Congenital ear malformation (CEM)

Abstract

Background

At present, there are not international unified standards and reports on Congenital Ear Malformation (CEM) in the world, which makes it difficult to transfer information and compare the literature.

Aims/objectives

Through the statistical analysis of a large sample of CEM, a unified standard of all aspects of CEM is proposed and the data are provided for reference, which is convenient for the international work and literature comparison in this field.

Materials and methods

Based on the author’s 30 years of clinical and scientific research work on CEM and the relevant cases of 3231 (4714 ears) in our hospital, and combined with literature, statistical analysis was made.

Results

This paper summarizes the classification, definition, epidemiology, embryonic development, pathogenic factors of CEM and elaborates on the clinical manifestations, examination and sequence therapy of representative Congenital Malformation of the Middle and Outer Ear (CMMOE). We also introduce malformation of the auricle and inner ear, so as to cover the outer, middle and inner ear. At the same time, we introduce our achievements and contributions in this field.

Conclusions and significance

This study provides reference to the international unified standard and treatment principle of the CEM.

Chinese Abstract

背景: 目前国际上尚无关于先天性耳畸形(CEM)的统一标准和报告, 这使得信息传递和比较文献变得困难。

目的: 通过对CEM大样本的统计分析, 提出CEM各方面的统一标准的建议并提供数据参考, 以方便该领域的国际合作和文献比较。

材料和方法: 基于作者30年的CEM临床和科研工作, 结合我院3231例(4714耳)相关病例, 并结合文献, 进行了统计分析。

结果: 本文总结了分类、定义、流行病学、胚胎发育、CEM的致病因素并阐述典型的中耳和外耳先天畸形(CMMOE)的临床表现、检查和顺序治疗。 我们还引入耳廓和内耳畸形, 以涵盖外耳、中耳和内耳。 同时, 介绍了我们在这个领域的成就和贡献。

结论及意义: 本研究为CEM的国际统一标准和治疗原理提供参考。

Keywords:

• Congenital ear malformation (CEM)
• congenital malformation of the middle and outer ear (CMMOE)
• Microtia
• Atresia of the Outer Ear Canal (OEC)
• sequence therapy

The ear is divided into three parts: the outer ear, the middle ear and the inner ear. The outer ear has the auricle (pinna) and the Outer Ear Canal (OEC); the middle ear has mainly three ossicles, the middle ear cavity (including the tympanic membrane), the mastoid process and the eustachian tube; the inner ear includes the cochlea, vestibule and three semicircular canals. Currently, there is no report on the unified classification standard for Congenital Ear Malformation (CEM) and its overall distribution, which makes comparison in the literature difficult. In this paper, based on the author’s 30 years of specialized clinical and scientific research work on CEM and the 3231 cases (4714 ears) accumulated by our hospital, CEM are systematically and comprehensively overview, among which the representative Congenital Malformation of the Middle and Outer Ear (CMMOE) are elaborated in detail, and auricle malformations and inner ear malformations are presented briefly, so as to cover the outer, middle and inner ears, to provide reference for the unified standard and principle of CEM treatment.

Classification of CEM

CEM alone

The malformation is limited to the ear, which can be divided into: (1) A single part malformation of the outer ear, middle ear and inner ear: due to each part of the ear having multiple structures, simultaneous malformation is a single part malformation yet (Figure 1). For example, simultaneous malformations of the auricle and the OEC stenosis belong to the single malformation of the outer ear. (2) Two parts simultaneous malformation of the outer ear, middle ear and inner ear: such as congenital middle ear and outer ear malformation, including all combination types of part or all middle ear and outer ear structures at the same time, including CMMOE specific phenotype, see in section ‘CMMOE’. (3) Three parts simultaneous malformation of the outer ear, middle ear and inner ear.

Figure 1. Classification of congenital ear malformations (CEMs). M: malformation; CMMOE: congenital malformation of the middle and outer ear; three parts: the outer ear, the middle ear and the inner ear.

Multiple malformation including CEM

Refers to any malformation of the outer, middle and inner ear with one or more than one malformation of other tissues, organs and systems, such as microtia with cleft lip and palate.

Syndromes including CEM

The syndrome has the same principle of treatment as the multiple malformations.

In addition, complications such as cholesteatoma and infection in or around the ear, nasal and pharyngeal lesions can also occur [1].

The meanings of the nouns are as follows:

1. CEM alone. (1) Refers to malformations confined to the ear, including multiple structural abnormalities of one or more parts or a single part of the outer ear, middle ear and inner ear. (2) One or more structural abnormalities of a single part of the outer ear, middle ear and inner ear belong to the malformation of one part. For example, microtia alone or with the OEC stenosis are both malformations of the outer ear.

2. Multiple malformations and syndrome. The former refers to those that include CEM and with one or more than one malformation of other structures or organs, except the ear, which can appear randomly or according to certain rules. Hence, different patients can present different phenotypes. The syndrome belongs to a type of multiple malformations that appears as a specific rule, and is distinguished from multiple malformations as a separate class. Therefore, the main phenotype of syndrome in different patients is similar, but the degree can be different.

3. The difference between the middle and outer ear malformations and congenital malformation of the middle and outer ear (CMMOE). The latter CMMOE belongs to a type of the former one. The middle and outer ear malformations include: ① CMMOE, the main symptoms are microtia, the OEC atresia or stenosis or normal, and middle ear malformation, ② other auricle malformation instead of microtia in CMMOE, such as protruding ear or cup ear, and ③ the OEC and middle ear malformation without auricle malformation.

