PRENATAL DIAGNOSIS, VOL.
12,699-70 1 (1 992)
SHORT COMMUNICATION
MORPHOLOGICAL FEATURES OF A CASE OF RETINOIC ACID EMBRYOPATHY LIONEL VAN MALDERGEM, ERIC JAUNIAUX A N D YVES GILLEROT Centre de Genetique Humaine, Institut de Morphologie Pathologique de Loverval. Belgium
SUMMARY
A case of retinoic acid embryopathy which was retrospectively diagnosed after delivery is presented.The affected fetus was exposed to the drug during the first month of pregnancy and second-trimestersonographicexaminationshowed hydrocephalusandcardiacmalformation. The diagnosis was made on the basis of autopsy findings and genetic enquiry. KEY WORDS
Retinoic acid Pregnancy First trimester Embryopathy Cardiac malformation
Hydrocephaly
INTRODUCTION The administration of retinoids during early gestation is known to induce various congenital malformations in both human and animal species (Lammer et al., 1985; Koren et al., 1987; Abbott et al., 1990). Retinoids are commonly used for the treatment of severe cystic acne and other chronic dermatoses. However, despite regular warning about their use in female patients of childbearing age not having contraception, inadvertent treatment continues. Adverse pregnancy outcomes have been reported mainly in the U.S.A.and Canada (Lammer ef al., 1985; Rosa, 1986, 1987; Lammer, 1988). This paper describes the perinatal features of a fetus presenting with retinoic acid embryopathy following exposure to the drug during the first month of pregnancy. CASE REPORT A 25-year-old Caucasian woman, gravida 0, presented to her obstetrician for routine ultrasound examination at 26 weeks’ gestation. Her past medical history was unremarkable. Sonographic investigations revealed hydrocephaly and a major congenital heart defect. At that time, the patient denied any knowledge of medication intake and the pregnancy had been uncomplicated. After discussion with the couple, the pregnancy was terminated. At autopsy, the female fetus had an enlarged and elongated head (Figure la) with facial dysmorphogenesis including low-set microtic ears, hypertelorism, and a flat and depressed nasal bridge (Figure 1b). Macroscopic examination confirmed ventriculomegaly of the lateral ventricles and showed cerebellar hypoplasia. There was dextrocardia. The Addressee for correspondence: Lionel Van Maldergem, MD, Institut de Morphologie Pathologique, Allte des Ternpliers 41, B-6280 Loverval, Belgium.
0197-3851 /92/080699-03$06.50 0 1992 by John Wiley & Sons, Ltd.
Received 13 August 1991 Accepted 20 December 1991
700
L. VAN MALDERGEM ET AL.
Figure 1 . Facial appearance. (a) Profile. Note elongation of the calvariurn and hypoplastic, low-set ears. (b) Frontal view. Note hypertelorisrn and broad nasal bridge
heart was enlarged and there was a supracristal ventricular septa1 defect and a single truncus arteriosus. The digits were normal and palmar creases were present. Histological examination of the fetal organs showed no abnormality. In particular, the liver was normal. Chromosome analysis confirmed a normal 46,XX karyotype. The couple was referred for genetic counselling. There was no history of consanguinity or genetic disease. The pattern of malformations presented by the fetus were suggestive of teratogen exposure and the mother was interviewed about drug intake at the time of conception. She revealed having used isotretinoin (Roaccutane), at a dose of 20 mg per day, during the 3-month period before conception and until the end of the first month of gestation, because of mild facial acne. She was not aware of the teratogenic effect and her obstetrician was not aware of the treatment .
DISCUSSION Retinoic acid became available in North America in 1982 and during the next 6 years more than 100 cases of adverse pregnancy outcome were reported (Lammer et al., 1985; Rosa, 1986; Lammer, 1987). In contrast, in Europe, where the drug was introduced in 1985, less than ten cases of retinoic acid embryopathy have been described (Ayme et al., 1988; Anon., 1989).Our case illustrates the typical pattern of malformations associated with embryonic exposure to retinoic acid, i.e., hydrocephaly, cerebellar vermis agenesis, microtic low-set ears, and severe cardiac malformation (Figure 1). In addition, dextrocardia, which has not been described
RETINOIC ACID EMBRYOPATHY
70 1
previously in retinoic acid embryopathy, was present. These malformations are diagnosable prenatally by ultrasound (Koren et al., 1987) and any fetus with the pattern of findings described can be suspected of having retinoic acid embryopathy. Our experience with this patient, confirming that of Ayme et al. (1988), demonstrates that even exposure to a low dose ofisotretinoin can induce the full expression of the syndrome. A similar embryopathy can also occur in an infant conceived 1 year after termination of etretinate, which, unlike isotretinoin, is stored in maternal adipose tissue (Lammer, 1988). We believe that until these drugs are used more carefully in female patients of childbearing age, single case reports will continue to generate significant alarm in both medical and scientific communities.
