Sener (1994) described a female child who had facial dysmorphism with hypodontia, dental occlusion, and buccal frenula. In addition she had thin hair and dystrophic nails. Her development was normal until the age of 5 years, and she ... Sener (1994) described a female child who had facial dysmorphism with hypodontia, dental occlusion, and buccal frenula. In addition she had thin hair and dystrophic nails. Her development was normal until the age of 5 years, and she subsequently developed mild developmental delay. An MRI scan showed multiple cysts of curvilinear configuration, representing extremely dilated Virchow-Robin spaces (the perivascular spaces lined by ependymal/leptomeningeal cells). Sener (1994) described this as a distinct neurocutaneous syndrome. Lynch et al. (2000) described 2 children who they believed had the same condition as that described by Sener (1994). Both children were male. Case 1 had edema of the neck at birth with a large anterior fontanel, a short penis with large scrotum, and anteriorly placed anus. Cranial ultrasound showed partial agenesis of the corpus callosum, and renal ultrasound showed mild dilatation of the pelvicalyceal system. Bilateral inguinal herniae were repaired at 4 months of age. Ophthalmologic examination showed hypoplastic left disc and a small coloboma of the right disc. He had hypertelorism with a wide mouth, long, smooth philtrum, and small posteriorly rotated ears. His hair was coarse and brittle. The teeth were irregular and pointed. Karyotype, Skeletal survey, and metabolic investigations were normal. Case 2 had similar dysmorphic features but in addition had a midline cleft of the upper alveolar margin and 2 neonatal teeth. Both patients were developmentally delayed. MRI scan in both children showed multiple cystic areas within the white matter radiating from the ventricles into oval lobes with sparing of the basal ganglia, brainstem, and corpus callosum. Lynch et al. (2000) observed that the distribution of cystic changes in the MRI scan of their cases mirrored the perivascular distribution of the Virchow-Robin spaces. They noted that similar MRI findings had been described in the mucopolysaccharidoses (see 607014); however, screening of urinary amino acids was negative in their cases. Winter (2001) reviewed several reports that are listed in this entry and in entries 606155 and 608578. He noted considerable overlap between the cases and suggested that they represent a syndrome, called the cerebrofrontofacial syndrome, that is comprised of 3 types based on brain MRI findings. The brain scans in type 1 are characterized by periventricular nodular heterotopia. In type 2, there are multiple cystic areas in the white matter radiating at right angles to the ventricles. These are interpreted as being dilated Virchow-Robin spaces. In type 3, there is no periventricular nodular heterotopia or cystic areas of the brain.