Synonyms: Lissencephaly type I, Miller-Dieker syndrome (MDS), chromosome 17p13 syndrome, chromosomal deletion 17p13.

Definition: Agyria of the brain with or without pachygyria, minimal or no hydrocephalus, a wide cortical mantle, and characteristic dysmorphic features.

Etymology: From the Greek: ­lissoV = smooth and enkefaloV = within the head.

Prevalence: Unknown but rare, M1:F2.25.

Etiology: Monosomy for the terminal segment of the short arm of chromosome 17, especially band 17p13. May be very discrete.

Pathogenesis: Defective neuronal migration with four, rather than six, layers in the cortex.

Associated anomalies: Duodenal atresia, urinary tract abnormalities, congenital heart defects, cryptorchidism, inguinal hernia, clinodactyly, polydactyly, ear anomalies.

Differential diagnosis: Isolated lissencephaly sequence, Norman Roberts syndrome, lissencephaly syndromes type II such as HARD+/-E syndrome and COM syndrome, and Neu-Laxova syndrome as a third lissencephaly type.

Prognosis: Usually severe mental retardation. Failure to thrive. Infantile spasms and seizures. Reduced chances for surviving. Death occurs usually within the first six years.

Recurrence risk: If de novo deletion or translocation, the recurrence risk is low. If the translocation is inherited from one parent, the recurrence risk may be as high as 25%. Affected children will not grow up to reproductive age.

Management: No causal treatment. Usually the ultrasound diagnosis is made during the third trimester, and termination is not an option.

MESH Brain-Abnormalities, Cerebral-cortex-abnormalities MIM 247200 BDE 0603 POS 3134 ICD9 744.2 CDC 742.240

Address correspondence to Harm-Gerd Blaas, MD, National Center for Fetal Dia­gnosis and Therapy, Dept. of Obstetrics and Gynecology, Trondheim University Hospital, N-7006 Trondheim, Norway Ph: 47-7-998-307; Fax: 47-7-997-696

Introduction

Lissencephaly is a cerebral developmental disorder with reduced or absent brain gyri, which is caused by disturbed neuronal migration in the neocortex. Two main distinctive types (type I and type II) exist, both with subconditions^1-3. The first observations of Miller-Dieker syndrome, a type I liss­encephaly, were made by Miller in 1963 and Dieker in 1969. The causal chromosomal defect was found by Dobyns in 1983⁴. This chromosomal defect can be so discrete that DNA analysis is necessary to detect it^5,6.

Only two cases have previously been diagnosed prenatally using ultrasound, both of them by Saltzman⁷. One woman had a series of antenatal ultrasound examinations because of a family history of lissencephaly in an unresolved fetal chromosomal abnormality (46, del(17)(13)mat). The diagnosis of lissencephaly was made at 32 weeks of gestation. The other patient had polyhydramnios, a fetal heart defect and suspicious cerebral ultrasound findings at 31.5 weeks of gestation. The karyotype also revealed 17p13.3 deletion⁷.

We present the sonographic diagnosis of type I lissencephaly confirmed by karyotyping (17p13.2 deletion) in a 27 weeks pregnant woman who had been referred to our department for polyhydramnios and suspected esophageal atresia. An overview of the various lissencephaly types is included in the discussion.

Case report

A 28-year-old G₃P₂ was referred for polyhydramnios and suspected esophageal atresia in the 27^th week of pregnancy. There was no family history of hereditary disease. Ultrasound examination showed an actively moving fetus and marked polyhydramnios. The biometric values were adequate for gestational age (BPD 73 mm, OFD 83 mm, mean abdominal diameter 72 mm, and femur length 50 mm). The stomach was moderately filled, making the diagnosis of esophageal pathology unlikely. Discrete dysmorphic features were found: malformed low set ears, a small nose and slight micrognathia. The brain structures were easily visualized with a 7.5 MHz transvaginal ultrasound transducer. The parasagittal plane of the cortex resembled that of normal 27-week fetuses, but the sub­arachnoid space was asymmetric and moderately enlarged. The posterior horns of the lateral ventricles were dilated, with a transverse diameter of 14 mm. Thus the brain appeared atrophic. Further examination of the brain in coronal and transverse sections showed a total lack of sulci and gyri. The corpus callosum was absent.

Fig. 1: Parasagittal section of the head. Open arrow: section through the hemisphere showing the smooth surface. Triangle: The cranium with remarkable distance to the brain surface. Long arrow: posterior dilated portion of the lateral ventricle (27 weeks).

Fig. 2: The same intracranial structures as fig. 1, visualized by transvaginal ultrasound.

Fig. 3: Transverse section through the lateral hemisphere at 31 weeks of gestation. The small arrows show the smooth narrow cortex; the large arrow points to the dilated posterior part of the lateral ventricle.