REFERENCES Abbott, B.D.. Hill, L.G., Birnbaum, L.S. (1990). Processes involved in retinoic acid production of small embryonic shelves and limb defects, Teratology, 41,299-310. Anonymous (1988). Eurocaf Newsletr., 2 (7), 1-2. Anonymous ( 1989). Anomalies d u developpement liees aux acides retinoiques. Nouvelles du registre des malformations du sud Hainaut et du namurois, Eurocat, 6: 1-2. Ayme. S.. Julian, C., Gambarelli, D., Mariotti, B., Maurin, N. (1988). Isotretinoin dose and teratogenicity, Lancet, i, 655. Koren, G.,Edwards, M.B., Miskin, M . (1987). Antenatal sonography malformations associated with drugs and chemicals: a guide, Am. J . Obsret. Gynecol., 156,79-85. Lammer. E.J. (1987). Risk for major malformations among human fetuses exposed to isotretinoin, TeratoJogy, 35,68A. Lammer, E.J. (1988). Embryopathy in infant conceived one year after termination of maternal etretinate, Lancet, ii, 1080-108 1. Lammer, E.J., Chen, D.T., Hoar, R.M. eta/. (1985). Retinoic acid embryopathy, N . Engl. J. Med., 313,837-841. Rosa, F. (1986). Retinoic acid embryopathy, N . Engl. J . Med., 315,262. Rosa, F. (1987). Isotretinoin dose and teratogenicity, Lancet, ii, 1 154.
12,699-70 1 (1 992)
SHORT COMMUNICATION
MORPHOLOGICAL FEATURES OF A CASE OF RETINOIC ACID EMBRYOPATHY LIONEL VAN MALDERGEM, ERIC JAUNIAUX A N D YVES GILLEROT Centre de Genetique Humaine, Institut de Morphologie Pathologique de Loverval. Belgium
SUMMARY
A case of retinoic acid embryopathy which was retrospectively diagnosed after delivery is presented.The affected fetus was exposed to the drug during the first month of pregnancy and second-trimestersonographicexaminationshowed hydrocephalusandcardiacmalformation. The diagnosis was made on the basis of autopsy findings and genetic enquiry. KEY WORDS
Retinoic acid Pregnancy First trimester Embryopathy Cardiac malformation
Hydrocephaly
INTRODUCTION The administration of retinoids during early gestation is known to induce various congenital malformations in both human and animal species (Lammer et al., 1985; Koren et al., 1987; Abbott et al., 1990). Retinoids are commonly used for the treatment of severe cystic acne and other chronic dermatoses. However, despite regular warning about their use in female patients of childbearing age not having contraception, inadvertent treatment continues. Adverse pregnancy outcomes have been reported mainly in the U.S.A.and Canada (Lammer ef al., 1985; Rosa, 1986, 1987; Lammer, 1988). This paper describes the perinatal features of a fetus presenting with retinoic acid embryopathy following exposure to the drug during the first month of pregnancy. CASE REPORT A 25-year-old Caucasian woman, gravida 0, presented to her obstetrician for routine ultrasound examination at 26 weeks’ gestation. Her past medical history was unremarkable. Sonographic investigations revealed hydrocephaly and a major congenital heart defect. At that time, the patient denied any knowledge of medication intake and the pregnancy had been uncomplicated. After discussion with the couple, the pregnancy was terminated. At autopsy, the female fetus had an enlarged and elongated head (Figure la) with facial dysmorphogenesis including low-set microtic ears, hypertelorism, and a flat and depressed nasal bridge (Figure 1b). Macroscopic examination confirmed ventriculomegaly of the lateral ventricles and showed cerebellar hypoplasia. There was dextrocardia. The Addressee for correspondence: Lionel Van Maldergem, MD, Institut de Morphologie Pathologique, Allte des Ternpliers 41, B-6280 Loverval, Belgium.
