Prenatal diagnosis of lissencephaly: A case report

Case Report

Prenatal Diagnosis of Lissencephaly: A Case Report Halil Aslan, MD,1 Kemal Gungorduk, MD,2 Dog˘ukan Yıldırım, MD,2 Og˘uz Aslan, MD,2 Gokhan Yıldırım, MD,2 Yavuz Ceylan, MD2 1

Department of Perinatology, Bakirkoy Maternity and Children’s Teaching Hospital, Istanbul, Turkey Department of Obstetrics and Gynecology, Istanbul Bakirkoy Maternity and Children Research Hospital, Istanbul, Turkey 2

Received 16 March 2008; accepted 22 January 2009

ABSTRACT: We describe the abnormal sonographic findings in the brain of a 26-week fetus, which increased the suspicion of isolated lissencephaly. Follow-up ultrasound examination and MRI depicted diffuse cortical agyria, microcephaly, hypotelorism, and proptosis. Cordocentesis showed a normal 46,XY karyotype, and no short arm deletion of chromosome 17 was detectable. Postmortem examination confirmed complete agyria of the whole fetal brain. Early detection of fetal microcephaly and other cranial abnormalities can be a sign of isolated lissencephaly and need to be evaluated carefully with ultrasound and MRI for detection of abnormal cortical developC 2009 Wiley Periodicals, Inc. ment of the fetal brain. V J Clin Ultrasound 37:245–248, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jcu.20572 Keywords: lissencephaly; prenatal diagnosis; Miller– Dieker syndrome; ultrasonography

issencephaly is a rare cortical dysplasia that results from impaired neuronal migration during the 12th and 16th weeks of gestation, characterized by a smooth cerebral surface, mental retardation, and seizures. Common findings are either absence or paucity of gyri. Other cranial and extracranial abnormalities may also occur in association with lissencephaly. The prognosis is often poor. In affected cases, death occurs in infancy or early childhood; therefore, prenatal diagnosis of an affected fetus allows optimization of obstetric management.1,2 Two clinicopathologic types have been described.2 In type I lissencephaly (classic), the nor-

mal 6-layer cortex seen at histologic analysis is replaced by an abnormally thick, remodeled, 4layer cortex, associated with phenotypes such as the Miller–Dieker syndrome or the Norman– Roberts syndrome.3 Type II lissencephaly is pathologically characterized by a disorganized, unlayered cortex, including Walker–Warburg syndrome, where hydrocephalus is a common feature.4 Two clinicopathologic types are characterized with areas of thick cortex, expanded ventricles, and hypomyelination. Sonography (US) enables detection of changes of the fetal cerebral cortex that are associated with disorders of gyration at various stages of gestation.5 MRI examination is beneficial for detecting and confirming abnormal cortical development.6 We report a case of prenatal diagnosis of isolated lissencephaly with high-resolution sonography and fetal MRI.

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Correspondence to: H. Aslan ' 2009 Wiley Periodicals, Inc. VOL. 37, NO. 4, MAY 2009

CASE REPORT

A 20-year-old primigravid woman at 26 weeks’ gestation who married her cousin was referred to our clinic. The presumptive diagnosis was that of fetal microcephaly. Her medical history was unremarkable. Detailed US examination was performed using a Voluson 730 Expert scanner and a 2–7-MHz probe (GE Healthcare, Milwaukee, WI). At the 26th week of gestation, fetal biometry parameters were as follows: femur length, 44 mm; abdominal circumference, 208 mm; estimated fetal weight, 673 g. Biparietal diameter was 47 mm, and head circumference was 175 mm, which are below the 2nd percentile for gestational age, suggesting 245

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FIGURE 2. Coronal MRI at 26 weeks demonstrates microcephaly with smooth cerebral hemispheres.

FIGURE 1. (A) Transverse sonogram at 26 weeks of gestational age shows lateral ventriculomegaly (arrow). (B) Transverse sonogram shows the shallow and flat Sylvian fissure/insula (arrow). (C) Transverse sonogram of a normal fetus at 22 weeks of gestation for comparison shows normal ‘square’ appearance of the Sylvian fissure/ insula with distinct angularity (black arrow) at the margin of the insula (white arrow).

microcephaly. Abnormal US findings included agyri, hypotelorism, propytosis, smooth, shallow Sylvian fissure, and cerebellar hypoplasia (Figure 1). Infection markers (including TORCH) were unremarkable. Prenatal karyotyping was performed after genetic counseling. Chromosome analysis from 246

fetal blood sampling revealed a normal chromosome 46,XY karyotype, and no short-arm deletion of chromosome 17 (Miller–Dieker syndrome) was detectable. Fluorescent in situ hybridization studies using S. Orange and S. Green probes revealed no absence on the short arm of the derivative segments of the chromosomes of 17p13 (LSI1) and 17.q21.1 (LSI RARA). Fetal MRI examination performed at 27 weeks’ gestation showed reduced occipitofrontal circumference, narrow biparietal diameter, sloping forehead, hypoplastic cerebral parenchyma with enlarged ventricles, and cerebral agyria, suggesting lissencephaly (Figure 2). After the parents were informed of poor prognosis of the syndrome, they opted for termination of pregnancy. Intracardiac injection of 3 cc KCl was followed with vaginal misoprostol induction. A 697-g male fetus was delivered. Postmortem examination of the fetus confirmed prenatal US findings, including microcephaly, hypotelorism, prominent forehead, short nose, thickened upper lip, low-set ears, small jaw, and agyria (Figure 3). No other anomaly was detected. Histopathologic examination of the brain cortex confirmed absence of normal neuronal lamination (Figure 4).

