Correspondence

A Classic Twin Study of External Ear Malformations, Including Microtia

N Engl J Med 2009; 361:1216-1218September 17, 2009DOI: 10.1056/NEJMc0902556

Article

To the Editor:

The pathogenesis of microtia, a rare congenital malformation of the external ear, remains elusive. Phenotypes range from minor deformities, such as preauricular tags, to anotia, the complete absence of the external ear (Figure 1Figure 1Normal and Malformed Ears in One Pair of Monozygotic Twins.). Prevalence ranges from 0.66 per 10,000 in England to 17.4 per 10,000 in Quito, Ecuador.1 The relative contributions of environmental and genetic factors to microtia were assessed in a classic twin study.

In this study, we identified 13 monozygotic and 22 dizygotic twin pairs at three microtia reconstruction centers, one in the United States, one in Ecuador, and one in Colombia. In other words, each twin pair was ascertained because at least one sibling had severe nonsyndromic microtia requiring surgical repair. There was no ear malformation in 40% of subjects, malformation of the right ear in 34%, malformation of the left ear in 13%, and bilateral anomalies in 12%. Ear-malformation laterality was indistinguishable among monozygotic and dizygotic twins. None of the twins reported first-degree relatives with ear malformations, but 20% had at least one, more distant relative with an ear malformation.

The concordance rate for all auricular malformations was higher in monozygotic twins than in dizygotic twins (61.5% and 4.5%, respectively; P=0.003) (Table 1Table 1Concordance and Discordance of Ear Malformations in Monozygotic and Dizygotic Twins.). Concordance rates for microtia (excluding skin tags and minor pinna malformation) among monozygotic and dizygotic twins were also significantly different — 38.5% and 4.5%, respectively (Table 1).

A literature review identified 37 twin pairs with microtia in whom other auricular malformations were rarely reported.2-5 When the results of this study are combined with those of our study of 35 twin pairs, the 72 sets of twins show significant differences in the concordance rate for monozygotic twins (10 in 38, or 26.3%), and the concordance rate for dizygotic twins (1 in 34, or 2.9%) (odds ratio, 11.5; 95% confidence interval, 1.4 to 93.7; P=0.023).

In summary, twin studies indicate that there is a strong genetic contribution to malformations of the external ear. Shared genotype in monozygotic twins increased the risk of auricular malformations by a factor of about 30. Environment also contributes to the risk of auricular malformations, accounting for discordance in 40% of monozygotic twins.

Our data are consistent with two models. A concordance of 60% in monozygotic twins is consistent with a germ-line mutation that is incompletely penetrant. Alternatively, microtia may result from somatic mutations or epigenetic events that occur early in embryogenesis, since monozygotic twins separate by the 12th day after fertilization. Regardless of the model, identification of the genetic basis for asymmetric ear morphologies may provide new insights into mammalian pattern formation.

Maria A. Artunduaga, M.D.
Maria D.L. Quintanilla-Dieck, M.D.
Steven Greenway, M.D.
Harvard Medical School, Boston, MA

Rebecca Betensky, Ph.D.
Harvard School of Public Health, Boston, MA

Yamileth Nicolau, M.D.
University of California School of Medicine, San Diego, CA

Usama Hamdan, M.D.
Global Smile Foundation, Lexington, MA

Patricia Jarrin, M.D.
Fundación Tierra Nueva, Quito, Ecuador

Gabriel Osorno, M.D.
National University of Colombia School of Medicine, Bogotá, Colombia

Burt Brent, M.D.
El Camino Hospital, Mountain View, CA

Roland Eavey, M.D.
Vanderbilt University School of Medicine, Nashville, TN

Christine Seidman, M.D.
Howard Hughes Medical Institute, Boston, MA

J.G. Seidman, Ph.D.
Harvard Medical School, Boston, MA
seidman@genetics.med.harvard.edu

Supported by grants from the National Institutes of Health (R01 DC007453, to Drs. C. Seidman and J. Seidman; and UL1RR025758, to Dr. Betensky), the Eavey Young Investigators Fund of the Massachusetts Eye and Ear Infirmary, Boston (to Dr. Eavey), and the International Fellowship of the American Association of University Women (to Dr. Artunduaga).

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Citing Articles (6)

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   Chenlong Li, Shaojuan Hao, Huijun Wang, Lei Jin, Fenghua Qing, Fengyun Zheng, Ping Zhang, Long Chen, Duan Ma, Tianyu Zhang. (2013) MicroRNA expression profiling and target genes study in congenital microtia. International Journal of Pediatric Otorhinolaryngology 77:4, 483-487
   

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   Development of Eyes and Ears. In: The Developing Human. Elsevier, 2013:429-449.
   

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   Daniela V. Luquetti, Carrie L. Heike, Anne V. Hing, Michael L. Cunningham, Timothy C. Cox. (2012) Microtia: Epidemiology and genetics. American Journal of Medical Genetics Part A 158A:1, 124-139
   

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   Anna Carina Schulz, Enrika Bartels, Rüdiger Stressig, Jochen Ritgen, Eberhard Schmiedeke, Manuel Mattheisen, Markus Draaken, Michael Ludwig, Soyhan Bagci, Andreas Müller, Ulrich Gembruch, Annegret Geipel, Christoph Berg, Andreas Heydweiller, Haitham Bachour, Johannes Schumacher, Peter Bartmann, Markus M. Nöthen, Heiko Reutter. (2012) Nine new twin pairs with esophageal atresia: A review of the literature and performance of a twin study of the disorder. Birth Defects Research Part A: Clinical and Molecular Teratologyn/a-n/a
   

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   Daniela Varela Luquetti, Emanuele Leoncini, Pierpaolo Mastroiacovo. (2011) Microtia-anotia: A global review of prevalence rates. Birth Defects Research Part A: Clinical and Molecular Teratology 91:9, 813-822
   

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   Burt Brent. (2011) Repair of Microtia With Sculpted Rib Cartilage Grafts in Identical, Mirror-Image Twins. Annals of Plastic Surgery 66:1, 62-64