Epidemiology

CEM is a common birth defect. In China, microtia, belonging to the outer ear, has ranked in the top 10 out of more than 8000 birth defects for 16 consecutive years [2]. In our epidemiological clinical study of 3231 cases (4714 ears) with CEM and related malformations, 2658 CEM cases (4064 ears), it was observed that 64.9% were male and 35.1% female, resulting in a male-to-female ratio of 1.8:1. The bilateral ears were affected in 52.9% of the cases (of which 33.1% were the large vestibular aqueduct of the inner ear), while the right ear was affected in 29.1% and the left ear in 18.0%. The distribution of the three types of CEM was as follows: (i) 69.9% confined to the ear; (ii) multiple malformations including CEM occurred in 29.1%, among which 24.8% had both middle and outer ear malformations (including 24.3% cases for CMMOE); (iii) syndromes including CEM observed in 1.0%. The statistical data gathered, as well as the proportions of each CEM, were as follows: outer ear malformations (3.9%), middle ear malformations (18.6%), inner ear malformations (33.6%), middle and outer ear malformations (42.4%) (mainly CMMOE 39.5%), middle and inner ear malformations (0.7%), and outer, middle and inner ear malformations (0.8%). There were 1090 cases (1379 ears) of microtia, corresponding to 41% of CEM cases, and 96.3% of microtia belonged to CMMOE [1].

Embryonic development of the ear

The outer ear and middle ear originated from the first and second pharyngeal arches formed by the migration of neural crest cells in the R1–R5 region of the posterior midbrain and rhombencephalon (Figure 2). The auricle evolves from the six small humic ridges on the surface of the first and second pharyngeal arches. The OEC originates from the first pharyngeal fissure that separates the first and second pharyngeal arches. The stapes comes from the second pharyngeal arch, the malleus and incus come mainly from the first pharyngeal arch, and all the middle and outer ear structures are developed by the 30th week. The inner ear originates from the ectodermal tissue in R5–R6 regions of the rhombus and develops at week 23 [3,4].

Figure 2. Embryonic development of the ear diagram of segmental migration of neural crest cells. BA1–4: pharyngeal arches 1–4; R1–7: rhombencephalon segments 1–7; O: otic ear sac; S: stapes location.

The origin and location of embryonic development of the inner ear are completely different from those of the middle and outer ear, which may be the root cause of the clinical malformation of the middle and outer ear occurring simultaneously, while the inner ear malformation usually occurs separately. In some cases of simultaneous malformations of the outer, middle and inner ear, the possible reasons are: (1) the malformations occur in the early stage of embryonic development, and distorted primitive cells migrate and develop in the outer, middle and inner ear. (2) The malformation occurs at a relatively late stage of embryonic development, and the damage caused by teratogenic factors is severe and involves a large range, resulting in involvement of the outer, middle and inner ear.

Pathogenic factors of CEM

Genes and inheritance

Human genes are mainly nuclear genes and 0.1% mitochondrial genes. Except for a few unique inner ear malformations and syndromes containing CEM, pathogenic genes have been identified, and no clear responsible gene has been found for most of CEM. CMMOE pedigree has been reported in 1–5 generations, supporting the possibility of inheritance. Only one of the twins developed the disease, not excluding the possibility of genetic mutation or environmental factors, but the pathogenic gene was not identified. Whether patients with CEM have heredity or not is an important factor in determining eugenics and pregnancy, so doctors, patients and family members hope to understand and choose genetic screening. The types and basic principles of nuclear gene screening for patients with CEM are as follows:

1. Candidate gene screening. For patients with highly suspected known pathogenic genetic diseases, candidate genes can be screened using this pathogenic gene, such as large vestibular aqueduct syndrome, and genes closely related to ear development found in our previous experiments [5], which can be used as candidate genes for screening in patients with clinically similar phenotypes.

2. Screening of deafness panel gene. Gathering the found deafness-causing genes, which covers about 80% of the clinical congenital sensorineural deafness patients and is suitable for such patients.

3. Whole exome screening. Screening all transcribed genes but not introns, which may miss intron-related genetic information but already contains about 85% of the human disease mutation. It is suitable for patients with no specific genetic information.

4. Whole gene screening. Including all exons and introns. For patients with CEM who do not find any potentially related genes, whole-exome or whole-gene screening plus mitochondrial gene screening are more likely to find clues.

Environmental factors

Environmental factors include chemicals, drugs, radiation, viruses and others. Follicle hormone estriol, ovulation-promoting drug clomiphene, vitamin A and thalidomide are all known drugs that cause CEM [6,7].

Blood supply and maternal diseases during pregnancy

Disturbances of blood supply and maternal diseases during fetal development are important factors leading to fetal congenital malformations such as fetal microtia caused by maternal diabetes [8,9].

Hypoxia

We believe that fetal hypoxia is a closely related factor leading to CEM. Evidence: (1) microtia is more common in the right ear and in males, and the reasons are analyzed, the mitochondrial maturity of the right ear is later than that of the left side, and male androgens can reduce the rate of mitochondrial respiration and increase the sensitivity to chemical hypoxia [10]. (2) The incidence of microtia has increased significantly in the plateau region (hypoxia) [11].

Other factors

Any other factors that cause the development of the first and second pharyngeal arches can lead to the occurrence of CMMOE.

The following is clinical common CMMOE, because it represents the largest proportion in CEM, and includes malformations of the middle and outer ear, and very few combined with malformations of the inner ear, the treatment covers all aspects of the CEM, which is the most representative. Then, a brief overview of common auricle malformation and inner ear malformation is presented, respectively. Thus, malformations of the outer, middle and inner ear are largely covered.

CMMOE

Definition

We define concomitant congenital microtia, OEC malformations including atresia or stenosis or normal and middle ear malformations as CMMOE, manifested as appearance malformation and hearing impairment (Figure 3). Microtia can be visually displayed, and the degree of deformity is positively correlated with the degree of hearing loss [12].

