Inv21p12q22del21q22 and intellectual disability

Chromosomal rearrangements are common in humans. Pericentric inversions are among the most frequent aberrations (1-2%). Most inversions are balanced and do not cause problems in carriers unless one of the breakpoints disrupts important functional genes, has near submicroscopic copy number variants or hosts "cryptic" complex chromosomal rearrangements. Pericentric inversions can lead to imbalance in offspring. Less than 3% of Down syndrome patients have duplication as a result of parental pericentric inversion of chromosome 21. We report a family with an apparently balanced pericentric inversion of chromosome 21. The proband, a 23-year-old female was referred for prenatal diagnosis at 16weeks gestation because of increased nuchal translucency. She has a familial history of Down's syndrome and moderate intellectual disability, a personal history of four spontaneous abortions and learning difficulties. Peripheral blood and amniotic fluid samples were collected to perform proband's and fetus' cytogenetic analyses. Additionally, another six family members were evaluated and cytogenetic analysis was performed. Complementary FISH and MLPA studies were carried out. An apparent balanced chromosome 21 pericentric inversion was observed in four family members, two revealed a recombinant chromosome 21 with partial trisomy, and one a full trisomy 21 with an inverted chromosome 21. Array CGH analysis was performed in the mother and the brother's proband. MLPA and aCGH studies identified a deletion of about 1.7Mb on the long arm of inverted chromosome 21q22.11. We believe the cause of the intellectual disability/learning difficulties observed in the members with the inversion is related to this deletion. The recombinant chromosome 21 has a partial trisomy including the DSCR with no deletion. The risk for carriers of having a child with multiple malformations/intellectual disability is about 30% depending on whether and how this rearrangement interferes with meiosis

Inhibition of fucosylation in human invasive ductal carcinoma reduces E-selectin ligand expression, cell proliferation, and ERK1/2 and p38 MAPK activation

Breast cancer tissue overexpresses fucosylated glycans, such as sialyl-Lewis X/A (sLeX/A), and a-1,3/4-fucosyltransferases (FUTs) in relation to increased disease progression and metastasis. These glycans in tumor circulating cells mediate binding to vascular E-selectin, initiating tumor extravasation. However, their role in breast carcinogenesis is still unknown. Here, we aimed to define the contribution of the fucosylated structures, including sLeX/A, to cell adhesion, cell signaling, and cell proliferation in invasive ductal carcinomas (IDC), the most frequent type of breast cancer. We first analyzed expression of E-selectin ligands in IDC tissue and established primary cell cultures from the tissue. We observed strong reactivity with E-selectin and anti-sLeX/A antibodies in both IDC tissue and cell lines, and expression of a-1,3/4 FUTs FUT4, FUT5, FUT6, FUT10, and FUT11. To further assess the role of fucosylation in IDC biology, we immortalized a primary IDC cell line with human telomerase reverse transcriptase to create the ‘CF1_T cell line’. Treatment with 2-fluorofucose (2-FF), a fucosylation inhibitor, completely abrogated its sLeX/A expression and dramatically reduced adherence of CF1_T cells to E-selectin under hemodynamic flow conditions. In addition, 2-FF-treated CF1_T cells showed a reduced migratory ability, as well as decreased cell proliferation rate. Notably, 2-FF treatment lowered the growth factor expression of CF1_T cells, prominently for FGF2, vascular endothelial growth factor, and transforming growth factor beta, and negatively affected activation of signal-regulating protein kinases 1 and 2 and p38 mitogen-activated protein kinase signaling pathways. These data indicate that fucosylation licenses several malignant features of IDC, such as cell adhesion, migration, proliferation, and growth factor expression, contributing to tumor progression.The authors acknowledge the financial support from the LPCC/Pfizer 2011 and Portuguese Foundation for Science and Technology (FCT)—SFRH/BD/100970/ 2014 (MAC), SFRH/BD/81860/2011 (MS), and the United States National Institutes of Health National Heart Blood Institute (NHLBI Grant HL107146, RS). We also thank Dr Nicole Okeley from Seattle Genetics for the valuable help and opinions

Doença de Coats: diferentes apresentações

Introdução: A Doença de Coats caracteriza-se pelo desenvolvimento anormal dos vasos retinianos (telangiectasia), com deposição progressiva de exsudados intra e subretinianos e consequente descolamento de retina exsudativo. É uma patologia rara, esporádica, idiopática e unilateral (95%), que afecta maioritariamente indivíduos do sexo masculino (75%). A idade média de diagnóstico é aos 10 anos de idade. Na maioria dos doentes manifesta-se por diminuição da acuidade visual, estrabismo e/ou leucocória. O diagnóstico é clínico baseando-se nos achados fundoscópicos característicos. Vários exames complementares como a angiografia fluoresceínica, podem auxiliar a caracterizar a patologia. A classificação da Doença de Coats é útil para a escolha da opção terapêutica e prognóstico. Material e métodos: Os autores descrevem 4 casos clínicos de Doença de Coats, quanto à sua clínica, abordagem diagnóstica, opções terapêuticas e seguimento em consulta. Resultados: Os doentes foram submetidos a fotocoagulação laser indirecta e a crioterapia quando indicada. Após tratamento demonstraram melhoria clínica e funcional. Conclusão: A laserterapia e a crioterapia são opções terapêuticas nos estádios iniciais da patologia, permitindo a estabilização da doença. O diagnóstico precoce e a abordagem terapêutica atempada são essenciais para prevenir a diminuição progressiva da função visual. O tempo médio de recorrência da doença é de dez anos, sendo um seguimento regular e a longo prazo essenciais. Bibliografia: 1. Shields J, Shields C. Coats disease: The 2001 LuEsther T. Mertz Lecture. Retina. 2002; 22(1): 80-91. 2. Shields J, Shields C, Honavar S, Demirci H. Clinical variations and complications of Coats disease in 150 cases: The 2000 Sanford Gifford Memorial Lecture. Am J Ophthalmol. 2001 May; 131(5): 561-71. 3. Shields J, Shields C, Honavar S, Demirci H, Cater J. Classification and management of Coats disease: The 2000 Proctor Lecture. Am J Ophthalmol. 2001 May; 131(5): 572-83. 4. Hu Z, Gao R, Jin C, Liang X, Zhang S. Photocoagulation and scleral cryotherapy for Coats disease. Yan Ke Xue Bao. 1996 Dec; 12(4): 199-201. 5. Mosin I, Moshetova L. Tactics of treating children with Coats disease. Vestn Oftalmol. 2002 Mar-Apr; 118(2): 11-5