CEDNIK: Phenotypic and Molecular Characterization of an Additional Patient and Review of the Literature

Abstract

Synaptosomal-associated protein 29 (SNAP29) is a t-SNARE protein that is implicated in intracellular vesicle fusion. Mutations in the SNAP29 gene have been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK). In patients with 22q11.2 deletion syndrome, mutations in SNAP29 on the nondeleted chromosome are linked to similar ichthyotic and neurological phenotypes. Here, the authors report a patient with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome who presented with global developmental delay, polymicrogyria, dysgenesis of the corpus callosum, optic nerve dysplasia, gaze apraxia, and dysmorphic features. He has developed ichthyosis and palmoplantar keratoderma as he has grown. Exome sequencing identified a homozygous nonsense mutation in SNAP29 gene designated as c.85C>T (p.Arg29X). The authors compare the findings in the proband with previously reported cases. The previously unreported mutation in this patient and his phenotype add to the characterization of cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome and the accumulating scientific evidence that implicates synaptic protein dysfunction in various neuroectodermal conditions.

Keywords: CEDNIK; SNAP29; developmental delay; ichthyosis; polymicrogyria.

Figure 1.

Family tree and clinical features. A, Pedigree of the family. B, Frontal view of the proband. Note synophrys, hirsutism, low frontal hairline, bushy eyebrows, large nose, and deep-set eyes. C, Left foot heel with xerosis and hyperkeratotic plaques. D, Right hand with a hyperkeratotic plaque on hypothenar eminence. The findings in C and D are consistent with palmoplantar keratoderma.

Figure 2.

Brain magnetic resonance imaging (MRI) findings in the proband. A, Sagittal T1-weighted magnetic resonance (MR) sequence demonstrates dysgenesis of the corpus callosum. Specifically, the splenium of the corpus callosum is hypoplastic (hollow arrow). B, Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MR sequence reveals marked hyperintensity in the white matter of the centrum semi ovale (yellow arrows). C, Axial T2-weighted turbo spin echo (TSE) MR sequence is notable for bilateral frontoparietal polymicrogyria and abnormal cortical folding (white arrows). D, The intraconal optic nerves are hypoplastic (black circles). E, The optic chiasm (down arrow), the intracranial optic nerves, and optic tracts are normal.