Adams-Oliver Syndrome: A Clinical Diagnosis in the Genomic Era

Adams-Oliver syndrome (AOS) is a rare congenital condition marked by defects of the scalp and malformations of the distal extremities. Although several causative genes have been identified, including ARHGAP31, DLL4, NOTCH1, and DOCK6, a subset of clinically suspected cases remains genetically unresolved. We report the case of a four-year-old female patient, the firstborn of a third-degree consanguineous marriage, who presented with a febrile seizure. Physical examination revealed aplasia cutis congenita (ACC) over the parietal scalp, low-set ears, and bilateral lower limb hypoplasia with absent nails, fulfilling two major diagnostic criteria for AOS. Echocardiography revealed a small ostium secundum atrial septal defect, meeting one minor criterion. Whole-exome sequencing (WES) did not identify any pathogenic variant. The child was referred for surgical evaluation of scalp and limb anomalies and is under multidisciplinary follow-up. Even with breakthroughs in next-generation sequencing, some patients may not have detectable mutations due to genomic heterogeneity, deep intronic or structural alterations, or unidentified new genes. The vascular disruption theory is supported as a likely pathogenic mechanism by the clinical triad of ACC, limb reduction abnormalities, and cardiac anomalies. This example illustrates the continued importance of clinical judgment in diagnosing AOS, even when genomic testing yields conflicting results. Careful phenotypic assessment, guided by established diagnostic criteria, remains essential for appropriate multidisciplinary management and genetic counseling.