Costello syndrome ... (Costello syndrome) - Gen HRAS
Costello syndrome is a multisystem disorder characterized by developmental delay and mental retardation, high birthweight, short stature due to a reduction in the levels of growth hormone, unusually flexible joints and characteristic facial features including a large mouth . In addition, affected individuals have heart problems such as arrhythmias, structural heart defects and hypertrophic cardiomyopathy. Other signs and symptoms of the disease may include strained Achilles tendons, hypotonia, a structural abnormality of the brain called Chiari I malformation, skeletal abnormalities, dental problems and problems with vision. In addition, affected individuals may have a predisposition to the development of malignant or benign tumors. The most common benign tumors are perinasal, perioral papillomas or perianal. The most common malignant tumor, rhabdomyosarcoma is followed neuroblastoma and bladder carcinoma.
Signs and symptoms Costello syndrome overlap with two other genetic alterations: syndrome Cutaneous cardiofaciocutaneous (CFC) and Noonan syndrome. In newborns affected, it may be difficult to differentiate the three diseases based on their physical characteristics. However, they can be differentiated by their genetic cause and the specific signs and symptoms that develop during childhood.
Costello syndrome is due to mutations in the HRAS gene, located on the short arm of chromosome 11 (11p15.5). This gene encodes the H- Ras protein primarily involved in the regulation of cell division. Through a process known as signal transduction, protein H- Ras transmits signals from outside the cell to the cell nucleus. H- Ras protein is a GTPase, which means that converts GTP molecule in a GDP molecule. H ras proteins acting as a switch, and is toggled by GTP and GDP molecules. To transmit signals, the protein must be activated by binding to a molecule of GTP. H- Ras protein is inactivated when converts GTP to GDP. When the protein is bound to GDP, does not transmit signals to the cell nucleus. HRAS gene belongs to a class of genes known as oncogenes. When oncogenes have mutations, they can cause normal cells to become cancerous.
They have identified at least 15 mutations in HRAS gene in people with Costello syndrome. These mutations change amino acids in a critical region of the protein H- Ras. The most common mutation, representing over 80% of cases, replacing the amino acid glycine by serine at amino acid position 12 of the protein (or Gly12Ser G12S). Mutations result in a protein coding H- Ras that abnormally activated in cells throughout the body. Instead of triggering cell growth in response to signals from outside the cell, overactive protein causes cells to grow and divide constantly. This uncontrolled cell division can lead to the formation of non - cancerous and cancerous tumors. It is unclear how mutations in the HRAS gene give rise to the other features of Costello syndrome and intellectual disability, characteristic facial features and heart problems, but many of the signs and symptoms are likely due to cell overgrowth and abnormal cell division. Some people with signs and symptoms of Costello syndrome have a mutation in the HRAS gene identified. These people may have CFC syndrome or Noonan syndrome, which are due to mutations in other genes related.
Costello syndrome is considered an autosomal dominant disorder, which means that a copy of the altered gene in each cell is sufficient to express the disease. However, lmost all reported cases are due to new genetic mutations and occur in people with no family history of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Costello syndrome, by PCR amplification of exons HRAS gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).