The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects

Abstract

The combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD) is often referred to as the eponymous Adams-Oliver syndrome (AOS). The molecular basis of this disorder remains unknown, although the common occurrence of cardiac and vascular anomalies suggests a primary defect of vasculogenesis. Through the description of three previously unreported affected individuals, ascertained through the Adams-Oliver Syndrome European Consortium, we illustrate the phenotypic variability characteristically observed within extended families with AOS. Taken in combination with a detailed review of the available literature, we provide evidence for distinct clinical entities within the ACC/TTLD spectrum, which may reflect genetic heterogeneity within this spectrum of disorders.

Autosomal recessive Adams–Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase

“…1 Limb defects range from nail dystrophy and syndactyly to asymmetric shortening of hands and feet, to absence of digital extremities. 2 Deformities of the skull are found in some cases. Additional clinical manifestations can include congenital cardiac malformations, vascular defects, and neurological abnormalities.…”

“…Additional clinical manifestations can include congenital cardiac malformations, vascular defects, and neurological abnormalities. 2 AOS has been described in both autosomal dominant and recessive modes of inheritance. 2 Recent identification of AOS-causing dominant mutations in ARHGAP31 (MIM 610911) 3 and recessive mutations in DOCK6 (MIM 614194) 4 confirms both modes of inheritance and highlights Cdc42/Rac1 regulation of actin cytoskeleton during early human development.…”

“…2 AOS has been described in both autosomal dominant and recessive modes of inheritance. 2 Recent identification of AOS-causing dominant mutations in ARHGAP31 (MIM 610911) 3 and recessive mutations in DOCK6 (MIM 614194) 4 confirms both modes of inheritance and highlights Cdc42/Rac1 regulation of actin cytoskeleton during early human development. AOS can be caused also by dominant mutations in RBPJ (MIM 147183), a transcriptional regulator of the NOTCH signaling pathway, further demonstrating the genetic heterogeneity of the phenotype.…”

“…AOS can be caused also by dominant mutations in RBPJ (MIM 147183), a transcriptional regulator of the NOTCH signaling pathway, further demonstrating the genetic heterogeneity of the phenotype. 5 As some features of AOS are consistent with vascular disruption pathogenesis, 2 it is yet unclear how disrupted Cdc42/Rac1 or NOTCH signaling intersects in the pathogenesis of AOS. Identification of additional genes implicated in AOS might elucidate common molecular pathways leading to this disease.…”

Adams-Olıver syndrome: A case report

“…Congenital heart diseases associated with the syndrome are seen in more than 20% of AOS patients and present a serious mortality risks 2,3 . The most frequent cardiac defect resulting from anomalies in systemic vascular structures has been stated as cutis marmorata telangiectasia congenita (CMTC) 4 . A phenotypic variation seen in AOS is differentiated from an autosomal dominant feature.…”