Figure 3. Congenital malformation of the middle and outer ear (CMMOE). (1) (A–E) Microtia grades I–V, (2) F-R: multiple malformation including CMMOE, (F) 1 accessory ear, and 2 (G) tragus deformity, (H) preauricular fistula, (I) cleft lip (after repaired), (J) soft palatine tonsil deformity, (K) hemifacial microsomia and large mouth deformity, (L) facial paralysis, (M) 1 cervical branchial fistula and 2 abscess (cyst), (N) Goldenhar syndrome (showing microtia, keratodermoid, torticular neck, etc.), (O) Treacher-Collins syndrome (showing microtia, eye cleft down oblique, mandibular dysplasia, etc.), (P–R) microtia with polydactyly/oligodactyly, and (S, T) CMMOE with infection. S: retroauricular abscess, T: 1 outer ear canal cholesteatoma and 2 mastoiditis.

Incidence

CMMOE incidence accounts for 39.5% (1050/2658 cases) of CEM, and microtia is among the top 10 birth defects in China [2], with an incidence between 0.83 and 174/10,000 and 5.18/10,000 (1/1930) in China, and a growing trend year on year. The incidence of white or black people is lower than that of yellow ones [6,13,14]. 96.3% (1050/1090 cases) of microtia belong to CMMOE. Microtia is often confused with CMMOE in the literature. It is clear from the above definition that microtia may not belong to the CMMOE, but the incidence is very low, 3.7% (40/1090 cases) in our statistics [1].

Classification

According to our statistics, 1050 cases CMMOE can be divided into three categories: (1) 36.3% (381/1050 cases) are specifically confined to CMMOE. (2) Multiple malformations including CMMOE 61.4% (645/1050 cases), mainly are hemifacial microsomia, accessory ear, preauricular fistula, cardiac and renal malformations, and others. (3) Syndromes include CMMOE 2.3% (24/1050 cases). In addition, there may be complications, usually in or around the ear, such as otitis media, OEC cholesteatoma, retroauricular abscess, or nasal and pharynx complications [1].

Clinical manifestations

It mainly involves hearing and appearance, and may be associated with complications, multiple deformities or syndromes.

Hearing

The main manifestation is conductive deafness, accounting for 84.3% (296/351 ears) in our statistics, and the Average Air-Conduction Threshold (AACT) of pure tone 0.5–4 KHz is 67 ± 10 dB HL, among which 56–80 dB HL accounted for 78.1% (274/351) [15]. Bilateral malformation affects communication due to poor hearing. Unilateral malformation of daily communication is good, but the affected side of the sound source location ability is poor, usually depends on turning the head to compensate, binaural stereo sound and sound volume balance are weakened. Patients with inner ear deformity can manifest as sensorineural deafness or mixed deafness, which usually speak with unclear words, while conductive deafness with clear words can be used as a preliminary determination of the deafness types and if accompanied by inner ear deformity.

Appearance

The main manifestations are microtia and malformations of the OEC, including atresia or stenosis or normal, while middle ear deformity requires computed tomography (CT) scan of temporal bone or auditory examination, other appearance manifestations are listed under multiple deformities.

1. Microtia. Although degree classification has been reported, some even mix classification of auricle, OEC and middle ear deformity, which is unclear and difficult to implement in practice. According to the author’s 30 years of clinical practice, we divided microtia into five degrees with clear characteristics according to the malformation degree (Table 1, Figure 3), and statistically classified 1105 ears, with the highest proportion of grade III 74.1% [1], and the degree of microtia is positively correlated with the degree of the OEC malformation (atresia, stenosis and normal), and the degree of deafness, the latter is positively correlated with the degree of middle ear deformity [12,16]. This has major clinical implications. The degree of middle ear deformity and deafness can be preliminarily determined after assessing the degree of microtia. It is of great reference value for the diagnosis and treatment of physicians, especially for some places that do not have conditions for examinations of temporal bone CT and hearing. Even for high-level doctors it can save test time and money for patients.

2. Malformation of the Outer Ear Canal (OEC). It can be atresia, stenosis or normal. Complete closure of the OEC anywhere between the opening of the OEC and the tympanic membrane is named atresia, and any cross-section diameter of the OEC less than 4 mm is stenosis [17]. According to our statistics, 1331 ears with CMMOE were 86.5% atresia, 9.9% stenosis, and 3.6% normal [1]. Although the degree of atresia for OEC has some classification, it is often difficult to define in practical application. According to our own clinical practice, the classification was based on CT of the temporal bone or surgery, and the assessment was made in combination with the appearance (Table 2). Several special conditions are considered: (1) the OEC is only partially developed and stenosis, which is atresia; (2) the OEC is full length, but the transverse diameter is less than 4 mm at a certain level, which is stenosis; (3) the inner and outer segments of the OEC are developed, but the connection point is blind, which is atresia; if there is a small needle-like hole at the connection point, which is stenosis; (4) the bony OEC is absent, but the soft tissue OEC is fully developed, which is stenosis.

Table 1. Standard for microtia grades I–V and percentage by 1105 ears.

Grades	Standard	Proportion (%)
I	3 or 4 of the 5 main auricle structures (helix, antihelix, triangular fossa, scaphoid fossa, earlobe) are fully developed and shaped. Or the 5 main structures are developed, but significantly smaller than the normal or contralateral auricle.	5.2
II	2 of the 5 main auricle structures are fully developed and shaped, or more than 2 main structures are developed but not enough for the grade I.	10.5
III	The residual auricle is strip, peanut and sausage shape.	74.1
IV	The residual auricle is only small skin tag or hillet or ectopic earlobe.	6.9
V	There is no auricular structure at all.	3.3

Table 2. Standard for atresia grades I–IV of the outer ear canal (OEC) and percentage by 87 ears.

