Prenatal diagnosis of schizencephaly after inhalation of organic solvents

A primigravid woman was referred at 20 weeks' gestation for ultrasound examination after first-trimester exposure to toxic agents (acetone, white spirit and paint remover). She inhaled these products daily in the first and second trimesters (until 18 weeks) because she worked as a painter and she was not aware of being pregnant. Ultrasound imaging at 20 weeks showed absence of the cavum septi pellucidi and a bilateral symmetrical cleft with communication between the ventricles and the subarachnoid space (Figures 1 and 2). There was evidence of intraventricular clotting. There were no associated facial malformations. Karyotype was normal female, 46,XX, and no mutation in the EMX2 gene was found. Magnetic resonance imaging (MRI) confirmed the ultrasound findings with gray matter lining the cerebral defects (Figure 3a). Parental HPA-subtypes were compatible and platelet antibodies were negative. The parents were aware of the risk of developmental problems and epilepsy and they decided to continue the pregnancy. MRI at 33 weeks' gestation showed additional migration disorders delineating the cortical defect (Figure 3b). Transverse ultrasound image of the fetal head at 20 weeks' gestation, showing absence of the septum pellucidum. Ultrasound image showing the cerebral cleft. Magnetic resonance images at 22 weeks (a) and 33 weeks (b) of gestation. A bilateral ‘cleft’ can be seen involving the (supra)insular cortex on both sides with additional migration disorders delineating the cortical defect at 33 weeks. Spontaneous delivery occurred at 38 weeks' gestation (weight, 3000 g; length, 48 cm; head circumference, 31 cm). Four months postnatally (at the time of writing: weight, 5600 g; length, 58 cm; head circumference, 38 cm (3rd centile)) neurological follow-up was good and no epileptic insults had occurred. Schizencephaly is a central nervous system malformation characterized by clefts (often bilateral) in the cerebral mantle, lined with pia-ependyma, with a communication between the ventricles and the subarachnoid space1-3. Prenatal diagnosis of schizencephaly is possible by ultrasound imaging and MRI, which show a cleft in the cerebral mantle extending from the pial surface to the ventricular wall lined by gray matter. The cavum septi pellucidi is absent in two out of three cases and the corpus callosum is focally thin or may be absent. Polymicrogyria and heterotopias are common1. The main differential diagnosis is porencephaly, which may appear similar to schizencephaly if bilateral and located near the Sylvian fissures, but unlike schizencephaly will not show lining of the defect with gray matter on MRI. Familial porencephaly was reported with mutations in the Col 4a1 gene4. The etiology of schizencephaly is unclear. Familial cases have been reported, suggesting a genetic origin within a group of migration disorders5. Yakovlev and Wadsworth2, 3 contend that a failure of normal migration of the primitive neuroblasts results in the cerebral cleft, and the continuity of gray matter along the associated cerebral malformations supports this theory. Heterogeneous mutations of the EMX2 gene are reported to give rise to schizencephaly6. In addition, cytomegalovirus, abdominal trauma and toxic agents have been reported to be associated with schizencephaly, possibly as the result of a vascular insult7, 8. Clinical presentation of schizencephaly includes varying degrees of developmental delay, motor impairment and seizures. The effect on fetal development of prenatal occupational exposure to organic solvents is difficult to assess. Firstly, high-dose animal data cannot be compared to lower level human exposure; secondly, the dose of exposure is difficult to assess; and thirdly, occupational exposures typically include multiple agents, which confound information on toxicity for a single agent9. Khattak et al. examined 125 women exposed to organic solvents and found major malformations in 13 of the 113 live births (11.5%), of which one neonate had a migration disorder10. The risk of major malformations after exposure to organic solvents was higher in women who reported symptoms related to the exposure (such as eye/respiratory irritation and headache)10. Organic solvents such as toluene are also considered neurotoxins, possibly increasing the risk for developmental delay11. Toluene is an industrial chemical, used widely as a solvent in paints and glues, that crosses the placenta readily. Its abuse causes variable growth deficiency, minor craniofacial and limb anomalies, central nervous system dysfunction and microcephaly, known as ‘fetal solvent syndrome’ or ‘toluene embryopathy’, in human and animal (rat) offspring12. Moreover, the affinity of toluene for lipid-rich tissue results in neurotoxicity in chronic abusers, which mainfests as cerebellar degeneration and cortical atrophy. One previous report has described second-trimester toluene exposure, with the development of microgyria13. Given the inconclusive but concerning information on occupational exposure to organic solvents during pregnancy, exposure to these products should be minimized and ideally avoided. I. Witters*, M. Cannie , P. Casaer , K. Devriendt§, J.-P. Fryns§, * Department of Obstetrics and Gynecology, University of Leuven, Herestraat 49, 3000 Leuven, Belgium, Department of Radiology, University of Leuven, Herestraat 49, 3000 Leuven, Belgium, Department of Pediatric Neurology, University of Leuven, Herestraat 49, 3000 Leuven, Belgium, § Center for Human Genetics, University of Leuven, Herestraat 49, 3000 Leuven, Belgium