Failure to Fuse Shut Eyelids, a Novel Unique Sign in Affected Fetus with Homozygous PPP1R13L Pathogenic Variant—A Case Report and Review of the Literature

Prompted by a fetus with a homozygous PPP1R13L pathogenic variant and persistent open eyelids on sonography, suggesting fusion failure, this study marks the first prenatal human description linking PPP1R13L to eyelid closure, mirroring waved with open eyelids 2(woe2) and waved 3 (wa3) mouse models. Eyelid morphogenesis involves complex epidermal–dermal interactions. We reviewed the literature to understand embryonic/fetal development and identify molecular pathways crucial for proper eyelid morphology. Known signaling pathways in eyelid closure and reopening include NF-κB, p53, Wnt, TGF-β, BMP4, MAPK, SMAD, ECM–receptor interaction, and integrin signaling. Open-eye phenotypes are associated with pathogenic variants affecting the Wnt/β-catenin pathway, p63, and the TGFβ family. Notably, SMAD molecules are common to all these pathways. Eyelid closure seems regulated by SMAD protein activation in the supraorbital epithelium and underlying mesenchyme, promoting cell proliferation and adhesion. Physiological SMAD1 downregulation is crucial for eyelid reopening. Given SMAD signaling’s importance in development, its disruption likely impacts eyelid closure or reopening.