Grades	Appearance	CT of temporal bone or surgical operation	Proportion (%)
I	The opening of the OEC (OOEC) is almost normal.	Both the lateral and medial segments of the OEC are developed, but being connected by the blind end or foramen.	13.8
II	The OOEC is obviously small, needle-like or absent.	Only the lateral segment of the OEC developed, and its medial is blind end, or only the medial segment of the bony OEC developed, in which cholesteatoma epithelium or cerumen can be stored.	11.5
III	The OOEC is absent.	There is only a shallow sag at the location of bony OEC.	70.1
IV	The OOEC is absent.	There is no discernible OEC structure present.	4.6

Combined with the clinical results and our research on the embryonic development of the ear, in addition to the gradual invagination of the epithelium along the first pharyngeal fissure, the development of the OEC may have a second pathway: the internal and lateral segments of the OEC develops separately and then comes together and integrates. Interference at different times in this process leads to the abnormal phenotype at the stage.

1. Middle ear malformation. Middle ear malformation and stenosis or atresia of the medial segment of the OEC need to be determined by CT of the temporal bone or surgical surgery, but the degree of microtia and atresia of the OEC and pure-tone hearing threshold can be preliminarily evaluated [12]. In the 1331 ears with CMMOE, 98.3% are ossicle malformation [1]. Among 147 ears with clear ossicular numbers, the number of ossicular bones from 0 to 3 represented 3.4%, 10.2%, 58.5% and 27.9%, respectively, that is, most of them had two ossicles. In 138 ears with clear ossicular morphology, fusion between malleus and incus 55.1% (76/138), the stapes is developed in 80.4% (111/138) and the stapes is not explored in 19.5% (27/138). Narrow tympanic cavity correspond 94.1% in 119 ears. In 146 ears with detection of vestibular window development, 76.7% are developed and 23.3% are not. In cases with thick and smooth mucous membrane in the tympanic cavity, which could easily be mistaken for otitis media by the preoperative CT scan of the temporal bone, while in fact it is perhaps the residual mesoderm tissue during embryonic development.

Grades of the malformation degree. As malformations of the middle ear and outer ear occur at the same time, the literature classification standard usually combines with malformations of the auricle, OEC and middle ear, which is difficult to define and implement clinically. From the perspective of embryonic development of the ear, the auricle, OEC and middle ear develop relatively independently and then integrate, and development in the integration area is correlated with each other [7]. According to our data analysis, the degree of deformity of these structures is positively correlated. Therefore, we believe that it is better to classify a single structure, it is simple and accurate.

CMMOE with inner ear malformations

The incidence of simultaneous malformations of the outer ear, middle ear and inner ear is extremely low, corresponding to 0.8% in our statistics of 2658 cases (4064 ears) of CEM. The possible causes have been analyzed in the embryonic development of the ear, which could be the relationship between the source of tissues and the developmental location.

CMMOE with multiple malformations

Multiple malformations refer to those involving CMMOE and one or more structures and organs other than the ear. According to the anatomical position of the ear to the periphery, from near to far: (1) around the ear: preauricular fistula, accessory ear and tragus deformity are common; (2) head, face and neck: hemifacial microsomia, facial paralysis, keratodermoid, large mouth deformity, small jaw, soft palatine tonsil deformity, torticular neck, cervical branchial fistula, abscess (cyst), and others (Figure 3). Hemifacial microsomia means that the development of one side of the face is shorter than the opposite side, and CMMOE is more frequent, accounting for 50.5% (530/1050), because the mandible and middle ear malleus and incus during embryonic development come from the same primitive [4]. In patients with severe CMMOE, there may be different degrees of facial nerve malformation, facial nerve branching or abnormal walking, showing different degrees of peripheral facial paralysis. (3) Malformations of distal organ system: The cardiovascular, urinary, digestive, and motor systems can be malformed, and clinical cardiac and renal malformations are common, representing 7.1% (13/184 cases) and 2.0% (3/150 cases), respectively, according to our statistics [1]. Therefore, cardiac and renal ultrasound is a routine preoperative examination item for patients with CMMOE, and the treatment of cardiac and renal malformations takes precedence over CMMOE.

CMMOE with syndromes

The most common cases were Treacher-Collins syndrome 1.4% (15/1050 cases) and Goldenhar syndrome 0.9% (9/1050 cases), with one case of Alport syndrome and two cases of Waardenburg syndrome.

Complications

(1) Ear and peri-ear infections and cholesteatoma, responsible for 16.9% (177/1050 cases), mainly middle ear mastoiditis, OEC cholesteatoma, middle ear cholesteatoma, retroauricular abscess and others. (2) Nasal and pharyngeal complications accounted for 18.6% (195/1050 cases), mainly including tonsil hypertrophy, sinusitis, nasal septum deviation, adenoid hypertrophy and others. There was no direct evidence of correlation between CMMOE and nasal and pharyngeal complications [1].