0197-3851 /92/080699-03$06.50 0 1992 by John Wiley & Sons, Ltd.
Received 13 August 1991 Accepted 20 December 1991
700
L. VAN MALDERGEM ET AL.
Figure 1 . Facial appearance. (a) Profile. Note elongation of the calvariurn and hypoplastic, low-set ears. (b) Frontal view. Note hypertelorisrn and broad nasal bridge
heart was enlarged and there was a supracristal ventricular septa1 defect and a single truncus arteriosus. The digits were normal and palmar creases were present. Histological examination of the fetal organs showed no abnormality. In particular, the liver was normal. Chromosome analysis confirmed a normal 46,XX karyotype. The couple was referred for genetic counselling. There was no history of consanguinity or genetic disease. The pattern of malformations presented by the fetus were suggestive of teratogen exposure and the mother was interviewed about drug intake at the time of conception. She revealed having used isotretinoin (Roaccutane), at a dose of 20 mg per day, during the 3-month period before conception and until the end of the first month of gestation, because of mild facial acne. She was not aware of the teratogenic effect and her obstetrician was not aware of the treatment .
DISCUSSION Retinoic acid became available in North America in 1982 and during the next 6 years more than 100 cases of adverse pregnancy outcome were reported (Lammer et al., 1985; Rosa, 1986; Lammer, 1987). In contrast, in Europe, where the drug was introduced in 1985, less than ten cases of retinoic acid embryopathy have been described (Ayme et al., 1988; Anon., 1989).Our case illustrates the typical pattern of malformations associated with embryonic exposure to retinoic acid, i.e., hydrocephaly, cerebellar vermis agenesis, microtic low-set ears, and severe cardiac malformation (Figure 1). In addition, dextrocardia, which has not been described
RETINOIC ACID EMBRYOPATHY
70 1
previously in retinoic acid embryopathy, was present. These malformations are diagnosable prenatally by ultrasound (Koren et al., 1987) and any fetus with the pattern of findings described can be suspected of having retinoic acid embryopathy. Our experience with this patient, confirming that of Ayme et al. (1988), demonstrates that even exposure to a low dose ofisotretinoin can induce the full expression of the syndrome. A similar embryopathy can also occur in an infant conceived 1 year after termination of etretinate, which, unlike isotretinoin, is stored in maternal adipose tissue (Lammer, 1988). We believe that until these drugs are used more carefully in female patients of childbearing age, single case reports will continue to generate significant alarm in both medical and scientific communities.
REFERENCES Abbott, B.D.. Hill, L.G., Birnbaum, L.S. (1990). Processes involved in retinoic acid production of small embryonic shelves and limb defects, Teratology, 41,299-310. Anonymous (1988). Eurocaf Newsletr., 2 (7), 1-2. Anonymous ( 1989). Anomalies d u developpement liees aux acides retinoiques. Nouvelles du registre des malformations du sud Hainaut et du namurois, Eurocat, 6: 1-2. Ayme. S.. Julian, C., Gambarelli, D., Mariotti, B., Maurin, N. (1988). Isotretinoin dose and teratogenicity, Lancet, i, 655. Koren, G.,Edwards, M.B., Miskin, M . (1987). Antenatal sonography malformations associated with drugs and chemicals: a guide, Am. J . Obsret. Gynecol., 156,79-85. Lammer. E.J. (1987). Risk for major malformations among human fetuses exposed to isotretinoin, TeratoJogy, 35,68A. Lammer, E.J. (1988). Embryopathy in infant conceived one year after termination of maternal etretinate, Lancet, ii, 1080-108 1. Lammer, E.J., Chen, D.T., Hoar, R.M. eta/. (1985). Retinoic acid embryopathy, N . Engl. J. Med., 313,837-841. Rosa, F. (1986). Retinoic acid embryopathy, N . Engl. J . Med., 315,262. Rosa, F. (1987). Isotretinoin dose and teratogenicity, Lancet, ii, 1 154.
