Abstract

Introduction: Adams–Oliver syndrome (AOS) is an orphan disorder of terminal transverse limb defects and aplasia cutis congenita, hypothesized to occur as a consequence of disordered vasculogenesis. AOS is estimated to affect 1 in 225,000 live births; however, comprehensive studies of geographical prevalence remain limited. Areas covered: This review summarizes current opinion in the molecular genetics of AOS and provides recommended updates to the diagnostic criteria. Understanding of the clinical features associated with AOS has been much improved due to recent advancement in establishing the underlying genetic causes of the condition. To date, six causal genes have been described, which together specifically implicate Rho GTPase dysregulation and perturbed Notch signaling as central to disease development. Despite these genetic advances, mutations in the established genes only represent 36% of reported AOS cases, indicating a large degree of missing heritability still to be resolved. Furthermore, the fundamental mechanisms underlying AOS remain undefined, impeding diagnostic and treatment progression. Expert opinion: Further work to examine structural variation and identify novel genes is necessary to explain the missing heritability in AOS. In the future, dedicated functional analyses will be required to delineate the pathogenic mechanisms and facilitate focused evaluation of targeted therapies.