Check of the CMMOE

(1) Preliminary assessment of the hearing level according to the grades of microtia. (2) Determine the type of deafness according to speech articulation. For patients with normal vocal structure, sensorineural deafness (such as those with inner ear deformity) often spit out words indistinctly, while the opposite occur for patients with conductive deafness. (3) Tuning fork check. CMMOE was mostly conductive deafness, RT test (–), WT test was biased towards the affected side. For patients who can cooperate, a simple C256 tuning fork examination can determine the type of deafness, which is more reliable than pure tone audiometry results. When pure tone audiometry is inconsistent with the tuning fork examination, the tuning fork shall prevail. Special reminder: We often think that children cannot accurately cooperate with tuning fork inspection, but from our professional experience, it is just the opposite. At the same time, we found and summarized two practical and contrary phenomena in the long-term clinical work, which is also a challenge for the current theory of audiology: ① the RT test requires the comparison of the duration time between air-conduction and bone-conduction after the sound of the tuning fork, while we make a direct comparison based on the intensity of the sound heard by the patients to identify the difference. For patients with CMMOE, the results are consistent and the reason remains to be studied. This makes it less time-consuming and more reliable. ② In some patients with bilateral deformity, when hearing on one side improved after surgery but not beyond the contralateral side, the WT test favored the side with improved hearing rover the side with severe deafness, the reason is not clear. (4) Hearing examination. We selected different examination methods according to different age groups of patients: ① children ≤3 months old select hearing screening. ② 3 months old ≤ children ≤ 2 years old, multifrequency steady-state potential (ASSR) and brain stem evoked potential threshold values (ABR) by air-conduction and bone-conduction were selected. For patients with unilateral deformity, special attention should be paid to full frequency masking, otherwise, the shadow curve of the opposite side can be obtained [18]. ③ 2 years old ≤ children ≤ 6 years, choose behavioral audiometry. ④ 6 years old ≤ children choose pure tone audiometry. However, the above age limit is not absolute and can be selected according to the patients’ degree of cooperation. In addition, for unilateral malformations, only hearing screening on apparent non-malformed side should be done before three months of age to confirm that its hearing is good. If it is also poor, auditory intervention measures should be taken at age of three months for both sides, otherwise only for malformed side. For bilateral malformations, hearing screening cannot be performed, children’s ability to seek sound responses can be observed, and auditory intervention can be performed at age of three months. (5) Acoustic impedance. It can help to determine the condition of the middle ear and help to identify conductive deafness and neurotic deafness. However, there is no need to screen those with atresia or severe stenosis of the OEC who cannot insert detection earplugs. (6) Distortion product otoacoustic emission (DPOAE), auditory brainstem response (ABR) latency, 40 Hz correlation potential. For patients with inner ear deformity, the items should be selected. (7) CT of temporal bone. It can be used to understand the development of the inner, middle and outer ear, facial nerve, location and range of lesions, and others. (8) Magnetic resonance imaging (MRI) examination. Including brain MRI and water imaging of the internal auditory canal, to understand nerve development in the internal auditory canal and inner ear. (9) Other examinations include appearance, complications, and other malformations or syndrome, etc.

Note: (1) Pure tone audiometry for CMMOE mainly manifests as conductive deafness, and the level of air conduction threshold can preliminarily assess ossicle malformation in the middle ear [16]. Our experience: pure tone air conduction threshold of 40–60 dB HL, mainly malleus external fixation, 60–70 dB HL, malleus and incus malformation, ossicle chain dysfunction, fixed or interrupted state, 70–80 dB HL, especially above 80 dB HL, the stapes footplate is fixed or poorly developed, or the vestibular window is not developed. (2) ABR threshold is more objective and accurate than pure tone audiometry. (3) For most of CMMOE, the above two types of checks can meet the audiometry requirements. (4) Masking in audiometry. Our study confirms that binaural hearing differences are common in people with normal hearing on one side and malformation on the other side, although differences <40 dB HL. During audiometry, the poor side must also be masked to prevent misjudgment caused by the shadow curve on the opposite side [18]. If it is contralateral shadow curve before surgery and postoperative audiometry is accurate, it will be mistaken for a surgical injury. However, in bone conduction threshold audiometry, if the difference between the two sides is large, it is often difficult to mask, then ABR bone conduction threshold audiometry is chosen, which is relatively more objective and reliable.

Treatment of CMMOE

It involves appearance (plastic surgery), hearing and complications (otologist), multiple deformities and syndromes (other specialties) and psychological treatment (psychology), and others. Methods for improving hearing can be divided into surgery and hearing aid devices. Currently, there are four methods to improve the appearance, namely auricle reconstruction, auricle orthosis, auricle prosthesis and auricle regeneration.

Methods to improve hearing

(1) Surgery. Currently, the commonly used surgical methods are as follows (Figure 4):

Figure 4. Therapy methods, sequence therapy and pathogenesis of congenital malformation of the middle and outer ear (CMMOE). The therapy of CMMOE includes hearing improvement, appearance improvement, treatment of complications and multiple malformations, as well as the study of pathological mechanisms. Each aspect needs optical selection from many approaches, and then all the optical selections requires sequence therapy. BAHA: bone anchor hearing aid.

① Reconstruction of the OEC. That can be performed alone or in combination with tympanoplasty, up to 48% of re-atresia and re-stenosis are likely to occur after reconstruction of the OEC [19–21]. However, after adopting our new strategies and methods, good results were obtained, and the incidence of re-atresia and re-stenosis was reduced to 14.3% [22]. ② Tympanoplasty. This should be done in conjunction with the reconstruction of the OEC. Different hearing reconstruction methods were adopted according to the development of the ossicles. By our clinical data, short-term postoperative hearing improved greatly, but the average air conduction threshold (AACT) 0.5–4 KHz is about 50 dB HL, far away from the normal ≤25 dB HL. While long-term hearing did not significantly improve. ③ Fenestration of the inner ear or stapedectomy. For patients with undeveloped or fixed vestibular window or stapes footplate, fenestration of the inner ear or stapes footplate resection should be performed and piston implantation, and some patients showed significant improvement in hearing [23].

