltia other specialists is required. The union of the first pouch and pharyngeal cleft with the surrounding tissue of the pharyngeal arches I and II form the structures of the middle and external ear.
Microtia & Atresia | Ear Community
The pharyngeal arches are comprised of mesenchymal cells of mesodermal origin and cells from the neural crest. The structures of the internal ear arise from the superficial ectoderm.
The external auditory canal is formed by the invagination of the pharyngeal cleft, whereas the ectoderm of the cleft forms the epithelium for the duct. The outer ear is formed from six auricular mounds coming from the tissue of the pharyngeal arches I and II. These surround the pharyngeal cleft and contribute to its specific components. Initially these structures fuse in the region of the neck and reach the height of the ocular globes due to mandibular growth.
Its development begins in the fifth week of gestation and is completed at 12 weeks. Migration of the outer ear to their normal placement occurs at 20 weeks. Different signaling molecules and proteins are involved in the morphogenetic process and in the differentiation of the outer ear.
Association with syndromic entities. Part of the complexity of the study of microtia-atresia is because in only a small number of cases is it possible to identify a purely genetic cause in monogenic presentations or purely environmental. In the majority of cases, a multifactorial etiology is established.
The one occasionally associated with syndromic entities has important implications with regard to its management, treatment and genetic counseling of the patients. Among the most common clinical entities in which microtia-atresia may be present as part of the pleiotropic effect of the syndromes are considered the eye-ear-vertebral spectrum, Treacher-Collins syndrome, velocardiofacial syndrome associated with deletion of 22q The eye-ear-vertebral spectrum OMIM a has a variability of expression that includes the hemifacial microsomy and Goldenhar Syndrome up to the facio-auriclevertebral sequence.
This alteration involves the derivatives of the first and second branchial arches and presents craniofacial, cardiac, vertebral and central nervous system CNS disorders. It presents unilateral malformation of the external ear and facial malformation of the affected side as well as epibulbar dermoid cysts. Among the genes associated with this syndrome, the GSC gene has been studied and no mutations have been found. However, the BAPX1 gene could cause malformations due to changes in its epigenetic regulation.
Treacher-Collins-1 syndrome OMIM a is characterized by downward oblique palpebral fissures, coloboma of the eyelid, micrognathia, microtia, zygomatic hypoplasia and macrostomia. It has an autosomal dominant pattern of inheritance. Velocardiofacial syndrome OMIM a associated with 22q This deletion has also been associated with the DiGeorge Syndrome and with conotruncal cardiac disorders.
Given the loss of one of the chromosomal regions of 22q The syndromes mentioned are not the only ones in which microtia-atresia has been reported in a high percentage of the cases. In a family of Iraqi descent with autosomal recessive segregation, bilateral microtia, hearing alterations and cleft palate have been reported.
These genes codify for transcription factors and a mutation in the HOXA2 gene has been demonstrated. Accordingly, the etiology of microtia-atresia has been related with entities that have an autosomal dominant, autosomal recessive, multifactorial pattern of inheritance as well as alterations in the number of copies of potential genes involved, as suggested by its presence in trisomies 13, 18 and 21, and other unbalanced chromosomal alterations for example, in the partial deletions of 5p, 18p, 18q and 22q Identification of genes related with the presentation of microtia-atresia in syndromic forms is promising because it leads to the consideration that these genes play a role in the preservation of hearing.
Changes in these genes or in their interactions can lead to the presentation of the malformation. New technologies are required such as the aforementioned GWAS to identify genes responsible and protein products or regulators that these have during specific periods of embryonic development along with their interactions with the environment and the genome. Therefore, it is important to consider the genetic aspects where the specific genes identified as the responsible individual of some types of microtia-atresia are studied and the genomic aspects where the genome is studied in its entirety to establish the possible causes of microtia-atresia.
When it is syndromic, generally it is part of a specific pattern of multiple congenital malformations and the complete entity can be associated with the following factors: When dealing with mutations of only one gene, there is familial aggregation and different forms of Mendelian inheritance are observed, autosomal recessive, autosomal dominant and X-linked.
It must also be taken into consideration that the alterations in any of the genes involved that lead to the generation of microtia are not limited to the change in the sequence of the nucleotides; one gene without mutations could be subject to epigenetic changes that alter its transcription or the alteration could be found in the molecules that regulate the genetic expression at the post-translational level.
Development of the external ear is orchestrated by multiple genes.
A large number of syndromes demonstrate microtia, 23,53 which calls attention that many genes intervene in the development of the external ear. To date, all genes that play a role in these syndromes have not been identified; however, there is evidence that some are involved in the morphogenetic processes of development of the ear Table 1. These genes are very important in ontological human development because they function by regulating a not yet established number of genes that are their transcriptional targets.
Microtia: Epidemiology & Genetics
The HOXA2 gene, especially directly related with microtia, 46 is a transcription factor that acts as a gene selector that will express in the morphogenesis of the neural crest and in the second branchial arch, structures that give rise to the formation of the ear. The number of genes implicated in the development of the external ear and the fact that their dysfunction could cause microtia increases because the HOX genes, in turn, could be regulated by another type of genomic component such as microRNA miRNA.
It is known that mutations in MIR96 could be related with nonsyndromic deafness. Recently, Li et al. When TRPS1 acts, it represses the transcription of genes that have been implicated in multiple functions and in the proliferation of chondrocytes, important cells in the development of the external ear, as abnormal development of the cartilage is a central characteristic in microtia.
Other target genes of miRc are OSR1 Odd-skipped related 1 gene related with the development of intermediate mesoderm and branchial arches during embryogenesis and GLI3 associated with the Pallister-Hall syndrome with microtia. An important observation is that miRNA are also subject to the CNV, adding complexity to the underlying genome related to the appearance of microtia.
Microtia is associated with unbalanced genomes. Genomic imbalances come in different sizes. A CNV could be simple in its structure such as tandem duplication or could imply complex gains or losses of homologous sequences found in multiple sites in the genome. CNV could influence gene expression by interrupting genes or altering the gene dose. Some examples are syndromes of microdeletion or microduplication but also can be associated with complex characteristics or diseases.
In patients with microtia, in addition to the main genes and their regulators, syndromic cases are commonly associated with changes in the copy number such as duplications or deletions, which is found in virtually every human chromosome Table 2 suggesting that the basic defect is in a pathway of organogenesis.
Microtia has been part of the clinical picture in the most common aneuploidies such as trisomy 13 and Similarly, Forrester and Merz found four cases with trisomy 18 in 41 patients with microtia. This suggests that the haploinsufficiency of genes located in the involved regions is related with the generation of microtia.
However, the presence of a large number of copies in some genetic regions also can give rise to microtia, as observed in trisomy 13 and 18, but also by the presence of CNV consisting of five copies of a kb amplicon located on the short arm of chromosome 4. This CNV segregates with microtia and other malformations in an autosomal dominant inheritance mode.
In summary, information about the association of microtia with mutations or alterations in the amount of major and minor genes and their regulators such as miRNA reveals that there are a large number of loci required in the normal formation of the outer ear.
For this, it can be mucrotia that its development is the result of a concerted genomic activity in quantity, time and space of various genes and environmental factors that must act harmoniously for normal organ development. Some failure in genomic or environmental factors or their interactions could cause microtia. As shown, microtia-atresia is a malformation of great significance for a variety of health services in Mexico because of the different areas and specialists involved that includes but is not limited to pediatricians, plastic surgeons, audiologists and speech therapists, otolaryngologists and medical geneticists.
It is important that professionals working with these patients be aware of the clinical, molecular and hereditary bases of the disease.