Differential Diagnosis
The greatest difficulty in the diagnosis of lissencephaly and subcortical band heterotopia (SBH) is recognizing the malformation. Lissencephaly is subdivided into several types depending on gradient and grade of gyral malformation and cortical thickness . Several different cortical malformations that are sometimes mistaken for lissencephaly have been described, including severe congenital microcephaly with reduced number of gyri, cobblestone malformations as seen in Walker-Warburg and other syndromes, polymicrogyria, and polymicrogyria-like variants associated with pathogenic variants of tubulin genes. This leads to inefficient molecular testing and incorrect diagnosis and counseling. Clinical features can help distinguish children who have lissencephaly from those who have other brain malformations. Children with lissencephaly usually have normal or slightly small OFC at birth (-3 SD) and diffuse hypotonia except for mildly increased tone at the wrists and ankles. Children with severe congenital (i.e., primary) microcephaly and gyral abnormalities have smaller birth OFC (≤-3 SD) and may be hypotonic or spastic. Infants with polymicrogyria, especially when the frontal lobes are involved, frequently have spastic quadriparesis. Brain imaging (preferably by MRI) and/or neuropathologic examination during autopsy is necessary to confirm a diagnosis of lissencephaly. Classic Lissencephaly The differential diagnosis of classic lissencephaly is summarized in . These disorders are distinguished by mode of inheritance, grade and gradient of lissencephaly or SBH (see Clinical Description, ), presence of other congenital anomalies, clinical features, and results of molecular genetic testing. Table 3. Genes of Interest in the Differential Diagnosis of Classic Lissencephaly
Gene | Disorder | MOI | Gradient of LIS or SBH1,2 | Features Differentiating Disorder from PAFAH1B1 Malformations |
|---|
Baraitser-Winter cerebrofrontofacial syndrome | AD | ap | Trigonocephaly; shallow orbits; ptosis; colobomas of the iris, choroid, or both; DD, LIS, epilepsy in some persons; malformations of other organ systems | — |
APC2 | Cortical dysplasia complex, w/other brain malformations 10 (OMIM 618677) | AR | pa | Severe DD, epilepsy, cortical dysplasia or LIS, thin CC, heterotopias |
CDK5 | CDK5 lissencephaly (OMIM 616342) | AD | Diffuse | Early lethal course. Agyria, agenesis of CC, cerebellar pontine hypoplasia; facial dysmorphisms; arthrogryposis multiplex |
CRADD | ID w/variant lissencephaly (OMIM 614499) | AR | ap | head circumference / megalencephaly, "thin" LIS DCX |
DCX-related disorders | XL | ap | SBH in females, LIS in males. | — |
Source: GeneReviews — "PAFAH1B1-Related Lissencephaly/ Subcortical Band Heterotopia"