(2) Hearing aid devices (Figure 4). There are many types, the common are as follows:

①Hearing aids. There are two types of air-conduction and bone-conduction. The bone-conduction hearing aids are preferred for most of CMMOE with conductive deafness, no need of the OEC, wearing glasses does not affect the appearance, no ear blocking effect and noise damage, patients are easier to receive. For a small number of patients with mixed deafness or reconstruction of the OEC, air-conduction hearing aids can also be chosen. ② Bone anchor hearing aid (BAHA). No OEC required. There are two ways to use it: softband and implant. Softband is simple, safe and effective in children. Full implants require no nursing and can further improve hearing by about 10 dB HL than the softband. Our study found that the optimal BAHA improvement frequency is 1 KHz, followed by 0.5 KHz and 2 KHz [24]. The operation was similar to the bone bridge (BB), but the skull implant site was less damaged and the external body was more evident than the BB. ③ Bone bridge. To understand the effect, softband can be used before surgery. This hearing solution has been applied in the clinic since 2011 and consists of two parts: bone implants (floating mass transducer, BC-FMT) and in vitro auditory processors. We found the advantage of having full frequencies to improve hearing, but could not reach the normal level [24]. ④ Vibrating sound bridge (VSB). It is a middle ear implant for patients with moderate and severe sensorineural deafness, conductive deafness and mixed deafness. There is no need for an OEC, similar to BB, it has two parts: the implant (FMT) and the in vitro auditory processor. Compared with the BC-FMT BB implant, the FMT is thin and has slender wires, while the in vitro processor has the same appearance, and both parts are absorbed by magnetic force. Vibrating sound bridge has a good effect in improving high-frequency hearing of 2–4 KHz [24], but the surgical difficulty is much higher than BB and BAHA. (5) Cochlear implant. It is considered for patients with severe sensorineural deafness accompanied by inner ear malformation. There is usually no need for cochlear implants in patients with CMMOE.

The ways of wear hearing aid devices. BAHA, BB and VSB all have softbands and implants. The implants can further improve hearing by 5–20 dB compared to the softbands [24], but the surgery is risky. While softbands are worn directly without surgery.

Methods for improving appearance

(1) Reconstruction of auricle. Requires auricle scaffold and the skin covering the scaffold (Figure 4).

Classification: 1) As scaffold material. The reconstruction method can be divided into autologous rib cartilage scaffold and artificial material scaffold. About 95% selecting the former in the world in the past 15 years by our literature study, the artificial material is mainly used Medpor, which is hard and easy to cause the covering skin to break, so it is usually selected when the autologous rib cartilage cannot be used. 2) As time. There are one-stage and multiple-stage methods. One-stage surgery can save time, but the skin is thick and the effect is not so good. The multiple-stages are time-consuming, expensive and have better effect than the one-stage. 3) Skin expansion method. An ‘extra’ skin flap can be obtained behind the ear in order to restore the color, texture and sensory function of the reconstructed auricle. At present, the relatively effective method is auricle reconstruction with skin expansion, autologous rib cartilage scaffold, and multiple-stage, and hearing reconstruction surgery can be completed at the same time during the third stage of auricle reconstruction repair. Meanwhile, we present the criteria for evaluating the effect of auricle reconstruction [7].

Timing. There is still controversy about the surgery age for auricle reconstruction. Our statistical analysis found that the best effect occurs around age 12 (10–15) years old, but from psychological needs point of view, the earlier the better. Therefore, to take into account the psychological needs and physiological development of patients, for minority of them, the earliest operation is 6 years, just ‘sacrifice the effect in exchange for psychological treatment’.

(2) Auricle orthosis. For infants with microtia grade I or II, if the size difference from the opposite side is not evident, a non-surgical auricular orthosis can be used, which can avoid further auricle plastic or reconstructive surgery. The method and effect are the same as the correction of auricular deformity described in section ‘Congenital auricle malformations’.

(3) Auricle prosthesis. For the elderly or patients who are reluctant to undergo surgery or who are waiting for the best surgery time, the adhesive 3D printed auricle prosthesis can be considered direct use with biological glue to improve the appearance. In this way, the residual ear and local skin integrity can be preserved for later auricle reconstruction, solving aesthetic problems and avoiding psychological obstacles. But the questions of the auricular prosthesis color and the power of the glue are still difficult. In addition, auricular prosthesis implants are not recommended due to in vitro exposure, need for care, pain due to sleep pressure, and harmful conditions of auricle reconstruction.

(4) Auricle regeneration. Auricle regeneration by tissue engineering is the most ideal way, but it is still in the experimental and theoretical stage and has not been applied in the clinic.

Treatment of complications

It is mainly ear and periauricular infection or cholesteatoma. Common cases include preauricular fistula infection, retroauricular abscess, middle ear mastoiditis, and cholesteatoma of the OEC, and others. Infected lesions must be removed before auricle reconstruction, otherwise, it is easy to cause infection of the reconstructed auricle. Our novel surgery incision can be removed the lesions and reserved the skin flap and blood supply of the later auricle reconstruction [25].

Treatment of multiple malformations/syndromes

After several rounds of discussion with renowned experts in relevant specialties in China, the author sorts out the treatment opportunities of common non-infection-multiple malformations in various specialties as follows, the timing when the patients are (1) 1–3 months old, for auricle orthosis, (2) 3 months old, for hearing examination, wearing bone conduction hearing aids, consulting and making schedule of ophthalmology, cleft lip and palate, maxillofacial surgery, (3) 1 year old, for examining CT of temporal bone and cardio-renal ultrasound, (4) 4 years old, oral orthodontics, (5) 10–12 years old, performing auricle reconstruction and (6) 15 years old, OEC and hearing reconstruction, and hemifacial microsomia correction. For patients with infection, infected lesions must be cleaned first, our novel surgery incision can be removed the lesions and reserved the skin flap and blood supply of the later auricle reconstruction [25]. Then following the steps as non-infection cases.

Selection of CMMOE sequence therapy

1. The importance of sequence therapy. There are many ways to improve appearance and hearing, respectively, which one should be chosen? Hearing, appearance, treatment sequence of complications and multiple deformities, as well as the selection of the best moment of each treatment, have a significant impact on the final effect and are interrelated, so it requires global planning and belongs to sequence treatment. But the situation is: improvement in hearing and appearance, and multiple deformities are treated by separate related specialists. Due to the lack of a unified plan, the overall effect is often unsatisfactory and even the follow-up surgery cannot be completed. Therefore, ideally, auricular plastic surgery and auditory reconstruction should be performed by the same physician or the collaboration of otologists and plastic surgeons, and the multiple deformity should be discussed by related specialists to develop personalized and sequence treatment plans.

