Retinoic Acid Embryopathy

Abstract

Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

“…Interestingly, overexpression of Tbx1 can cause a similar spectrum of DGS-like defects to those observed in the haploinsufficiency models (Merscher et al, 2001). Previously, the effects of hyper-and hypovitaminosis A were attributed to defects within the neural crest, but a role in pharyngeal endodermal patterning now seems most likely (Lammer et al, 1985;Mulder et al, 1998Mulder et al, , 2000Wendling et al, 2000;Quinlan et al, 2002;Niederreither et al, 2003;Vermot et al, 2003), particularly because retinoic acid treatment of amphioxus embryos, which do not contain neural crest cells, results in loss of pharyngeal arches/pouches by means of action upon the pharyngeal endoderm (Escriva et al, 2002).…”

“…Human fetuses exposed to retinoids during gestation can phenocopy DGS (Happle et al, 1984;Lammer et al, 1985;Rosa et al, 1986). Exogenous retinoic acid applied to other vertebrate species, including monkeys and rodents results in similar anomalies (Kalter, 1960;Kalter and Warkany, 1961;Kochhar and Johnson, 1965;Shenefelt, 1972;Fantel et al, 1977;Kistler, 1981;Mulder et al, 1998Mulder et al, , 2000.…”

TGIF, a gene associated with human brain defects, regulates neuronal development

“…Because TGIF competitively inhibits RXR binding to target DNA sequences, an increase in TGIF could lead to decreased relative RXR binding, causing a decrease in RXR-mediated expression. Of note, prenatal exposure to retinoic acid can cause craniofacial and brain anomalies similar to those seen in the HPE spectrum in both human reports and in animal models (Lammer et al, 1985;Sulik et al, 1995;Cohen and Shiota, 2002). If TGIF represses retinoic acid signaling by preventing binding of RXR, then decreased TGIF activity may mimic increased signaling through the retinoic acid pathway, leading to malformations.…”

Stage and tissue‐specific expression of the alcohol dehydrogenase 1 (Adh‐1) gene during mouse development

“…The offspring of vitamin A deficient dams exhibit a number of developmental defects, indicating that retinoids are also critical for embryogenesis (Wilson et al, 1953). Exposure to retinoids can alter specific steps of vertebrate development, such as growth and patterning of the head, hindbrain, branchial apparatus, axial and limb skeleton (Shenefelt, 1972;Lammer et al, 1985;Webster et al, 1986;Durston et al, 1989;Kessel and Gruss, 1991;Ruiz i Altaba and Jessell, 1991;Tickle et al, 1982;Morriss-Kay, 1993). It is known that with the notable exception of vision (which involves retinaldehyde), the active retinoids are acidic derivatives, i.e., all-trans retinoic acid (RA) and some stereoisomers (reviewed in Leid et al, 1992;Linney, 1992).…”