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Adams Oliver syndrome: Description of a new phenotype with cerebellar abnormalities in a family.

ABSTRACT: BACKGROUND:To describe cerebellar abnormalities in a family composed by a father and two affected sibs with Adams Oliver syndrome (AOS) (OMIM 100300). MATERIAL/METHODS:Brain MRI and MR angiography were performed at 1.5T. RESULTS:The siblings presented cerebellar cortex dysplasia characterized by the presence of cysts. CONCLUSIONS:Abnormalities of CNS are an unusual manifestation of AOS. To our knowledge, this is the first report of cerebellar cortical dysplasia in a family with AOS.

SUBMITTER: D'Amico A

PROVIDER: S-EPMC3908514 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Adams Oliver syndrome: Description of a new phenotype with cerebellar abnormalities in a family.

D'Amico Alessandra A Melis Daniela D D'Arco Felice F Di Paolo Nilde N Carotenuto Barbara B D'Anna Gennaro G Russo Carmela C Boemio Pasquale P Brunetti Arturo A

Polish journal of radiology 20131001 4

<h4>Background</h4>To describe cerebellar abnormalities in a family composed by a father and two affected sibs with Adams Oliver syndrome (AOS) (OMIM 100300).<h4>Material/methods</h4>Brain MRI and MR angiography were performed at 1.5T.<h4>Results</h4>The siblings presented cerebellar cortex dysplasia characterized by the presence of cysts.<h4>Conclusions</h4>Abnormalities of CNS are an unusual manifestation of AOS. To our knowledge, this is the first report of cerebellar cortical dysplasia in a ...[more]

PMID: 24505229

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A Case of Adams-Oliver Syndrome.

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Project description:Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

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Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

Project description:BackgroundAdams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS.Methods and resultsWhole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway.ConclusionsThese findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders.

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