The incidence of ear malformations has been informed in approximately 1 per 3,800 newborns (1), while the incidence of external ear malformations occurs in 1 per 6,000 (2) to 6,830 newborns (3). Around 30% of them are associated with syndromes involving additional malformations and/or functional loss of organs and organ systems, such as Treacher-Collins, oculo-auriculo-vertebral spectrum or OAVS (also referred as Goldenhar syndrome or hemifacial microsomia), Crouzon, Apert, Klippel-Feil, Wildervanck, van der Hoeve-de-Kleyn, Albers-Schönberg, Patau, Edwards, Down, and 18q syndromes (4, 5). They can either affect the ear orientation, position (low set ear), size and/or shape of the auricle (microtia, cup ear, unfolded helix/Stahl ear); or result in a completely absent ear (anotia), while the middle ear can be atretic or hypoplastic. Minor malformations, such as ear tags, ear sinus and ear pits, may be also found (4). Atresia of the outer ear canal has been rarely observed in patients with a normal auricle (6).

Congenital anomalies of the external ear are genetic or acquired inborn anomalies of the auricle (4). They can be classified as deformations and malformations (7). A deformed ear is presented with fully developed components, with a misshaped auricle or pinna with intact cartilage and skin; while a malformed ear shows auricle alterations due to a partial or complete absence of cartilage and/or skin, because of underdevelopment during embryogenesis (8, 9). Most ear anomalies are acquired and originate from external forces applied to normal ear components in utero or postnatally (10), or by exposure to exogenous factors during the first trimester of pregnancy, such as: (a) infections, mainly viral, confirmed for rubella, cytomegalovirus, and herpes simplex virus; and possible for measles, mumps, hepatitis, poliomyelitis, chickenpox, Coxsackie virus and ECHO virus, and for toxoplasmosis, and syphilis; (b) chemical agents and medical drugs, such as thalidomide, quinine and aminoglycoside antibiotics, diphenylhydantoin, trimethadione, valproic acid, and excessively high doses of retinoic acid; (c) malnutrition and vitamin A deficiency during pregnancy; (d) Rh incompatibility; (e) hypoxia; (f) bleeding during the first trimester of pregnancy and disturbances of metabolism, such as diabetes. Environmental factors, including irradiation, atmospheric pressure changes, and noise exposure, should be also taken into consideration (1, 11–13). In many cases, however, the actual cause is unknown (14), because clinical and anamnestic data of exposure and exogenic influences are often missing or unclear (4).

Microtia/anotia is probably the most extensively studied external ear malformation. A recent metanalysis by Huang et al. (15), identified multiple risk factors with significant association for isolated microtia, including parental demographics, prenatal and perinatal characteristics (birth weight, chemical/medicinal exposure, infections), as well as familial history of ear malformations, among others, emphasizing the importance of identifying them to bring awareness and reinforce prevention. Expanding the scope for other congenital ear anomalies, that have received less attention and might also have consequences later in life, including non-isolated cases published reports, as well as exploring their associations with other congenital anomalies, could provide a more compelling review.

External ear anomalies could cause conductive hearing loss with a significant childhood disability, especially in bilateral cases (16, 17). Additionally, their effect on appearance may lead to psychological distress, anxiety, social avoidance, and behavioral problems (18). The purpose of this study was to compile and review published literature of isolated and non-isolated external ear anomalies, their characteristics, associated factors, and associated malformations/deformations in non-isolated cases.

A total of 1,266 studies were identified −880 from Google Scholar, 158 from PubMed, and 228 from ScienceDirect. After screening of titles and abstracts, removing duplicates, and verifying eligibility criteria, 26 articles remained to be included in this review (Figure 1).

Sixteen studies were case-control studies (20–35), eight were retrospective reviews (36–43), one was a cohort study (44), and other was a cross-sectional study (45). Ten were studies from the U.S.A (22, 23, 25, 26, 29, 31, 33, 36–38), ten from China (21, 27, 28, 30, 32, 39–43), three from Mexico, Colombia, and South America (20, 24, 34), and the rest from Israel, Japan, and South Korea [n = 1, each] (35, 44, 45), as shown in Table 1. All studies were published in English.

