Iridic and retinal coloboma associated with prenatal methimazole exposure

Aramaki, Michihiko; Hokuto, Isamu; Matsumoto, Tadashi; Ishimoto, Hitoshi; Inoue, Makoto; Kimura, Tokuhiro; Oikawa, Yo Ichi; Ikeda, Kazushige; Yoshimura, Yasunori; Takahashi, Tsuyoshi; Kosaki, Kenjiro

doi:10.1002/ajmg.a.30917

Cited by 20 publications

(11 citation statements)

References 12 publications

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“…In MMI embryopathy, exposure occurred before the seventh week of gestation. Aramaki et al (17) reported a case of multiple anomalies, including ocular coloboma and nipple hypoplasia, in a newborn who had been prenatally exposed to MMI. Over a three-decade period, more than 20 cases of aplasia cutis congenita have been reported as possibly associated with MMI or CMZ exposure during pregnancy (12, 18 -24).…”

Section: Discussionmentioning

confidence: 99%

Treatment of Graves' Disease with Antithyroid Drugs in the First Trimester of Pregnancy and the Prevalence of Congenital Malformation

Yoshihara

Noh

Yamaguchi

et al. 2012

The Journal of Clinical Endocrinology & Metabolism

209

180

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Section: Discussionmentioning

confidence: 99%

Treatment of Graves' Disease with Antithyroid Drugs in the First Trimester of Pregnancy and the Prevalence of Congenital Malformation

Yoshihara

Noh

Yamaguchi

et al. 2012

The Journal of Clinical Endocrinology & Metabolism

209

180

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“…Despite several reports of an association of birth defects and prenatal use of MMI [19], [20], [21], [22], this association remains unclear [8]. Momotani et al reported that among 643 infants of mothers with Graves' disease, uncontrolled maternal hyperthyroidism was associated with congenital malformations, whereas MMI treatment was not [24].…”

Section: Discussionmentioning

confidence: 99%

“…Reports suggest a relationship between congenital anomalies (choanal atresia, aplasia cutis, esophageal atresia, facial abnormalities, hypothelia, cardiovascular defects) and prenatal exposure to MMI, a constellation of features termed MMI embryopathy [19], [20], [21], [22]. Large cohort studies, however, have found birth defects associated with maternal GD to be attributed to the hyperthyroid state rather than to the ATDs themselves [23], [24], [25].…”

Section: Introductionmentioning

confidence: 99%

Propylthiouracil Is Teratogenic in Murine Embryos

et al. 2012

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BackgroundHyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed.MethodsWe examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis.ResultsWhen dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.

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“…Here, the author wishes to illustrate how detailed case studies can contribute to epidemiological studies, using methimazole embryopathy as an example (Aramaki et al 2005). Whether methimazole, an antithyroid drug, represents a teratogen has been the subject of debate.…”

Section: Methimazole Embryopathy As Phenocopy Of Charge Syndromementioning

confidence: 99%

“…So, the natural question to ask would be whether methimazole may be associated with another very specific feature of CHARGE syndrome, coloboma of the eyes. Indeed, the author recently evaluated a newborn female who had been prenatally exposed to methimazole (Aramaki et al 2005). The patient exhibited multiple anomalies, including vitelline duct anomalies and nipple hypoplasia.…”

Section: Methimazole Embryopathy As Phenocopy Of Charge Syndromementioning

confidence: 99%

Role of rare cases in deciphering the mechanisms of congenital anomalies: CHARGE syndrome research

Kosaki¹

2011

Congenital Anomalies

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In this review, our work on CHARGE syndrome will be used to exemplify the role of rare cases in birth defects research. The analysis of 29 cases with mutations of CHD7, the causative gene for CHARGE syndrome, clarified the relative importance of the cardinal features, including facial nerve palsy and facial asymmetry. Concurrently, in situ hybridization using chick embryos studies were performed to delineate the expression pattern of Chd7. The Chd7-positive regions in the chick embryos and the anatomical defects commonly seen in patients with CHARGE syndrome were well correlated: expression in the optic placode corresponded with defects such as coloboma, neural tube with mental retardation, and otic placode with ear abnormalities. The correlation between expression in the branchial arches and nasal placode with the clinical symptoms of CHARGE syndrome, however, became apparent when we encountered two unique CHARGE syndrome patients: one with a DiGeorge syndrome phenotype and the other with a Kallman syndrome phenotype. A unifying hypothesis that could explain both the DiGeorge syndrome phenotype and the Kallman syndrome phenotype in patients with CHARGE syndrome may be that the mutation in CHD7 is likely to exert its effect in the common branch of the two pathways of neural crest cells. As exemplified in CHARGE syndrome research, rare cases play a critical role in deciphering the mechanisms of human development. Close collaboration among animal researchers, epidemiologists and clinicians hopefully will enhance and maximize the scientific value of rare cases.

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Iridic and retinal coloboma associated with prenatal methimazole exposure

Cited by 20 publications

References 12 publications

Treatment of Graves' Disease with Antithyroid Drugs in the First Trimester of Pregnancy and the Prevalence of Congenital Malformation

Treatment of Graves' Disease with Antithyroid Drugs in the First Trimester of Pregnancy and the Prevalence of Congenital Malformation

Propylthiouracil Is Teratogenic in Murine Embryos

Role of rare cases in deciphering the mechanisms of congenital anomalies: CHARGE syndrome research

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