ADAM15, a member of the A Disintegrin And Metalloproteinase (ADAM) family, is a membrane protein containing an adhesion domain that binds to alpha5beta1 integrin through a unique RGD domain. ADAM15, ...expressed by human normal colonocytes, is involved in epithelial wound healing and tissue remodeling in inflammatory bowel disease. The aims of our study were (i) to analyze ADAM15 expression in a series of colon carcinomas and paired normal mucosa and (ii) to integrate the spatial relationship of ADAM15 with its binding partners alpha5beta1 integrin, a mesenchymal marker, as well as with other adhesion molecules, alpha3beta1 integrin and E-cadherin. A series of 94 colon carcinomas of the non other specified category were graded according to the World Health Organization classification. Immunohistochemistry was performed on frozen tissue sections using antibodies directed to ADAM15, alpha5beta1 and alpha3beta1 integrins, and E-cadherin. ADAM15 was quantified at the mRNA level. Finally, promoter methylation of ADAM15 was examined as well as the microsatellite instability status (MSS/MSI). Thirty-six percent of colorectal carcinomas displayed a reduced expression of ADAM15 in cancer cells, confirmed at the mRNA level in most cases, without promoter methylation. ADAM15 down-regulation was associated with histologically poorly differentiated carcinomas. In addition, it was associated with the acquisition of alpha5beta1 by cancer cells and down-regulation of alpha3beta1 integrin and E-cadherin. Finally this profile that includes characteristic of epithelial to mesenchymal transition is a late progression event of colon cancer with a poor prognosis. PUBLICATION ABSTRACT
Abstract 5313
VWD 2B and PT-VWD are rare diseases, due to mutations inducing a gain of function respectively of von Willebrand factor (VWF) and of its platelet receptor, Glycoprotein (GP)1bα
We ...report here the case of a young girl, born with an extensive purpura and a severe thrombocytopenia: platelet count: 16G/L. There was no associated biological nor clinical abnormality. A high dose of 1g/kg of immunoglobulin G infused on day 1 was unsuccessful, and a HPA-1a (−) platelet concentrate infusion led to a partial and transient increase of the platelet count up to 60G/L. Thrombocytopenia then resolved spontaneously.
Biological study showed no sign of materno-fetal allo- or auto-immunity, parents were not consanguineous.
The diagnosis of type 2B VWD was performed when she was 5 months old: VWF:RCo < 13 IU/dl, VWF:Ag 60 IU/dl, positive ristocetin induced platelet aggregation (RIPA) at a low ristocetin concentration (0.5 mg/ml). RIPA mixing studies were unconclusive.
The same biological abnormalities were found in the father, whereas the mother had normal hemostasis tests. The biological phenotype also included a study of the multimeric VWF structure, showing a marked decrease in percentage of VWF high and intermediate molecular multimers. Genetic analysis performed on VWF gene showed the heterozygous p.Pro1266Leu missense mutation in the VWF A1 domain. This mutation ( o ) is only slightly deleterious, and induces usually a mild disease, without thrombocytopenia, even in stress situations, with normal VWF multimeric distribution; therefore, it could not explain the biological phenotype severity in this family.
GPIBA was then analysed, and a candidate point mutation p.Met239Ile was evidenced. This mutation had not been described yet, but p.Met255Val had already been found in diagnosed cases of PT-VWD.
This case underlines the utmost importance to characterize precisely neonatal thrombocytopenia mechanism. Furthermore, it points out the difficulties to performing PT-VWD diagnosis, which incidence is most probably underestimated. In our case, it was the systematic and extensive biological workout performed in this case of isolated neonatal thrombocytopenia, without any obvious cause, which led to the diagnosis of a PT-VWD, inducing a severe biological phenotype, associated with type 2B VWD characterized by a mild expression. It is, to our knowledge, the first case described to date of such a morbid association.
No relevant conflicts of interest to declare.
The association of Coats disease with intrauterine growth retardation, intracranial calcification, leukodystrophy, brain cysts, osteopenia, and gastrointestinal bleeding defines Coats plus syndrome ...caused by mutations in the CTC1 gene, encoding conserved telomere maintenance component 1. Here, we report on a child with exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly, and short stature, in whom no mutations in CTC1 were found. Our patient shares some features seen in other diseases associated with telomere shortening including Hoyeraal-Hreidarsson and Revesz syndromes. We therefore measured telomere length by Flow-Fish which was normal. The association of duodenal atresia and microcephaly also suggested a diagnosis of Feingold syndrome. However, direct sequencing of MYCN was normal, and we did not detect any hemizygous deletion of the miR-17∼92 polycistronic miRNA cluster. To our knowledge, the phenotype we report on has not been described previously, leading us to speculate that this condition may represent a new syndrome.
Abstract Monosomy 1p36 is one of the most frequent subtelomeric microdeletion syndromes characterized by distinct craniofacial features and developmental delay/mental retardation. Other common ...symptoms include hypotonia, seizures, brain abnormalities, visual, auditory and heart defects. Neuroblastoma is a rare feature since to our knowledge only two patients with “pure” 1p36 deletion have been described. We report on a child with developmental delay and facial dysmorphy who developed neuroblastoma at 1 month of age. No primary site outside of the liver could be demonstrated and the tumour regressed spontaneously. Standard karyotyping was normal while subtelomeric screening using Multiplex Ligation-dependent Probe Amplification (MLPA) method revealed a constitutional de novo subtelomeric 1p36 deletion. Subsequent Agilent 244K oligonucleotide array-based comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis showed a complex 1p36.3 deletion/duplication rearrangement. Among the best candidate genes predisposing to the development of neuroblastoma located in 1p36, the AJAP1 gene is the only gene present in the duplication while CHD5 , TNFRSF25 and CAMTA1 are located outside of the rearrangement. Therefore, a gene-dosage effect involving a gene located in the duplication including AJAP1 might explain the neuroblastoma observed in our patient. The rearrangement might equally interfere with the expression of a gene located outside of it (including CHD5 located 1 Mb away from the rearrangement) playing a role in the tumorigenesis. In conclusion, this study illustrates the complexity of such rearrangement characterized by array CGH and strengthens that constitutional 1p36.3 rearrangement predisposes to the development of neuroblastoma.
Abstract We report on a fetus with multiple congenital anomalies including atypical lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, cleft palate, ventricular septal defect, and ...hypoplastic aortic arch. The initial routine chromosome study failed to detect any abnormality. Subtelomeres analysis by MLPA identified an 18q23 duplication inherited from its healthy father. We describe the anomalies identified and discuss diagnosis and the causability of this telomeric duplication.
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