Incontinentia pigmenti is a condition that can affect many body systems, particularly the skin. This condition occurs much more often in females than in males.

Incontinentia pigmenti is characterized by skin abnormalities that typically evolve throughout childhood and young adulthood. Many affected infants have a blistering rash at birth and in early infancy. Though this blistering heals spontaneously, it can recur during illnesses with high fever. This blistering stage is followed by the development of wart-like (verrucous) lesions that also heal spontaneously. The blisters and wart-like lesions primarily occur on the arms and legs.

In infancy and early childhood, the skin develops grey or brown patches (hyperpigmentation) that occur in a swirled pattern. These patches, which can occur anywhere on the body, fade with time. Adults with incontinentia pigmenti usually have lines of unusually light-colored skin (hypopigmentation) on their arms and legs. These markings follow the paths along which cells migrate as the skin develops before birth (called the lines of Blaschko).

Individuals with incontinentia pigmenti are at risk of stroke and vision loss, especially within the first year of life. These risks are due to abnormalities in blood vessels in the brain and in the light-sensitive tissue that lines the back of the eye (retina). Affected individuals at risk often have developmental delays, intellectual disabilities, seizures, or other neurological problems. In the absence of stroke or another brain abnormality, most people with incontinentia pigmenti have normal intelligence.

Other signs and symptoms of incontinentia pigmenti can include hair loss (alopecia) on the scalp and other parts of the body, dental abnormalities (such as small teeth or few teeth), and lined or pitted fingernails and toenails. The features of incontinentia pigmenti may be mild or gone by the time affected individuals reach adulthood.

Incontinentia pigmenti is estimated to affect 1.2 in 100,000 individuals worldwide. Between 900 and 1,200 affected individuals have been reported in the scientific literature. Most of the individuals affected are female, but several dozen males with incontinentia pigmenti have also been identified.

Variants (also called mutations) in the IKBKG gene cause incontinentia pigmenti. The IKBKG gene provides instructions for making a protein that helps regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related proteins that helps protect cells from self-destructing (undergoing apoptosis) in response to certain signals.

Sixty to 80 percent of affected individuals have a change in the IKBKG gene that deletes some genetic material from the gene. This deletion probably leads to the production of an abnormally small, nonfunctional version of the IKBKG protein. Other people with incontinentia pigmenti have variants that prevent the production of any IKBKG protein. Without this protein, nuclear factor-kappa-B is not regulated properly, and cells are more sensitive to signals that trigger them to self-destruct. Researchers believe that this abnormal cell death leads to the signs and symptoms of incontinentia pigmenti.

Normal Function

The IKBKG gene provides instructions for producing one piece (subunit) of the IKK protein complex, which is a group of related proteins that regulates the activity of nuclear factor-kappa-B. Nuclear factor-kappa-B is a protein complex that binds to DNA and controls the activity of other genes.

When the protein complex is in the resting state (inactive), nuclear factor-kappa-B and the IKK complex are attached (bound) together. In response to certain chemical signals, the IKK complex releases nuclear factor-kappa-B.

The IKBKG protein plays a regulatory role in the IKK complex. Once the IKBKG protein is turned on (activated), it activates the other proteins in the complex, which in turn releases nuclear factor-kappa-B. The loose nuclear factor-kappa-B then moves into the nucleus and binds to DNA.

Nuclear factor-kappa-B regulates the activity of multiple genes, including genes that control the body's immune responses and inflammatory reactions. Nuclear factor-kappa-B also appears to play a role in the signaling pathway that is critical for the formation of ectodermal tissues, including the skin, hair, teeth, and sweat glands. In addition, it protects the cell from certain signals that would otherwise cause it to self-destruct (undergo apoptosis).

Health Conditions Related to Genetic Changes

Anhidrotic ectodermal dysplasia with immune deficiency

Variants (also called mutations) in the IKBKG gene have been found to cause anhidrotic ectodermal dysplasia with immune deficiency (EDA-ID). EDA-ID is a condition characterized by abnormal development of ectodermal tissues. In addition, immune system function is reduced in people with EDA-ID, resulting in recurrent infections.

The IKBKG gene variants that cause EDA-ID impair the function of the IKBKG protein but do not completely eliminate its ability to regulate nuclear factor-kappa-B. These changes disrupt certain signaling pathways within immune cells and cells that form ectodermal tissues.This impairs the immune system and disrupts the development of ectodermal tissues.

The severity of the signs and symptoms of EDA-ID depends on the amount of protein function remaining. A greater level of protein function is typically associated with milder disease.

Some people with EDA-ID have unusually dense bones (osteopetrosis) and swelling (lymphedema). This is sometimes referred to as OL-EDA-ID; the acronym is derived from each of the major features of the disorder. It is unclear how variants in the IKBKG gene contribute to osteopetrosis and lymphedema in EDA-ID.

Incontinentia pigmenti

Variants in the IKBKG gene have been identified in people with incontinentia pigmenti, a condition characterized by skin, tooth, and nail abnormalities as well as increased risks of stroke and vision loss.

The most common IKBKG gene change is a complex rearrangement that deletes some genetic material from the IKBKG gene. This change accounts for more than 60 to 80 percent of all cases of the condition. This common change probably leads to the production of an abnormally small, nonfunctional version of the IKBKG protein.

Other IKBKG gene variants that cause incontinentia pigmenti prevent the production of any IKBKG protein. Without this protein, nuclear factor-kappa-B cannot be activated. Cells without active nuclear factor-kappa-B are more sensitive to signals that trigger them to self-destruct. The resulting abnormal cell death likely leads to the signs and symptoms of incontinentia pigmenti.

Other disorders

IKBKG gene variants may account for some cases of a condition known as X-linked susceptibility to mycobacterial disease. People with this condition have an increased risk of infection with forms of bacteria called mycobacteria. Some of these foreign invaders are described as "opportunistic" organisms because they do not cause illness in people with a normal immune system. Another type of mycobacterium causes tuberculosis, a respiratory disease that can be serious or life-threatening.

The IKBKG gene variants associated with X-linked susceptibility to mycobacterial disease alter the structure of the IKBKG protein. The defective protein disrupts certain signaling pathways within immune cells, which prevents the immune system from defending the body effectively against mycobacterial infection.

Other Names for This Gene

• FIP-3
• FIP3
• Fip3p
• IKK-gamma
• inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma
• IP2
• NEMO
• NEMO_HUMAN
• NF-kappa-B essential modulator
• ZC2HC9

Genomic Location

Incontinentia pigmenti (IP) is an inherited (genetic) condition that affects the skin and other systems in the body. Skin symptoms change with time and begin with a blistering rash in infancy, followed by wart-like skin growths. The growths become swirled grey or brown patches in childhood, and then swirled light patches in adulthood.

Other signs and symptoms may include:

• Hair loss
• Small or missing teeth
• Eye abnormalities that can lead to vision loss
• Lined or pitted fingernails and toenails