Grade 1 microtia, wide anterior fontanel and novel type tracheo-esophageal fistula in methimazole embryopathy

Am J Med Genet A. 2011 Mar;155A(3):526-33. doi: 10.1002/ajmg.a.33705. Epub 2011 Feb 22.


Carbimazole (CMZ) and its active metabolite methimazole (MMI) are antithyroid medications, which can result in MMI/CMZ embryopathy in susceptible individuals. The incidence of birth defects related to MMI/CMZ embryopathy remains unclear as several epidemiologic studies failed to prove a correlation, despite positive case-control studies and numerous case reports. Malformations reported in exposed individuals and commonly recognized as MMI/CMZ embryopathy include cutis aplasia of the scalp, choanal atresia, esophageal atresia (EA), tracheo-esophageal fistula (TEF), persistent vitelline duct, athelia/hypothelia, and subtle facial dysmorphisms including sparse or arched eyebrows. Here, we report on individuals with early pregnancy exposure to MMI, with microtia and various other anomalies associated with MMI embryopathy, suggesting that microtia is also seen with increased frequency after prenatal MMI exposure. Additional unusual malformations among our patients include a previously unreported type of TEF with three separate esophageal pouches and a fistula connecting the middle pouch to the trachea in one child, and absence of the gall bladder in another. An enlarged anterior fontanel was seen in three patients, and clinodactyly of the fifth finger was noted in three. The similarities between our three patients with microtia after MMI exposure and the two previously reported with microtia after CMZ exposure support the concept of microtia being related to the MMI/CMZ exposure. Recognition of microtia as a manifestation of MMI/CMZ embryopathy will likely increase the number of diagnosed cases and thus affect ascertainment. We propose diagnostic criteria for MMI/CMZ embryopathy, including the presence of at least one major characteristic finding.

Publication types

  • Case Reports

MeSH terms

  • Child, Preschool
  • Congenital Abnormalities
  • Congenital Microtia
  • Cranial Fontanelles / abnormalities*
  • Ear / abnormalities
  • Facies
  • Female
  • Fetal Diseases / chemically induced*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Methimazole / adverse effects*
  • Pregnancy
  • Tracheoesophageal Fistula / chemically induced*
  • Tracheoesophageal Fistula / complications*
  • Tracheoesophageal Fistula / surgery


  • Methimazole