The features were most consistent with a type I lissencephaly syndrome. Karyotyping based on amniotic fluid confirmed a 17p deletion in the 13.2 band.

An ultrasound control at 31 weeks confirmed that there was no further development of the fetal cortex. The growth of the fetus was adequate. Amniocentesis was repeated to relieve the patient of painful polyhydramnios. The child was born at 36 weeks, weighting 2550g.

The characteristic dysmorphic appearance for Miller-Dieker syndrome was present. While the prenatal behavior was characterized by hectic movements, the child showed rather decreased spontaneous activity postnatally. It soon demonstrated feeding problems as he was not able to swallow. The features found prenatally (including smooth brain surface, corpus callosum agenesia, increased amount of fluid in the subarachnoid space and dilated ventricles) were confirmed by ultrasound examination and MRI. The karyotype of both parents proved to be normal, indicating a de novo chromosomal aberration in this child.

Discussion

Embryology & pathogenesis

When examined histologically, the adult cerebral neocortex has six layers from the cortex to the ventricle: 1) a plexiform layer, 2) an outer granular layer, 3) a pyramidal layer, 4) an inner granular layer, 5) a ganglionic layer, and 6) a multiform layer⁸. The lamination of the neocortex is already evident in the frontal lobe in fetuses of 120 mm crown-rump length (about 16 weeks), and then gradually involves the remainder of the neocortex⁹. Neuronal multiplication is most rapid from the 10^th to the 20^th gestational weeks, while neuronal migration and consecutive development of cortical layers mainly occur from the end of the first trimester to the end of the second trimester.

The surface of the hemispheres is smooth at 20 weeks of gestation. The fetal brain increases dramatically in weight at 24 to 26 weeks, and many sulci and gyri become well defined between 26 to 28 weeks^8,9. At 27 weeks of gestation, the central, cingulate, parieto-occipital, and calcarine sulci are usually evident. Secondary and tertiary gyration occur late in gestation. In lissencephaly, the brain malformation results from impairment of neuronal migration.

Types and subclassification

Lissencephaly is differentiated in two main groups with subtypes and a third distinctive type:

·        Lissencephaly type I

·        Miller-Dieker syndrome

·        Norman Roberts syndrome

·        Isolated lissencephaly

·        Lissencephaly type II

·        HARD+/-E syndrome

·        COM syndrome

·        Other subtypes

·        Neu-Laxova syndrome

Lissencephaly, type I

Lissencephaly, type I is characterized by agyria with or without pachygyria, a wide cortical mantle and minimal or no hydrocephalus. Both agyric and pachygyric regions have a four layer cortex: 1) a molecular layer, 2) an outer cellular layer (true cortex), 3) a cell sparse layer, and 4) a deep cellular layer composed of heterotopic incompletely migrated neurons¹⁰.

The subtypes are:

·        Miller-Dieker syndrome (17p13 deletion) has lissencephaly combined with dysmorphic facial features and other possible associated anomalies due to monosomy for the distal portion of the short arm of chromosome 17. These include corpus callosum agenesia, ventriculomegaly, midline calcifications, and sometimes mild cortical cerebellar dysplasia. Microcephaly is common. Facial dysmorphism is characterized by prominent forehead, bitemporal hollowing, wrinkling of the forehead, short nose with upturned nares, broad and flat nasal bridge, protuberant upper lip, and small jaw. Associated abnormalities include heart malformations, omphalocele, kidney dysplasia, and genital anomalies. Transverse palmar creases and clinodactyly are common. Polyhydramnios and decreased fetal movements are common^1,12.

·        In Norman-Roberts syndrome, no abnormal karyotype is found. In contrast to the Miller-Dieker syndrome, the ears are not displaced. This syndrome is autosomal recessively inherited¹. It is a type I lissencephaly with sloping forehead and other minor facial features described in a consanguineous family, where several children were affected.

·        Isolated type I lissencephaly is not associated with monosomy 17p13 and does not have dysmorphic features as found with the Miller-Dieker syndrome or Norman-Roberts syndrome¹. This syndrome may be more common than the Miller-Dieker syndrome³.

Lissencephaly, type II

In lissencephaly, type II the thickened cortex is disorganized without layering. Vascular bundles and fibroglial tissue are present in the cortex and subarachnoid space². Lissencephaly, type II typically has hydrocephalus and additional serious central nervous system defects. It is usually part of a syndrome².

·        HARD+/-E syndrome, an acronym for Hydrocephalus, Agyri, Retinal­ dysplasia, Encephalocele (Walker-Warburg syndrome), is an autosomal recessive lethal disorder. In addition to the main features of type II, other serious central nervous sytem malformations such as corpus callosum agenesia, cerebellar dysplasia with Dandy-Walker malformation, and white brain substance atrophy are found.

