Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome.

BACKGROUND: Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. RESULTS: We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS patients, these mice show H19 upregulation and Igf2 downregulation, leading to severe intrauterine and postnatal growth retardation. CONCLUSION: This is the first report of an imprinting disease model animal generated by targeted demethylation of specific loci of the epigenome in fertilized eggs. Epigenome-edited animals are also useful for exploring the causative epimutations in epigenetic diseases.

[Silver-Russell syndrome (hemihypertrophy) and cor triatriatum in a newborn]. / Símdrome de Silver-Russell (hemihipertrofia) y cor triatriatum en un neonato.

Hemihypertrophy syndrome and cor triatriatum are extremely rare pathologies. Hemihypertrophy is defined as complete or partial overgrowth of one of the hemibodies. Cor triatriatum is a congenital heart disease characterized by a membrane which separates the left atrium into two chambers; if that membrane has a restrictive hole, it causes obstruction to blood passage from the pulmonary veins into the left ventricle causing hypertension and pulmonary edema. In this context, the patent ductus arteriosus can act as a means of decompression of the pulmonary circuit, because it allows the blood passage from the pulmonary artery to the aorta. We report a patient with Silver-Rusell syndrome (hemihypertrophy), cor triatriatum and ductus arteriosus with reverse flow. To our knowledge, this association of rare pathologies and this clinical presentation have not been described previously.

Correction of the axial and appendicular deformities in a patient with Silver-Russel syndrome.

BACKGROUND: Scoliosis and limb length discrepancy are the major orthopaedic abnormalities in patients with Silver-Russel syndrome (SRS). In this paper, we describe a series of orthopaedic interventions in an attempt to overcome the progressive pathologic mechanism in a 7-year-old girl who manifested the full phenotypic features of SRS. MATERIALS AND METHODS: Unilateral hip dislocation, progressive scoliosis and limb length discrepancy have been dealt with through Pemberton osteotomy, spinal fusion and Taylor-Spatial-Frame respectively. RESULTS: In order to correct the axial and the appendicular deformities a sum of seven operations were performed (between the age of 7 years and 13 years). Pemberton osteotomy was performed to treat dislocation of her right hip because of developmental dysplasia of the hip. Spinal fusion (spondylodesis) of segments Th3-L5 was done to correct her scoliosis. And, to overcome the limb length discrepancy of 15-cm we used Taylor-Spatial-Frame with percutaneous distal corticotomy of the femur, and the proximal tibia, as well as the foot, were performed. We were able to minimize the limb length discrepancy to 5 cm. The girl became able to walk with the aid of a below knee orthosis and through lifting the left limb with 5-cm height shoe. CONCLUSION: Limb lengthening surgery in patients with multiple malformation complex as in SRS is associated with high recurrence risk because of; muscular hypotonia, overtubulation of the long bones, and the poor bone regenerative quality. Our interventions were principally directed towards improving the cosmetic outlook, functions and the biomechanics.

Cerebral aneurysms and accelerated atherosclerosis in Russell-Silver syndrome: a new subtype? Case report.

The authors describe the case of a 32-year-old woman known to have Russell-Silver syndrome who presented with repeated aneurysmal subarachnoid hemorrhage. Multiple intracranial aneurysms and advanced peripheral vascular disease were demonstrated. The authors postulate a link between these vascular features and the patient's genetic condition.