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Aplasia cutis congenita (ACC) is characterized by localized absence of skin, often involving the scalp, and frequently occurs in the context of Adams-Oliver syndrome. Heterozygous loss-of-function variants in DLL4, encoding the Notch ligand Delta-like 4, have been implicated in vascular defects and scalp aplasia. In a single case report, a full-term newborn male presented with an 8 cm × 9 cm scalp and skull defect and was diagnosed with Adams-Oliver syndrome following identification of a de novo large chromosome 15 deletion encompassing DLL4 (PMID:36713669). This case represents one proband with a structural deletion variant, with no additional affected relatives or segregation data available. The phenotype aligns with known haploinsufficiency mechanisms of DLL4 in vascular development but is limited to a single observation. Consequently, the overall genetic evidence for DLL4 in ACC currently remains Limited.
DLL4 functions as a critical regulator of angiogenesis and vascular integrity via Notch signaling, with haploinsufficiency leading to defective microvascular development. Although functional studies in other contexts have demonstrated that DLL4 deficiency disrupts endothelial cell sprouting and vessel maturation, no assays specifically addressing ACC skin defects have been reported. The mechanistic plausibility of vascular insufficiency causing focal skin aplasia supports a role for DLL4 loss-of-function in ACC pathogenesis. However, the absence of additional cases and disease-specific models prevents higher ClinGen categorization. Further case series, detailed genotype-phenotype correlation, and in vitro or animal investigations are needed to elucidate the contribution of DLL4 to ACC. Key Take-home: DLL4 haploinsufficiency remains a plausible but limited clinical association with aplasia cutis congenita in Adams-Oliver syndrome.
Gene–Disease AssociationLimitedSingle proband with a de novo DLL4-containing deletion presenting with ACC ([PMID:36713669]) Genetic EvidenceLimitedOne unrelated case with a structural deletion; no segregation or additional reports Functional EvidenceNo evidence reportedNo functional assays specific to ACC have been performed for DLL4 |