Discordant holoprosencephaly in monozygotic twins with ZIC2 mutation

Nakayama J, Kinugasa H, Ohto T, Tanaka R, Nakayama T, Noguchi E, Arinami T, Iwasaki N. Monozygotic twins with de novo ZIC2 gene mutations discordant for the type of holoprosencephaly. Neurology. 2016 Mar 9. pii:10.1212/WNL.0000000000002567. [Epub ahead of print]

Middle interhemispheric variant of holoprosencephaly (MIH) is a rare brain malformation; hemispheric fusion does not occur at the rostral forebrain, but rather across the posterior frontal region. Barkovich and Quint first described and proposed MIH as part of the holoprosencephaly (HPE) spectrum in 1993. Although classic HPE and MIH share several similarities, they are related to different embryological mechanisms: classic HPE is caused by a defect in the formation of the embryonic floor plate, whereas MIH occurs after a disturbance to the roof plate formation. The gene ZIC2 is important for the differentiation of the roof plate in the dorsal midline of the neural tube of the developing embryo. In humans, ZIC2 mutations have been identified in 3%–4% of HPE cases, including individuals with MIH, thus confirming that MIH is a variant of HPE.

Monozygotic (MZ) twins with HPE are rare, and only 11 pairs have been reported thus far. Furthermore, MZ twins with MIH have not yet been reported.

We report a case of MZ twins with a ZIC2 mutation showing the discordant manifestations of semilobar HPE (twin A) and MIH (twin B)...

Brain MRI Figure. In twin A (A–C), MRI shows a crescent-shaped holoventricle. A large dorsal cyst is seen posteriorly. The interhemispheric fissure and falx cerebri are not identifiable. The thalami are partially separated. The septum pellucidum and the corpus callosum are absent. These findings indicate semilobar type holoprosencephaly. In twin B (D–F), MRI shows that the falx cerebri and interhemispheric fissure are partially formed in the anterior and posterior portions of the brain, but in the middle portion, the hemispheres are fused (arrow). These findings indicate middle interhemispheric fusion. (A, B, D, and E: T1-weighted images in the axial view; C: T1-weighted image in the sagittal view; F: T2-weighted image in the coronal view.)