Down Syndrome Patients with Congenital Portosystemic Shunts: A Case Report and Review

Introduction: Down syndrome is due to trisomy 21 and is characterized by intellectual disability, dysmorphic facial features, congenital malformations, and gastrointestinal abnormalities. There is an increased appreciation of congenital portosystemic shunts in Down syndrome patients. Congenital portosystemic shunts have been associated with many defects in body systems, including cardiac, metabolic, and neurological. Case Presentation: Herein, we describe a portosystemic shunt in a Down syndrome patient that resulted in hyperammonemia with altered mental status and choreiform movements. Computed tomography angiography of the abdomen and pelvis identified a connection between the right portal vein and inferior vena cava. An 18 mm Amplatzer PFO closure device was placed within the congenital shunt, significantly improving symptoms. The patient has no sequelae from the related shunt or the device at the 2-year follow-up. We extensively reviewed the literature and identified cases of portosystemic shunts in Down syndrome patients. Shunts can either be extrahepatic or intrahepatic and are classified by vasculature connections. Conclusion: From our literature review and case presentation, we identify other conditions in patients, including cardiac and gastrointestinal defects. We then review the available treatment options, whether observation or surgical, depending on the patient’s clinical picture

Atypical Presentation of Trisomy 13 in the Context of Maternal Amphetamine and Benzodiazepine Abuse

Abstract Title: ATYPICAL PRESENTATION OF TRISOMY 13 IN THE CONTEXT OF MATERNAL AMPHETAMINE AND BENZODIAZEPINE ABUSE Abstract ID: 244 Abstract Category: Clinical Research Patrick Staso MD and Theotonius Gomes MD ABSTRACT: An atypical case of Trisomy 13 (47,+13) with three independent copies of Trisomy 13 identified by Microarray Analysis confirmed with limited chromosomal analysis. CASE: A term appearing infant later confirmed to be of 38 weeks gestational age was delivered in the pre-hospital setting via spontaneous vaginal delivery to a 33 year old G4P1022 mother with no prenatal care in ambulance en route to hospital. She had meconium stained amniotic fluid, ruptured at delivery with unknown GBS status. APGAR scores were noted at 3 and 6 at 1 and 5 minutes, respectively. Mother was unaware of her current pregnancy and had a history of preeclampsia, 2 prior spontaneous abortions, and depression. There was no history of maternal medication use; however, a urine drug screen was positive for amphetamines, methamphetamines and benzodiazepines. Mother’s history was also significant for prior previous term twin delivery. The child presented to the Neonatal Intensive Care Unit and was found to have an un-ruptured omphalocele (beside reduced at 9 hrs of life), postaxial polydactyly of bilateral hand and toes, partial syndactally of bilateral halluxes, and dysmorphic facial features. A portable CXR was obtained which showed meso/dextrocardia. A 3/6 loud systolic murmur was noted and a cardiac echo demonstrated a small secundum ASD, large mal-aligned VSD or possible double outlet right ventricle (DORV) and moderate sized PDA with mild biventricular hypertrophy. Discussion: Patau syndrome has a prevalence between 1:7,000-29,000 depending on the source and is the third most common autosomal trisomy. The average length of survival is approximately 9 months with 90% of patients dying before the age of 1 year. Methamphetamines have only been mentioned in one other case report as a possible cause and no association of benzodiazepines were found. As well, an omphalocele is not common to Patau, but rather, is associated with Edward Syndrome (Trisomy 18). Most cases of trisomy 13 result from nondisjunction and have a low chance of recurrence. Overall, the low prevalence of this disorder, distinct abnormalities to this case, and possible etiologies from illicit substances makes this case important to share with the medical community

Ex Vivo Expansion of Retrovirally Transduced Primate CD34+ Cells Results in Overrepresentation of Clones With MDS1/EVI1 Insertion Sites in the Myeloid Lineage After Transplantation

Activation of proto-oncogenes by retroviral insertion is an important issue delaying clinical development of gene therapy. We have reported the nonrandom persistence of hematopoietic clones with vector insertions within the MDS1/EVI1 locus following transplantation of rhesus macaques. We now ask whether prolonged culture of transduced CD34+ cells before transplantation selects for clones with insertions in the MDS1/EVI11 or other proto-oncogene loci. CD34+ cells were transduced with standard retroviral vectors for 4 days and then continued in culture for an additional 6 days before transplantation. A 15% of insertions identified in granulocytes 6 months post-transplant were in MDS1/EVI11, significantly increased compared to the frequency in animals transplanted with cells immediately following transduction. MDS1/EVI1 clones became more dominant over time post-transplantation in one animal that was followed long term, accompanied by an increased overall copy number of vector-containing granulocytes, with one MDS1/EVI1 clone eventually accounting for 100% of transduced granulocytes and marrow colony-forming unit (CFU). This vector insertion increased the expression of Evi1 mRNA. There was no overrepresentation of MDS1/EVI1 insertions contributing to lymphoid lineages. Strategies involving prolonged ex vivo expansion of transduced cells may increase the risk of genotoxicity

Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene

Malignancies arising from retrovirally transduced hematopoietic stem cells have been reported in animal models and human gene therapy trials. Whether mature lymphocytes are susceptible to insertional mutagenesis is unknown. We have characterized a primary human CD8+ T-cell clone, which exhibited logarithmic ex vivo growth in the absence of exogenous cytokine support for more than 1 year after transduction with a murine leukemia virus–based vector encoding the T-cell growth factor IL-15. Phenotypically, the clone was CD28−, CD45RA−, CD45RO+, and CD62L−, a profile consistent with effector memory T lymphocytes. After gene transfer with tumor-antigen–specific T-cell receptors, the clone secreted IFN-γ upon encountering tumor targets, providing further evidence that they derived from mature lymphocytes. Gene-expression analyses revealed no evidence of insertional activation of genes flanking the retroviral insertion sites. The clone exhibited constitutive telomerase activity, and the presence of autocrine loop was suggested by impaired cell proliferation following knockdown of IL-15Rα expression. The generation of this cell line suggests that nonphysiologic expression of IL-15 can result in the long-term in vitro growth of mature human T lymphocytes. The cytokine-independent growth of this line was a rare event that has not been observed in other IL-15 vector transduction experiments or with any other integrating vector system. It does not appear that the retroviral vector integration sites played a role in the continuous growth of this cell clone, but this remains under investigation