·        COMS (Cerebro-oculomuscular syndrome) with congenital muscular dysplasia is possibly a variant of the HARD+/-E syndrome, and is supposed to be autosomal recessively inherited.

·        Other subtypes of type II lissencephaly are possible².

Lissencephaly, Neu-Laxova

A third type of lissencephaly is found in Neu-Laxova syndrome, which is a lethal autosomal recessively inherited disorder consisting of growth retardation, microcephaly, lissencephaly, corpus callosum agenesis, intracranial calcifications, cerebellar hypoplasia, facial dysmorphism, microophthalmia, exophthalmus, cataracts, absent eyelids, hydrops, ichthyosis, contractures of extremities and syndactyly. A prenatal ultrasound diagnosis was published in 1987¹¹, but the sonographic evaluation of central nervous system features was not mentioned.

Diagnosis

The in utero diagnosis of lissencephaly by ultrasound is unusual, only two cases have been previously described⁷. As the development of gyri and sulci does not occur until the end of the second trimester, ultrasound diagnosis of this condition cannot be expected earlier. The examination may also be difficult due to polyhydramnios. In our case, the transvaginal ultrasound examination improved the image of the fetal brain and suggested the diagnosis of lissencephaly. Even at 27 weeks a certain differentiation of the cortex should be expected. The gestational age was reliable for our patient, so that the total lack of sulci development was significant.

Decreased spontaneous fetal movements are consistently reported as a typical feature for the Miller-Dieker syndrome^1,12. The fetus in our case showed hectic activity, though the mother did not always recognize these movements, possibly due to the polyhydramnios.

Saltzman et al.⁷ described the head circumference as lagging behind the other growth parameters in their case #1, and impaired head growth in case #2. Other reports^1,5,12 indicate that growth retardation is a postnatal phenomenon of the Miller-Dieker syndrome. Head circumference could be normal or small at birth, but head growth is slow postnatally, so most of the older patients are microcephalic⁵. Neither growth retardation nor microcephaly was observed prenatally in our case.

Prognosis

As stated by all authors, the prognosis of lissencephaly is universally poor, regardless of etiological type. This may have an impact on obstetrical management. Since several lissencephaly conditions are of autosomal recessive inheritance, a correct diagnosis is essential to evaluate the risk of recurrence.

References

1. Dobyns WB, Stratton RF, Greenberg F. Syndromes with lissencephaly. I: Miller Dieker and Norman Roberts syndrome and isolated lissencephaly. Am J Med Genet 18:509-526, 1984.

2. Dobyns WB, Kirkpatrick JB, Hittner HM, et al: Syndromes with lissencephaly II: WalkerWarburg and cerebrooculomuscular syndromes and a new type I lissencephaly. Am J Med Genet 22:157-195, 1985.

3. De Rijkvan Andel JF, Arts VFM, Barth PG, Loonen MCB. Diagnostic features and clinical signs of 21 patients with lissencephaly type I. Dev Med Child Neurol 32:707-717, 1990.

4. Stratton RF, Dobyns WB, Airhart SD, Ledbetter DH. New chromosomal syndrome: Miller Dieker syndrome and monosomy 17p13. Hum Genet 67:193-200, 1984.

5. Dobyns WB, Curry CJR, Hoyme HE, Turlington L, Ledbetter DH. Clinical and molecular diagnosis of Miller Dieker syndrome. Am J Hum Genet 48:584-594, 1991.

6. Oostra BA, de Rijkvan Andel JF, et al. DNA analysis in patients with lissencephaly type I and other cortical dysplasias. Am J Med Genet 40:383-388, 1991.

7. Saltzman DH, Krauss CM, Goldman JM, Benaceraff BR. Prenatal diagnosis of lissencephaly. Prenat Diagn 11:139-143, 1991.

8. England MA. Normal development of the central nervous system. In: Levene MI, Bennett MJ, Punt J (eds). Fetal and neonatal neurology and neurosurgery. Edinburgh Churchill Livingstone (ed) London Melbourne and New York, 13-27, 1988.

9. O"Rahilly R, Gardner E. The developmental anatomy and histology of the central nervous system. In: Vinken RJ, Bruyn GW (eds). Handbook of clinical neurology: congenital malformations of the brain and skull. Amsterdam XXX,i,1540, 1977.

10.Barchovich AJ, Koch TT, Carrol CL. The spectrum of lissencephaly: Report of ten patients analyzed by Magnetic Resonance Imaging. Ann Neurol 30:139146, 1991.

11. Muller LM, de Jong G, Mouton SCE, et al. A case of the NeuLaxova syndrome: Prenatal ultrasonographic monitoring in the third trimester and the histopathological findings. Am J Med Genet 26:421-429, 1987.

12. Lyons Jones K, Gilbert EF, Kaveggia EG, Opitz JM. The MillerDieker syndrome. Pediatrics 66:277-281,1980