Congenital Diaphragmatic Hernia and Microtia in a Newborn With Mycophenolate Mofetil (MMF) Exposure: Phenocopy for Fryns Syndrome or Broad Spectrum of Teratogenic Effects?

Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington 98105, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2009; 149A(6):1237-40. DOI: 10.1002/ajmg.a.32684
Source: PubMed


A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day 2 of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

Download full-text


Available from: Melissa Parisi,
  • Source
    • "Bilateral severe microtia, EAC atresia, facial and oral cleft, absence of orbits, eyelid, iris, and retinal coloboma, microphthalmia, cataracts, lens dislocation, mandibular hypoplasia, absent maxilla and orbits, agenesis of the corpus callosum, hydrocephalus, truncus arteriosus, aberrant right subclavian artery, single umbilical artery, esophageal atresia, rib defect, hemivertebrae, left renal agenesis, streak ovary, digitalized thumbs. Parisi et al., 2009 Kidney transplant, "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycophenolate mofetil is a widely prescribed immunosuppressive agent for transplant patients and autoimmune diseases. Potential teratogenic effects after in utero exposure to mycophenolate mofetil has been described in human clinical observations. The complete clinical pattern is still being delineated. We present four newborns with esophageal atresia and other congenital anomalies, prenatally exposed to mycophenolate mofetil during the first trimester. Two of the cases had other defects related to the embryopathy: microtia, eye abnormalities and oral clefts. Two cases did not show major craniofacial anomalies. We propose that esophageal atresia with or without tracheoesophageal fistula is a feature of mycophenolate embryopathy even without the presence of other major craniofacial anomalies. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed. Copyright © 2014 Elsevier Inc. All rights reserved.
    Reproductive Toxicology 10/2014; 50C:117-121. DOI:10.1016/j.reprotox.2014.10.015 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycophenolate mofetil (MMF) has become a major therapeutic option in the management of patients undergoing transplantation, as well as in the treatment of autoimmune conditions. Case reports have suggested that MMF use during pregnancy is associated with a specific pattern of congenital malformations. Because many pregnancies are unplanned, it is imperative to assess the teratogenic risk of MMF. Using the Organization of Teratology Information Specialists network, we prospectively identified and followed pregnant women exposed to MMF during pregnancy to update this teratogenic potential. Ten cases were identified and all received the drug during embryogenesis at the recommended doses (500 to 1500 mg daily). There were four miscarriages and one elective abortion due to fear of teratogenesis. None of the five live births had malformations. It is possible that, similar to other human teratogens discovered first by case reports, the absolute risk from MMF may be smaller than originally calculated based on case reports. Because the major malformations phenotypic of MMF may be visualized in utero (e.g., microtia, cleft palate, congenital diaphragmatic hernia, and cardiac malformation), diagnostic imaging should be performed.
    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 08/2010; 32(8):794-7.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mycophenolate mofetil (MMF) and its active metabolite mycophenolic acid (MPA) are both very effective immunosuppressive agents widely used for the prevention of organ rejection following transplantation and in the therapy of autoimmune diseases. In experimental studies performed in pregnant animals, MMF exhibited teratogenicity, which later was confirmed in humans, as documented in the United States National Transplantation Pregnancy Registry (NTPR). In 2008, a specific pattern of malformations associated with in utero exposure to MMF was suggested. Subsequently, numerous reports in the scientific literature of newborns having similar patterns of malformations born to mothers who had undergone transplantation and were receiving immunosuppressive therapy provided supporting evidence for the existence of a specific MMF embryopathy. The most consistent characteristics of the MMF embryopathy phenotype include cleft lip and palate, microtia and aural atresia, and ocular anomalies (hypertelorism, arching eyebrows). Perinatal clinicians should be aware of the potential teratogenicity of MMF. Importantly, effective contraception measures should be recommended to fertile women who have received transplants before they become pregnant. Given the cumulative effect of MMF, contraceptive measures should be continued for at least 6 months after discontinuing MMF therapy.
    NeoReviews 10/2010; 11(10):e578-e589. DOI:10.1542/neo.11-10-e578
Show more