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Holoprosencephaly (HPE) is a classic brain malformation involving defective forebrain induction and patterning. Cases of HPE bearing white matter abnormalities have not been well documented, with only rare cases exhibiting hypoxic-ischemic damage. However, neuroradiologic studies of HPE using diffusion tensor imaging have suggested the presence of white matter architectural disarray. Described in this case series are the clinicopathologic features of 8 fetuses with HPE who underwent autopsy at BC Children's Hospital. All 8 cases exhibited subacute to chronic, periventricular leukomalacia (PVL)-like white matter pathology, with 7 of 8 cases also demonstrating aberrant white matter tracts, one of which manifested as a discreet bundle crossing the midline within the ventral aspects of the fused deep gray nuclei. In 6 of these 7 cases, the PVL-like pathology resided within this aberrant white matter tract. Original workup, alongside an additional HPE-focused next-generation sequencing panel identified a likely etiologic cause for the HPE in 4 cases, with an additional 2 cases exhibiting a variant of unknown significance in genes previously suggested to be involved in HPE. Despite our in-depth clinicopathologic and molecular review, no unifying etiology was definitively identified among our series of fetal HPE bearing this unusual pattern of white matter pathology.
Das et al. (Tue,) studied this question.