Patients with DENNED presented with axial hypotonia, limb hypertonia, severe intellectual and language delays, microcephaly, distinctive facial dysmorphisms, and progressive cataracts. Brain imaging showed cerebral hypoplasia, enlarged ventricles, thin corpus callosum, hypomyelination, and simplified gyral patterns.
A patient with homozygous missense variant c.1227C> G (p.His409Gln), had normal gross motor development but exhibited severe intellectual and language impairments, bilateral cataracts, and normal MRI findings with no epilepsy (Dentici et al., 2022). A recent Chinese report described the first case with compound heterozygous variants c.1430G> T (p.Cys477Phe) and c.475 > T (p.Arg159*), characterized by ID, motor and language delays, distinctive facial features, visual impairment without cataracts, and Mongolian spots on the back and buttocks (Zhang, Du, et al. 2024). The latter patient reported (Li et al., 2025) with a combined frameshift variant (c.1426del; p.Val476Phefs*9) and a missense variant (c.1513T> C; p.Cys505Arg), presented with microcephaly, delayed speech and gross motor skills, and infantile spasticity seizures. He exhibited an MRI showing frontal gyral widening and thinning of the corpus callosum, along with an EEG revealing multifocal spike‐and‐slow wave discharges, resembling cases with LOF (loss of function) variant, but lacking cataracts and presenting with café‐au‐lait spots and mild hearing impairment.
ZNF526