2. Selection of precise hearing solution. This requires first understanding the advantages of various hearing solutions, then learning about the each patient’s individual hearing characteristics, and then matching them to select the precise solution. We completed the comparison of various hearing solutions and analyzed the hearing characteristics of the patients [15,16,23,24]. Then, accurate matching based on CT of the temporal bone and pure tone audiometry, preliminarily evaluating the postoperative effect before surgery for physician and patient selection.

3. Selection of appearance solution. Auricle regeneration was not applied in the clinic. Auricular prostheses are relatively few, mainly used in the elderly or patients who are reluctant to undergo surgery or who are waiting for the best surgery time. Auricle orthosis is used to improve the appearance of patients with auricular deformity and CMMOE microtia grades I and II. The most commonly used procedure is auricular reconstruction by staging with an scarfold of autologous rib cartilage and an expanded skin flap (Figure 4).

4. General principles of CMMOE sequence therapy. ① The surgical sequence is ‘infection before sterility, appearance before hearing’. The infected ear and peri-ear lesions are removed first, then auricle reconstruction surgery is performed, followed by OEC reconstruction or implantation of hearing aid devices. In special cases, if ‘hearing before appearance’ is necessary, special incisions must be designed to preserve good conditions for later auricle reconstruction [25]. ②Multiple malformations/syndromes should be discussed by relevant specialists to develop personalized and sequence treatment plans and gradually implemented. ③ Lateral differences. Unilateral deformity has a more urgent need for appearance, while binaural deformity has a more urgent need for hearing. However, in both cases, children should use softband bone-conduction devices to improve hearing at age of three months due to (1) the development of the auditory system is completed in three months old and there is usually no improvement later. (2) Sound stimulation at three months of age can help shape and develop the auditory system. (3) The motor system development of 3-month-old infants is not perfect, unable to remove the use aids, but after the age of five months they can, so there are two months of use adaptation time, training compliance. ④ Typical cases. The two most common types of CMMOE in clinic are patients without infection and with infection (Figure 3). Unilateral malformations are common in both cases, which may be accompanied by hemifacial microsomia, cardiac malformations and others. The timing of the sequence therapy as the above treatment of multiple malformations/syndromes.

Congenital auricle malformations

Classification

Congenital auricle malformations can be divided into morphological deformities and structural deformities. Morphological deformities refer to the existence of basic structure of auricular skin and cartilaginous tissue, but abnormal morphology, such as cryptotia, flaring ear, cup ear, ring contraction ear, and others (Figure 5). Structural deformity refers to partial or total loss of auricular skin and cartilaginous tissue, and the degree of loss is the degree of deformity, which can be classified as microtia and see in section CMMOE.

Figure 5. Auricle malformation. (A–D) Before correction, (A1–D1) after correction corresponding to A–D, (A) microtia, structure malformation, (B–D) morphology malformation: (B) flaring ear, (C) ring contraction ear, and (D) lop ear and cryptotia.

Incidence

The incidence of neonatal auricle morphological malformation is 55.2–57.5%, of which about 1/3 can recover to normal within two weeks after birth, but there is no clear screening criteria [26].

Treatment

At present, the simple and effective treatment method for auricular deformity is the auricular orthosis. Compared to surgery, it is also called non-invasive correction. Currently, it is believed that the correction time is two weeks to three months after birth, and the earlier the correction, the shorter the duration and the better the effect. For patients older than three months, surgical correction is usually required after age of 5–6 years old. Surgery has pain and multiple risks, and the effect is not as good as non-invasive correction in most cases. Therefore, for most parents of auricular deformity >3 months old, there is still a strong demand for non-invasive correction, and doctors have also conducted considerable exploration. In the expansion study on the indication of auricular orthotics, we explored patients [27]: (1) 3 months to 8 years old, and it was still effective 77.1% (27/35) (Figure 5). However, the relative effect is weak and easy to recover for the diseases such as narrow and flaring ear, while the good effect can still be obtained at the age of six years for cryptotia. (2) For those microtia grades I–II (Figure 5), among structural deformities, whose auricles have a rough shape and are not much different in size from the contralateral side, or are significantly different from the contralateral side, but can have a significantly improved appearance after correction, can be corrected according to the morphological deformity. For the first type, further auricle reconstruction surgery can be avoided. The second condition can reduce the difficulty of auricle reconstruction and the psychological impact before plastic surgery. (3) Auricle orthosis assists in shaping after orthopedic surgery, which is effective for both patients ≥6 years old. Therefore, we believe that, as long as the following conditions are met: ① The older children and parents have a strong desire to try non-invasive correction, ② children can cooperate with treatment, ③ family economic conditions allow, and ④ even if ineffective results can also be accept, then 1-6 weeks can be tried with non-invasive correction, if ineffective, choose surgery, so as to obtain an opportunity to get better results and avoid surgery.

Common auricle complications and management of auricular orthosis

(1) Allergies. Local skin redness, small papules, usually relieved after discontinuing correction 2–3 days. (2) Skin damage. Discontinue the orthotics, apply topical antibiotic ointment, and continue orthosis after full recovery. (3) Infection: Topical disinfection with iodophor, application of antibiotic ointment, if necessary oral antibiotic, and deal with the situation in time to prevent the occurrence of skin damage and infection.

