Updated 2006-01-18 by Juliana Leite, MD

Original text 1999-05-19 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

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

Definition: Lissencephaly is a cerebral developmental disorder, with agyria of the brain, accompanied or not by pachygyria, minimal or no hydrocephalus, a wide cortical mantle, and characteristic dysmorphic features. Miller in 1963 and Dieker in 1969 made the first descriptions. 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 sub conditions.

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

• Miller-Dieker syndrome
• Norman Roberts syndrome
• Isolated lissencephaly

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

• HARD+/-E syndrome
• COM syndrome
• Other subtypes

Neu-Laxova syndrome: lethal autosomal recessive inherited disorder consisting of growth retardation, microcephaly, lissencephaly, corpus callosum agenesis, intracranial calcifications, cerebellar hypoplasia, facial dysmorphism, microphthalmia, 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.

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

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

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

Diagnosis: Sonographic diagnosis in general is not accomplished earlier than late second trimester, when the characteristic cerebral anomalies can be noted. The progressive microcephaly and failure of development of both sulci and gyri (which in normal conditions is well defined from 26 to 28 weeks) are suggestive of lissencephaly. The occurrence of polyhydramnios associated with intrauterine growth restriction is an expected finding for the third trimester. If severe, polyhydramnios may complicate the diagnosis. Facial dysmorphism is characterized by prominent forehead, short nose, broad and flat nasal bridge, and protuberant upper lip.

Figure 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). (Reprinted with authorization from Harm-Gerd et al¹).

Figure 2: The same intracranial structures as fig. 1, visualized by transvaginal ultrasound. (Reprinted with authorization from Harm-Gerd et al¹).

Figure 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. (Reprinted with authorization from Harm-Gerd et al¹).

Genetic anomalies: Deletion at the 17p13.3 locus.

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, and ear anomalies may be found.

Differential diagnosis: Isolated lissencephaly sequence, Norman-Roberts syndrome, lissencephaly syndromes type II such as HARD+/-E (Walker-Warburg) syndrome and COM syndrome, and Neu-Laxova syndrome as a third lissencephaly type. All syndromes that may develop microcephaly should be suspected.

Prognosis: Usually severe mental retardation affects these patients. Failure to thrive, infantile spasms, and seizures are also expected. The prognosis is poor, and death occurs usually within the first 2 years of life.

Management: Karyotyping is recommended to detect the chromosomal defect. Differentiation from lissencephaly type II is important for genetic counseling purposes, considering that type II has an autosomal-recessive pattern of transmission. No causal treatment is available at this time. Usually, the ultrasound diagnosis is made during the third trimester, and termination is not an option. Standard prenatal care is not altered.

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