Microtia is a congenital anomaly of the ear that ranges in severity from mild structural abnormalities to complete absence of the ear, and can occur as an isolated birth defect or as part of a spectrum of anomalies or a syndrome. Microtia is often associated with hearing loss and patients typically require treatment for hearing impairment and surgical ear reconstruction. The reported prevalence varies among regions, from 0.83 to 17.4 per 10,000 births and the prevalence is considered to be higher in Hispanics, Asians, Native Americans, and Andeans. The etiology of microtia and the cause of this wide variability in prevalence are poorly understood. Strong evidence supports the role of environmental and genetic causes for microtia. Although some studies have identified candidate genetic variants for microtia, no causal genetic mutation has been confirmed. The application of novel strategies in developmental biology and genetics has facilitated elucidation of mechanisms controlling craniofacial development. In this paper we review current knowledge of the epidemiology and genetics of microtia, including potential candidate genes supported by evidence from human syndromes and animal models. We also discuss the possible etiopathogenesis in light of the hypotheses formulated to date: neural crest cells disturbance, vascular disruption and altitude.

Background There are few published studies on microtia-anotia frequency. Methods Using data from birth defects surveillance programs around the world, we conducted a systematic review on the frequency of microtia-anotia to further explore the differences in prevalence across countries. Ninety-two birth defects surveillance programs were evaluated with a total of 8,917 cases of microtia-anotia. We computed the prevalence per 10,000 births for each surveillance program for total cases of microtia-anotia (microtia types I to IV), microtia (types I to III), and anotia (type IV). Prevalence ratios were calculated by large geographical areas, race/ethnicity, and by surveillance methodologies. Results The overall prevalence were for microtia-anotia 2.06 (CI: 2.02–2.10), for microtia 1.55 (CI: 1.50–1.60), and for anotia 0.36 (CI: 0.34–0.38). Higher prevalence was observed in the Americas, Northern Europe and Asia, among Hispanics and Asians, and among active ascertainment and hospital-based surveillance programs. Conclusions We observed marked variation in the prevalence of microtia-anotia across surveillance programs and within countries. These results must be interpreted cautiously as this variability may be explained mainly by differences in surveillance methods. However, given the magnitude of some of the differences, other factors may also be involved. This study contributes to the knowledge on the prevalence of microtia-anotia by providing a critical analysis of the existing data. In addition, it supports the need for a coding system that allows complete phenotype characterization of microtia-anotia, including severity and laterality; as well as further studies on the variation of its frequency related to race and ethnicity.

Microtia is a term used to describe a wide array of phenotypic presentations of the outer ear. Although the majority of the cases are isolated in nature, much of our understanding of the causes of microtia has been driven by the identification of genes underlying syndromic forms where the anomaly co-presents with various other craniofacial and extra-craniofacial structural defects. In this review we discuss recent findings in mice deficient in Hoxa2, a key regulator of branchial arch patterning, which has necessitated a revision to the canonical model of pinna morphogenesis. The revised model will likely impact current classification schemes for microtia and, as we argue in this review, the interpretation of the developmental basis for various auricular malformations. In addition, we highlight recent studies in other mammalian species that are providing the first clues as to possible causes of at least some isolated anomalies and thus should now accelerate the search for the more elusive genetic contributions to the many isolated and non-syndromic cases of microtia. These findings, together with the application of new genome-level sequencing technologies and more thorough quantitative assessment of available mutant mouse resources, promise an exciting future for genetic studies in microtia.

Heterozygous mutations in the EFTUD2 were identified in 12 individuals with a rare sporadic craniofacial condition termed Mandibulofacial dysostosis with microcephaly (MIM 610536). We present clinical and radiographic features of three additional patients with de novo heterozygous mutations in EFTUD2.. Although clinical features overlap with findings of the original report (choanal atresia, cleft palate, maxillary and mandibular hypoplasia, and microtia), microcephaly was present in two of three patients and cognitive impairment was milder in those with head circumference proportional to height. Our cases expand the phenotypic spectrum to include epibulbar dermoids and zygomatic arch clefting. We suggest that craniofacial computed tomography studies to assess cleft of zygomatic arch may assist in making this diagnosis. We recommend consideration of EFTUD2 testing in individuals with features of oculo-auriculo-vertebral spectrum and bilateral microtia, or individuals with atypical CHARGE syndrome who do not have a CHD7 mutation, particularly those with a zygomatic arch cleft. The absence of microcephaly in one patient indicates that it is a highly variable phenotypic feature.

Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM.

The phenotypic assessment tool for craniofacial microsomia protocol provides a simple and standardized method for practitioners and researchers to classify patients with craniofacial microsomia. We anticipate that this tool can be used in multicenter investigational studies to evaluate the cause of this condition, its natural history, and comparative effectiveness research.

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10−10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.

BACKGROUND We compared the IQ and academic achievement of adolescents with craniofacial macrosomia (CFM) (“cases) and unaffected children (“controls”). Among cases we analyzed cognitive functioning by facial phenotype. METHODS We administered standardized tests of intelligence, reading, spelling, writing and math to 142 cases and 316 controls recruited from 26 cities across the U.S. and Canada. Phenotypic classification was based on integrated data from photographic images, health history, and medical chart reviews. Hearing screens were conducted for all participants. RESULTS After adjustment for demographics, cases’ average scores were lower than controls’ on all measures, but the magnitude of differences was small (standardized effect sizes (ES) = −0.04 to −0.2). There was little evidence that hearing status modified case-control group differences (Wald p>0.05 for all measures). Twenty-five percent of controls and 38% of cases were classified as having learning problems (adjusted OR=1.5, 95% CI 0.9–2.4). Comparison of cases with and without learning problems indicated that those with learning problems were more likely to be male, Hispanic and to come from lower income, bilingual families. Analyses by facial phenotype showed that case-control group differences were largest for cases with both microtia and mandibular hypoplasia (ES = −0.25 to −0.5). CONCLUSIONS The highest risk of cognitive-academic problems was observed in patients with combined microtia and mandibular hypoplasia. Developmental surveillance of this subgroup is recommended, especially in the context of high socioeconomic risk and bilingual families. Given the early stage of research on CFM and neurodevelopment, replication of these findings is needed.