Congenital inner ear malformations

Classification

Congenital inner ear malformations can be divided into single inner ear malformations, multiple malformations and syndromes including inner ear malformations. The single inner ear deformity can also be one, two or three malformations of the cochlea, vestibular and semicircular canals, as well as the common cavity deformity formed by the three undifferentiated ones. The clinical classification of cochlear deformity is based on the degree of deformity. From our clinical epidemiological studies on ear malformations, it was observed that inner ear malformations are mainly single malformations, and the most common clinical malformations are the large vestibular aquetube syndrome [1], because the malformations are mainly limited to the inner ear, rarely accompanied by other multiple malformations and syndromes, and clinical treatment is relatively simple, therefore, in this work, they are counted as single inner ear malformations.

Incidence

Our data showed that among 2658 cases of CEM, inner ear malformations represented 33.6%, of which 32.4% occurred in isolation and 1.1% with multiple malformations, second only to CMMOE, which represented 39.5% [1].

Clinical manifestations and diagnosis

The main manifestation is different degrees of sensorineural deafness, and severe cases in both ears can become deaf–mute. Diagnosis was mainly based on audiological examination, high-resolution CT of temporal bone, MRI examination, internal auditory canal hydroimaging, and others.

Treatment

Choose different methods according to the hearing condition and the degree of inner ear deformity. ① If mild and moderate sensorineural deafness, or the pure tone air-conduction threshold (ACT) ≤70 dB HL, the air-conduction hearing aids are optional. ② Severe, extremely severe sensorineural deafness or total deafness, ACT >70 dB HL, choose cochlear implants. Even if the common cavity is malformed, the cochlear implant is highly effective. For those who have not developed a cochlear, an auditory brainstem implant may be considered. However, surgical risks are high and even fatal, so the risks and benefits must be fully assessed, patients and their families should be thoroughly communicated and reach a consensus before implementation. Those who cannot use a cochlear implant and brainstem implant are trained in schools for the deaf and mute.

Our advantages and achievements in CEM

Based on our technical features, we have done many international innovative works to improve appearance, hearing, complications, multidisciplinary joint management and hierarchical multicenter diagnosis and treatment, as well as research on the mechanism of CEM (Figure 6). Let us take as an example the most representative malformation of the CMMOE. The main problems are as follows: (1) improvement in hearing and appearance without sequence treatment, resulting in poor overall results. (2) Re-stenosis or re-atresia after OEC reconstruction, long-term hearing loss. (3) The fidelity and bilateral symmetry of the reconstructed auricle need to be improved. (4) Lack of large sample research resources. We are committed to solving the above problems.

Figure 6. Our technology characteristics, main work, achievements, and influences: (1) based on the integration technology of our otologist, plastic surgery, and ear embryo development, and more than 30 years of clinical experience, in (2) appearance improvement, (3) hearing improvement, (4) complication management, (5) prevention, (6) establishment of specialized centers for sequence therapy, get (7) achievements: international first and original monograph and special issues, and many innovative achievement as listed in the figure, and (8) influence lectures live online 250,000 people.

Technical features and advantages

Otology, plastic surgery and ear embryo development are integrated to achieve the best results. With more than 30 years of experience in the field, we have created a special disease center, which can solve the problems of appearance, hearing, complications, multiple deformities, pathogenesis (prevention), and combine treatment and prevention, clinical and basic research.

Main works

For the first time, proposed and promoted (1) overall, the sequence treatment of CEM and standardized procedures were formulated (Figure 6). (2) Improve appearance. The ideal age and effectiveness evaluation criteria for auricle reconstruction. (3) Improve hearing. The selection of precise hearing solutions for CEM, innovative and improved technology for the OEC reconstruction, the frequency specificity of various bone conduction hearing aids devices, and the simple and direct pure tone hearing threshold method to replace Jahrsdoerfer scoring method, which is commonly used internationally, for the preoperative evaluation of CEM. (4) Complications treatment. The innovative surgery incision for CMMOE with infection to reserve conditions for later auricle reconstruction. (5) Research and prevention. By simulating the CEM process successfully with chicken embryos and searching for genes closely related to ear development, which can be used as candidate genes for screening in clinical patients with similar phenotypes, to explore the CEM mechanism so as to provide theoretical guidance for prevention of this malformation. At the same time, a large amount of clinical data have collected.

Main achievements

(1) Original works, the first CEM monograph in the world, two issues of Chinese journals, more than 60 articles (Figure 6). (2) Patents obtained seven national patents, of which two achievements were transformed. (3) A CEM resource bank was established. (4) CEM special center was established, which can solve appearance and hearing problems in sequence, combine treatment and prevention, clinic and research. (5) Establishment of a joint diagnosis and treatment system. Currently, there is no international report on this aspect. ① A multi-disciplinary system in China, involving otologist, plastic surgery, maxillofacial surgery, orthodontics, cardiology, urology, orthopedics, ophthalmology, and neurosurgery from nine specialties in China. So that patients can enjoy high-level ‘one-stop’ sequence therapy. ② A multi-center system in China: Establishing the Chinese Multi-center project for CEM involving more than 170 hospitals, conducting hierarchical diagnosis and treatment and two-way referral, carrying out national multi-center research and epidemiological analysis. ③ Preparing an international system. We provided technical support to the developing countries through China’s ‘One Belt and One Road’ initiative and the China’s joint diagnosis and treatment system for CEM is open to the world. We plan to establish an international joint diagnostic and treatment system and a CEM resource bank, so that patients can obtain the best medical services, while solving the public health problem of human birth defects.

Influence

(1) More than 2 million visitors to our website, and 250,000 live online to the author’s lecture (Figure 6). (2) Technology assistance provided internationally to the developing countries through China’s ‘Belt and Road Initiative’ and consulted by international patients.

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the National Clinical Medical Center Special Project (YiHui Zou 202100003); National Logistics Support Department Special Family Planning Project (YiHui Zou 22JSZ14).