2.1. Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann syndrome, a condition characterized by overgrowth and other signs and symptoms that affect many parts of the body, can result from changes that affect the IC1 region. In some people with this condition, the maternally inherited copy of the IC1 region is methylated along with the paternally inherited copy. Because the IC1 region controls the genomic imprinting of the IGF2 and H19 genes, this abnormality disrupts the regulation of both genes. Specifically, abnormal methylation of the IC1 region leads to increased IGF2 gene activity and a loss of H19 gene activity in many tissues. An increase in IGF2 gene activity, which promotes growth, and a loss of H19 gene activity, which normally restrains growth, together lead to overgrowth in people with Beckwith-Wiedemann syndrome.

In a few cases, Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the IC1 region. Like abnormal methylation, these deletions alter the activity of the IGF2 and H19 genes.

2.2. Russell-Silver syndrome

Changes in methylation of the IC1 region are also responsible for some cases of Russell-Silver syndrome, a disorder characterized by slow growth before and after birth. The changes are different than those seen in Beckwith-Wiedemann syndrome (described above) and have the opposite effect on growth.

In Russell-Silver syndrome, the paternally inherited copy of the IC1 region often has too few methyl groups attached (hypomethylation). Hypomethylation of the IC1 region leads to a loss of IGF2 gene activity and increased activity of the H19 gene in many tissues. A loss of IGF2 gene activity, which normally promotes growth, and an increase in H19 gene activity, which restrains growth, together lead to poor growth and short stature in people with Russell-Silver syndrome.

2.3. Wilms Tumor

Changes in methylation of the IC1 region have also been found in some cases of Wilms tumor, a rare form of kidney cancer that occurs almost exclusively in children.

In some people with Wilms tumor, the maternally inherited copy of the IC1 region is methylated along with the paternally inherited copy. Abnormal methylation of the IC1 region leads to a loss of H19 gene activity, which normally restrains cell growth, and increased IGF2 gene activity in kidney cells. Increased IGF2 gene activity raises insulin-like growth factor 2 protein production, which likely stimulates the growth of tumor cells in the kidney and prevents damaged cells from being destroyed. As this mechanism is similar to the one that causes Beckwith-Wiedemann syndrome (described above), it is thought that individuals with Wilms tumor caused by changes in IC1 methylation may later be diagnosed with Beckwith-Wiedemann syndrome.

In most cases, abnormal methylation of IC1 and subsequent changes in IGF2 and H19 gene activity are somatic, which means that they are acquired during a person's lifetime and present only in some tissues. Rarely, these changes are germline, which means they are present in all of the body's cells.

2.4. Other Cancers

Increased activity of the IGF2 gene has been associated with many types of cancer. Normally, the IGF2 gene undergoes genomic imprinting and only the copy inherited from a person's father is active. In some cancers, however, both the paternally inherited and the maternally inherited copies of the gene are active, increasing the amount of insulin-like growth factor 2 that cells can produce. This phenomenon, known as loss of imprinting (LOI), occurs during a person's lifetime in cells that ultimately give rise to cancer. An increased amount of insulin-like growth factor 2 may stimulate the growth of tumor cells and prevent damaged cells from being destroyed.

Loss of imprinting of the IGF2 gene has been identified in several types of cancer. In some cases these cancers occur without any other related health problems, in other cases they occur in people with Beckwith-Wiedemann syndrome (described above). These include cancer of blood-forming cells (leukemia), a cancer of muscle tissue called rhabdomyosarcoma, a form of liver cancer called hepatoblastoma, and cancers of the breast, prostate, lung, and colon. In some types of cancer, increased levels of insulin-like growth factor 2 are associated with the growth and spread of tumors.