Russell-Silver syndrome - H19, IGF2 genes and methylation of IC1.

The Silver-Russell syndrome (SRS), also known as dwarfism Russell-Silver, is a disorder characterized by growth slow growth before and after birth. Infants with this disorder have low birth and often stunted weight. Head growth is normal, so the head may appear unusually large compared to the rest of the body. Affected children are thin and have little appetite, and some develop hypoglycemia as a result of feeding difficulties. Adults with Russell-Silver syndrome have short stature. The average height for males affected is about 151 centimeters and the average height for women affected is about 140 centimeters. Other signs and symptoms of the disease include a small, triangular and face characteristic facial features, including a prominent forehead, narrow chin, small jaw and mouth downturned. Other features of the disorder can include clinodactyly, asymmetric or uneven parts of the organism growth, and abnormalities in the digestive system. The syndrome is also associated with an increased risk of developmental delay and learning.

Genetic causes of Russell-Silver syndrome are complex. This syndrome is usually due to an abnormal regulation of certain genes that control growth. Studies have focused on genes in certain regions of the chromosome chromosome 7 and 11. It is believed that 30 to 50 percent of all cases of Down syndrome Russell-Silver are due to methylation in the short arm of chromosome 11 ( 11p15). Specifically, the syndrome has been associated with changes in methylation genes involving H19 (H19, imprinted maternally -non-protein transcript Expressed coding-) and IGF2 (insulin like growth factor 2) located near one another in the chromosome 11. These genes are thought to be involved in the direction of normal growth. A loss of methylation alters the regulation of these genes, which leads to slow growth and other features of this syndrome. The defects involved genes of chromosome 7 also cause Silver-Russell syndrome. Between 7 percent and 10 percent of cases, people inherit two copies of chromosome 7 of his mother instead of one copy from each parent. This phenomenon is called maternal uniparental disomy (UPD) and causes people to have two active copies of maternally expressed imprinted genes rather than an active copy of the mother and father an inactive copy. These individuals do not have a paternal copy of chromosome 7. In at least 40 percent of people with Russell-Silver syndrome, the cause of the disease is unknown.

The H19 gene (H19, imprinted maternally -non-protein transcript Expressed coding-), located on the short arm of chromosome 11 (11p15.5), encodes an RNA molecule noncoding. Unlike many genes, the H19 gene does not encode a protein. Gene function is unknown but is thought to act as a tumor suppressor, preventing cells from growing and dividing too rapidly or uncontrollably. This gene is very active before birth and can play an important role in early development. People inherit a copy of most genes of the mother and father back. Both copies are usually active in cells. The H19 gene, however, is activated only when inherited from the mother.

The IGF2 (insulin like growth factor 2), located on the short arm of chromosome 11 (11p15.5), encodes a protein called factor insulin - like growth 2. This protein plays an essential role in the growth and development before birth. Studies suggest that the factor of insulin - like growth 2 promotes the growth and proliferation of cells in many different tissues. Although the IGF2 gene is active during fetal development, it is much less active in the adult. For IGF2, unlike what happens with H19 gene copy, the copy inherited from the father is the only active copy in most parts of the body.

In the Silver-Russell syndrome, the region has frequently IC1 hypomethylation, which results in a loss of activity of IGF2 gene and an increased activity of the H19 gene in many tissues. A loss of activity of IGF2 gene, which normally promotes growth, and an increase in the activity of the H19 gene, which restricts growth, leads to poor growth with short stature in people with Russell-Silver syndrome.

Most cases of Russell-Silver syndrome are sporadic, meaning that occur in people with no history of disease in your family. Less commonly, the Silver-Russell syndrome may be hereditary. In some affected families, the syndrome appears to have an autosomal dominant pattern of inheritance, meaning that one copy of a genetic change in each cell is sufficient to express the alteration. In other families, it has an autosomal recessive inheritance pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with Silver-Russell syndrome, through the study of IC1 (Imprinting Center 1) methylations, whih regulates the expression of IGF2 and H19 genes.

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).