Monozygotic twins with de novo ZIC2 gene mutations discordant for the type of holoprosencephaly.

Abstract

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 Quint1 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.2 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.3