The reported external ear anomalies and their frequency by sex, laterality, and ethnicity are shown in Table 2. The anotia/microtia was the most studied malformation (20–31, 33–43, 45). A study reported low set ears as the most common malformation (44), and two studies reported the frequency of deformations: Stahl ear and preauricular tags (34, 44).

From the selected studies, twenty-three reported subject sex, showing greater occurrence of ear anomalies in male population (20, 21, 24–33, 35–45). Fourteen studies reported laterality (20, 24, 27–29, 33, 35–38, 40, 43–45), from which thirteen reported that congenital external ear anomalies were mostly unilateral, and ten being the right ear the most affected (20, 24, 27, 28, 33, 35, 37, 40, 43, 45). Only one study reported higher prevalence for bilateral anomalies (44). Finally, eleven studies classified cases by ethnic background: nine observed higher frequency among Hispanic population, compared to non-Hispanic Caucasians and African Americans (22, 23, 25, 26, 29, 31, 33, 36, 38), and two studies focused on Jewish, Arab (44), Pacific Islanders and Filipino descendants (37) Table 3.

This review aimed to compile and analyze the literature describing external ear congenital anomalies occurrence, characteristics, and associated factors. Congenital anomalies of the external ear vary widely in type and severity, while severe malformations such as anotia/microtia are uncommon. The frequency reported by the studies in this review ranged from 0.21 to 4.34 cases per 10,000 live births (36, 38, 46), higher than the reported by the literature of 0.8 to 2.4 per 10 000 live births (39, 47, 48). This variation might be due to inclusion criteria or higher rates reported in certain regions in comparison with other countries.

The studies reviewed show that external ear anomalies are more frequent in males, usually unilateral, more often in the right ear, Hispanic and Asian populations show higher prevalence compared to other ethnicities. Paternal and maternal age, environmental and pharmacological exposures, pregnancy, or perinatal related complications have been also associated with congenital ear malformations. From the studies presented in this review, twenty-three reported a frequency ranging from 47.1% to 78.5% for males (20, 21, 24–33, 35–45). This is consistent with other studies reporting male predominance: 68.6% in China (27), 58% in Finland (46), 60% in the United States (29, 36, 38, 49) and 54% in Hungary (50). It is worth noticing that both male and female, show similar severity grades (27, 49).

The reports included in this review show that 84% of external ear anomalies are unilateral, and mostly on the right ear (20, 24, 27, 28, 33, 35, 37, 40, 43, 45), consistent with the information presented in other studies (1, 51–53). The mechanisms for this predominance are still unclear; some authors have hypothesized that the greater prevalence of unilateral microtia cases may be related to a localized effect during embryogenesis, resulting in occlusion of a single vessel and thus, causing unilateral alterations (54). This has been attributed to a reduced or complete loss of blood flow to pharyngeal arches, resulting in hypoxia and damage to normal tissue (55), due to the interruption of blood flow to previously formed tissue, vasoconstriction, or underdevelopment of the arterial system required for adequate blood supply to the developing tissues (56). However, epidemiological, or experimental data are insufficient to support this hypothesis; and furthermore, even malformations caused by genetic alterations occur unilaterally, thus other factors acting through nonvascular mechanisms should be considered (55).

