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Page 6 of 14                                    Velasquillo et al. Plast Aesthet Res 2020;7:31  I  http://dx.doi.org/10.20517/2347-9264.2020.30

               Congenital anomalies
               Congenital anomalies, also known as birth defects, are structural or functional anomalies that occur
                                   [65]
               during intrauterine life . These defects can be identified prenatally, at birth, or even during later infancy.
                                               [66]
               They occur in 2%-4% of live births  and are more common in stillborn spontaneous miscarriages.
                                                                                       [65]
               Approximately 50% of all congenital anomalies are not linked to a specific cause ; however, they are
               commonly caused by genetic abnormalities and/or environmental exposures. Genetic abnormalities
               include chromosomal alterations (e.g., Down syndrome) or single-gene/monogenic disorders. The latter
                                                                                                    [67]
               have different modes of inheritance such as autosomal dominant, autosomal recessive, or X-linked . On
               the other hand, environmental exposure to a teratogen, any agent that causes abnormalities in the form
               or function of the fetus, can produce cell death, alter normal growth of tissues, or interfere with normal
                                                               [68]
               cellular differentiation, resulting in a congenital anomaly .

               Birth defects are divided depending on the pathophysiology of the defect: (1) malformation when the
               intrinsic development is abnormal; (2) deformation when extrinsic mechanical forces modify a normally
               formed structure; (3) disruption when a vascular defect causes a malformation; or (4) dysplasia when there
                                                        [68]
               is an abnormal organization of cells into tissues . These defects can be isolated or present in syndromes
               or associated patterns that may affect one or more organ systems. A lot of preventive measures, as well as
               treatment measures, have been focused on these anomalies due to their medical, surgical, psychological,
               and cosmetic significance.


               Congenital microtia
               Congenital microtia is the incomplete formation or growth of the auricle, leading to the small or deformed
               auricle. It may occur as an isolated condition or as part of a syndrome or spectrum of anomalies. Microtia
               severity ranges from a complete absence of the auricle (anotia) to a mild size discrepancy. Most of the
                                                                                          [69]
               time, microtia occurs unilaterally (79%-93%), the right side being the most affected side . It is associated
               with hearing loss of the ipsilateral ear, but normal hearing in the unaffected ear. Speech and language
               development are usually normal. Individuals with microtia, however, are at a higher risk of communication
               delay and attention deficit disorders [70,71] .


               The etiology of microtia is poorly understood, though there is strong evidence supporting the importance
               of environmental causes such as altitude, and gestational exposure to certain drugs [72-75] . Ethnicity has been
               reported to be an important consideration due to the high incidence and prevalence of microtia among
               Asians, Hispanics, and Native Americans. In Mexico, the World Health Organization and the Mexican
               Registry and Epidemiological Surveillance of External Congenital Malformations (RYVEMCE) reported a
               prevalence of 6.15-7.37 cases per 10,000 childbirths, being one of the countries with the highest prevalence
               of microtia worldwide [72,75] . Due to the psychological and functional implications related to microtia,
               there have been several studies focusing on the surgical treatment and biotechnology measures needed to
               recreate an auricle as similar as possible to the native one.

               Auricle reconstruction with autologous rib cartilage remains the gold standard for patients with microtia/
                                [76]
                                                [77]
               anotia. Tanzer et al.  and Brent et al.  described this technique as an alternative to allogeneic implants
               in the late 1950s, overcoming several problems associated with these implants. Sculpted autologous costal
               cartilage graft is one of the most challenging procedures in plastic and reconstructive surgery since the
               surgeon has to handcraft the cartilage trying to create an ear similar in appearance to the contralateral
                                                                                         [77]
               one. Grafts have good long-term durability and grow concomitantly as the patient ages . However, costal
               cartilage grafts are not as consistent as synthetic implants: they require long operative time, harvesting
               results in donor-site morbidity, and, occasionally, there is an insufficient source of cartilage.


               Tissue engineering techniques emerged as an alternative treatment. The idea of preformed ear structures
                                                                [78]
               seeded with cells goes back to the 1940s when Peer et al.  started using diced cartilage placed inside an
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