Mutations in tubulin genes cause cortical malformations, rarely with minor dysmorphic features. Congenital circumferential skin creases are rare disorders characterized by ring creases associated with facial dysmorphism, intellectual disability and imaging brain data from normal to malformations involving corpus callosum and vermis. The cause was unknown until recent data demonstrated that mutations in TUBB are responsible for this syndrome for which neuropathological data have never been described.
A termination of pregnancy was performed at 28 WG for brain malformations. Karyotype was normal and whole-exome sequencing was performed for subject and parents. Examination disclosed severe dysmorphic features, circumferential creases and microcephaly. Neuropathological study demonstrated microlissencephaly, callosal agenesis, dysmorphic basal ganglia, cerebellar hypoplasia. Histological examination showed cortical glomerular structures, abnormal cortico-spinal tracts, heterotopic axonal fascicles, unusually large germinal zones, abnormal hippocampi, roughly-shaped dentate and olivary nuclei. Whole-exome sequencing demonstrated a heterozygous missense mutation in TUBB gene occurring de novo.
Neuropathological features are identical to those observed in other tubulinopathies. However, mutations in TUBB gene have not yet been reported in tubulinopathies with isolated cortical malformations. The association of circumferential skin creases, facial dysmorphism and a characteristic brain malformation resulting from a mutation in TUBB gene constitutes a new entity expanding the spectrum of tubulinopathies.