From the studies reporting ethnicity, nine found a higher prevalence among Hispanics compared to Caucasians and African Americans in the United States (22, 23, 25, 26, 29, 31, 33, 36, 38). Population-based studies have shown that the prevalence of external ear anomalies is more common in Asians, Hispanic, and Native American population, than in African American and Caucasian populations (57–59). This has been widely reported in studies from Mexico, Paraguay, China, Argentina, Chile, Ecuador, and Japan, where the prevalence ranges from 0.14 to 17.4 per 10,000 births (60–66), compared to studies from England, Italy, France, Hungary, and the United States of America, where the prevalence ranges between 0.66 to 4.34 per 10,000 births (36, 38, 50, 65–73). It is worth considering that prevalence rates are often calculated from live-births records, thus they might be underestimated in populations with high rates of stillbirths and abortions. Furthermore, several factors may relate to ethnicity differences in prevalence. For instance, the higher prevalence rate for Hispanic population in this review, for both US-born and Latin-American Hispanics (22, 23, 25, 26, 29, 31, 33, 36, 38) could be related to cultural behavior, regional differences, genetic variations, and environmental factors, such as socioeconomic status, nutrition, and prenatal care, or a combination of all (33, 56).

Studies report multiple environmental and demographic factors, that may be associated with external ear anomalies: parental age, education level, maternal employment, household income, residential area, altitude, environmental/chemical exposure during the three months before or after conception, drinking and smoking have shown to increase the risk of developing external ear malformations (21, 24–36, 38–40, 42, 45). Altitude has an important impact on external ear malformations in some countries in South America. For instance, there is a higher prevalence for microtia in Quito, Ecuador; La Paz, Bolivia; and Bogota, Colombia, that have higher altitude compared to other countries in South America (74–76). This is supported by the evidence of increased circulating levels of catecholamines and inflammatory cytokines during pregnancy, resulting in damage to the developing embryo and in intra-uterine growth restriction, and increased frequency of preeclampsia and stillbirths, in populations living at high-altitude (77, 78). Pregnancy and perinatal characteristics, as well as parental clinical features have shown to increase the risk of developing external ear anomalies. Among them: male sex, prematurity, low gestational weight, high maternal BMI, gestational diabetes, chronic illness, viral infections (common cold and influenza), some medications (NSAIDs, antihypertensives, antiemetics, progesterone, traditional Chinese medicines), low periconceptional vitamin intake, previous history of threatened abortion, bleeding, and anemia during the first trimester of pregnancy (20–33, 35–38, 40–45). Several risk factors differed between isolated and non-isolated cases of microtia/anotia. In the reviewed articles, the risk factors reported in isolated cases included: being of Asian and Hispanic descent (33, 36), low carbohydrate and folate intake (23), NSAIDs use, pre-existing maternal hypertension, multiple gestations (25), maternal education below high school (33), and urban residency (39); and protective factors were periconceptional folic acid intake (22) and maternal residence in border counties (33). Risk factors reported in non-isolated cases included: high cysteine intake (23), smoking ≥5 cigarettes daily, prematurity, BMI ≥30 (29), multiple births (33), and pre-gestational and gestational diabetes (29, 33); and maternal education above 12 years was reported as a protective factor (36). Notably, maternal diabetes has been consistently linked to a slight but significant increase in the risk of non-isolated cases of microtia/anotia by multiple studies (25, 31, 79–81).

These factors might disrupt the very complex sequence in the development of the external ear, but the mechanisms are not fully understood. This sequence can also be disrupted by mechanical trauma; as the external surface of the developing embryo is in close contact with the uterine wall, where increased tissue fragility or reduced cell-specific adhesiveness may increase the embryos susceptibility to physical or mechanical trauma (82), or in local vascular disruptions and transient focal tissue ischemia (56).

Some genetic studies have shown possible associations between gene mutations and their effect on the pharyngeal arches and external ear malformations. One of the most studied is HOXA2, an important transcriptional regulator for ear development (83, 84), suggesting that HOXA2 may be fundamental in orchestrating the auricle morphogenesis (56, 85, 86). Furthermore, twin studies, particularly those monozygotic with shared genotype, have also demonstrated a strong genetic association (87), suggesting that apart from environmental factors and behavioral factors, these malformations may also be linked genetically.