DISCUSSION

Environmental factors, such as specific genetic abnormalities, family history, and several structural defects are responsible for causing various cortical dysplasia. The degree of cerebral involvement in cortical dysplasia varies across a wide spectrum. Currently, the pathogenesis of the cortical dysplasia is not clear. Primary sulci can be visible as early as 19 weeks of gestation, but the brain is still smooth.7 The diagnosis of delayed cortical development JOURNAL OF CLINICAL ULTRASOUND

PRENATAL DIAGNOSIS OF LISSENCEPHALY

FIGURE 4. Photomicrograph of the brain cortex shows irregular neuronal lamination. The arachnoidal space is seen at the right side of the image (hematoxylin eosin 320).

FIGURE 3. (A) Postmortem examination. Photograph shows microcephaly, hypotelorism, prominent forehead, short nose, thickened upper lip, low-set ears, and small jaw. (B) Postmortem examination. Photograph shows the complete smooth surface of the fetal brain cortex.

should not be considered before 20 weeks of gestation. Transvaginal US shows relative flatness of the cortex until 24–25 weeks of gestation. Complete fissures and sulci will not be detectable by transabdominal US before 28–30 weeks of gestation; therefore, definite diagnosis based on ultrasonographic findings cannot be obtained before 28 weeks’ gestation. Microcephaly, which is seen in 16% of cases, failure of development of both sulci and gyri, widening of the cerebral ventricles, and abnormal shape of the head are suggestive of lissencephaly.8 Cases in which US examination is abnormal should be further investigated with MRI.9,10 In most cases, lissencephaly is still detected only in the postnatal period by MRI or during autopsy in cases of stillbirth or neonatal birth.11 MRI enables detection of clear and reproducible images of the smooth brain surface.6 However, isolated lissencephaly may not be detectable if MRI is performed too early in the pregnancy. Six genes associated with type I lissencephaly (LIS1, YWHAE, CRK, DCX, RELN, ARX genes, VOL. 37, NO. 4, MAY 2009

which are located on different loci of 17p13.3, Xq22.3, 7q22, and Xp22.13) have been identified.12–16 When agyria is detected at fetal US and MRI, Miller–Dieker syndrome can be confirmed with a fluorescence in situ hybridization analysis to detect a deletion at chromosome 17p13.3.17 Miller–Dieker syndrome (lissencephaly type I) can be associated with other anomalies, such as duodenal atresia, urinary tract abnormalities, congenital heart defects, cryptorchidism, omphalocele, and clinodactyly.10,17,18 Walker–Warburg syndrome (Lissencephaly type II) is a lethal autosomal recessive disorder, defined by hydrocephalus, agyria, and retinal dysplasia with or without encephalocele, which is often associated with muscular dystrophy. Microphtalmia, congenital glaucoma, microcephaly, Dandy-Walker malformation, and agenesis of corpus callosum may also occasionally be found. Association with other anomalies, such as cleft lip and genital abnormalities, has been reported.10 In our case, no abdominal, genital, or intracardiac abnormalities were present. We believe that severe microcephaly may be the first sign of abnormal or delayed brain maturation and that it should raise suspicion for isolated lissencephaly. A follow-up US examination, MRI, and genetic research at early 3rd trimester of gestation is necessary to evaluate sulcal development in fetuses with microcephaly.

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11. Breeze AC, Dey PK, Lees CC, et al. Obstetric and neonatal outcomes in apparently isolated mild fetal ventriculomegaly. J Perinat Med 2005;33:236. 12. Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 2003;12:R89. 13. Toyo-oka K, Shionoya A, Gambello MJ, et al. 14– 3–3_ is important for neuronal migration by binding to NUDEL: a molecular explanation for MillerDieker syndrome. Nat Genet 2003;34:274. 14. Cardoso C, Leventer RJ, Ward HL, et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, MillerDieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72: 918. 15. Pilz DT, Matsumoto N, Minnerath S, et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet 1998;7:2029. 16. des Portes V, Pinard JM, Billuart P, et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 1998;92:51. 17. Benacerraf BR. Miller-Dieker syndrome. In: Benacerraf BR, editor. Ultrasound of fetal syndromes. Philadelphia, PA: Churchill Livingstone; 1998, p 130. 18. Fong KW, Ghai S, Toi A, et al. Prenatal ultrasound findings of lissencephaly associated with MillerDieker syndrome and comparison with pre- and postnatal magnetic resonance imaging. Ultrasound Obstet Gynecol 2004;24:716.

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