Multiple pregnancies have been reported to increase the risk of external ear malformations (24, 25, 29–33, 37), and more frequently in those by assisted reproduction techniques (44). Studies of In-vitro Fertilization (IVF) and intracytoplasmic sperm injection (ICSI) compared with those conceived naturally have shown a significantly higher risk of congenital malformations (88, 89), including eye, ear, face, and neck malformations (89–91). It has been reported that the techniques used with these procedures, such as medications used to induce ovulation and/or to maintain the pregnancy, culture media composition, length of time in culture, the freezing of embryos, among others, may be involved (92, 93). However, the specific ear malformations were not mentioned in these studies, thus further research is needed to define the type of ear malformations that are associated with these techniques.

Other factors such as consanguinity have been studied, with some studies reporting cases of autosomal-recessive and non-syndromic forms of bilateral microtia in consanguineous families (94, 95) However, the information about this topic is limited, and the association with external ear anomalies is still unclear.

Congenital external ear malformations may occur as an isolated defect, or with other defects and syndromes. Cleft lip/palate, congenital heart defects, musculoskeletal deformities of skull, face and jaw, and preauricular tags and fistulas were the most reported malformation associated with congenital external ear malformations in non-isolated cases (28, 35, 40, 43), as reported from multiple studies (35, 43, 44, 96). Treacher-Collins, trisomy 18, 13 21, and OAVS were the most reported syndromes (25, 37, 38, 45). It is important to note that many syndromes may not be reported due to the requirements for a karyotype to establish a diagnosis (37), and for those with known diagnosis, certain external ear malformations, such as milder forms of microtia, may be wrongly classified or not reported (38).

External ear malformations may relate to hearing loss, particularly in bilateral cases, justifying routine newborn hearing screening for early detection and prompt treatment (6). Surgical corrections of external ear malformations require a wide understanding of ear anatomy and its development (10). Over the years many techniques have been used and modified to accomplish optimal functional and aesthetic results. The type of technique depends on the presented malformation and whether the malformation is bilateral or unilateral (97). Many surgical techniques include cartilage sculpting from autogenous costal cartilage, and the use of sutures to reshape the ear (10, 17, 97, 98). Several complications can occur with these techniques, ranging from restenosis and otorrhea, to facial nerve injury, cartilage fracture, ear deformations, tympanic membrane perforation and inner ear trauma, worsening hearing impairment (10, 17, 97, 99).

Non-surgical techniques have proven to be highly effective in correcting minor malformations and deformations (such as deformities of the conchal crus, helix, Stahl ears, lidded ears, and prominent ears). Some of the most described techniques include ear molding techniques (7, 10, 100, 101), or laser assisted cartilage reshaping (102), offering an effective approach that can provide optimal results without the need for invasive procedures (7, 101, 102).

Missed diagnoses of congenital external ear malformations can result in delayed intervention and thus, speech developmental delays. Hearing screening in newborns has been reported as the most efficient method for early detection of hearing impairment (6). Once a diagnosis has been made, it is important to carefully select patients, according to strict criteria, including age and absence of sensorineural components of hearing loss, to avoid cases on where surgical intervention may not show favorable results (17, 99).

Overall, the results of this review describe several factors associated with congenital external ear anomalies. However, it has some limitations. There are few studies on external ear malformations, most of them focused on anotia/microtia only. Furthermore, the information regarding race/ethnicity predisposition is limited to a few populations, where the cultural aspects may go under-reported. Moreover, no studies were found of these anomalies in fetuses, thus the reports are limited to registered live births. Nevertheless, this review shows the complexity surrounding the external ear development and some of the associated factors that can result in its malformations.

In conclusion, congenital external ear anomalies include a wide variety of malformations that can occur isolated or associated with other malformations or syndromes. It is important to take environmental, cultural, and social aspects into consideration as a possible explanation for the wide variation across populations. External ear anomalies may cause conductive hearing loss, especially in bilateral cases, since the ear structure aids in the transmission of sound to the middle and inner ear and, depending on their type and severity, can lead to speech impediments. This highlights the importance of an early detection, classification, and repair to avoid childhood disability.