Anhidrotic ectodermal dysplasia with immune deficiency (EDA-ID) is a form of ectodermal dysplasia, which is a group of conditions characterized by abnormal development of ectodermal tissues including the skin, hair, teeth, and sweat glands. In addition, immune system function is reduced in people with EDA-ID. The signs and symptoms of EDA-ID are evident soon after birth, and due to the severity of the immune system problems, most people with this condition survive only into childhood.

Skin abnormalities in children with EDA-ID include areas that are dry, wrinkled, or darker in color than the surrounding skin. Affected individuals tend to have sparse scalp and body hair (hypotrichosis). EDA-ID is also characterized by missing teeth (hypodontia) or teeth that are small and pointed. Most children with EDA-ID have a reduced ability to sweat (hypohidrosis) because they have fewer sweat glands than normal or their sweat glands do not function properly. An inability to sweat (anhidrosis) can lead to a dangerously high body temperature (hyperthermia), particularly in hot weather and during exercise, because the body cannot cool itself by evaporating sweat.

The immune deficiency in EDA-ID varies among individuals with this condition. Children with EDA-ID often produce abnormally low levels of proteins called antibodies or immunoglobulins. Antibodies help protect the body against infection by attaching to specific foreign particles and germs, marking them for destruction. A reduction in antibodies makes it difficult for children with this disorder to fight off infections. In EDA-ID, immune system cells called T cells and B cells have a decreased ability to recognize and respond to foreign invaders (such as bacteria, viruses, and yeast) that have sugar molecules attached to their surface (glycan antigens). Other key aspects of the immune system may also be impaired, leading to recurrent infections.

Children with EDA-ID commonly get infections in the lungs (pneumonia), ears (otitis media), sinuses (sinusitis), lymph nodes (lymphadenitis), skin, bones, and gastrointestinal tract. Approximately one quarter of individuals with EDA-ID have disorders involving abnormal inflammation, such as inflammatory bowel disease or rheumatoid arthritis.

There are two forms of EDA-ID that have similar signs and symptoms and are distinguished by the modes of inheritance: X-linked recessive or autosomal dominant.

Variants (also known as mutations in the IKBKG gene cause X-linked recessive EDA-ID, and variants in the NFKBIA gene cause autosomal dominant EDA-ID. The proteins produced from these two genes regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related proteins (a protein complex) that binds to DNA and controls the activity of other genes, including genes that direct the body's immune responses and inflammatory reactions. It also protects cells from certain signals that would otherwise cause them to self-destruct (undergo apoptosis).

The IKBKG and NFKBIA gene variants responsible for EDA-ID result in the production of proteins with altered function, which reduces activation of nuclear factor-kappa-B. These changes disrupt certain signaling pathways within immune cells, resulting in immune deficiency. It is unclear how gene variants alter the development of the skin, teeth, sweat glands, and other tissues, although it is likely caused by abnormal nuclear factor-kappa-B signaling in other types of cells.

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

Normal Function

The NFKBIA gene provides instructions for making one piece (the alpha 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 it is turned off (inactive), nuclear factor-kappa-B is attached (bound) to the IKK complex. In response to certain signals, the IKK complex turns on (activates) nuclear factor-kappa-B and releases it.

The NFKBIA protein helps keep nuclear factor-kappa-B bound in the IKK complex. When the NFKBIA protein receives a signal that nuclear factor-kappa-B is to be released, it breaks down so the factor can be turned on (activated) and released from the complex. Once the active factor is released, it 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

At least five mutations in the NFKBIA gene have been found to cause anhidrotic ectodermal dysplasia with immune deficiency (EDA-ID). EDA-ID is a condition characterized by reduced function of the immune system, resulting in recurrent infections, and abnormal development of ectodermal tissues. The NFKBIA gene mutations that cause EDA-ID impair the protein's breakdown. As a result, nuclear factor-kappa-B is not activated or released from the IKK complex. Without nuclear factor-kappa-B available in the nucleus to regulate gene activity, certain signaling pathways within immune cells and cells that form ectodermal tissues are disrupted, resulting in immune deficiency and incomplete development of tissues of the ectoderm as occurs in individuals with EDA-ID.

Other Names for This Gene

• I-kappa-B-alpha
• IkappaBalpha
• ikB-alpha
• IKBA
• IKBA_HUMAN
• MAD-3
• major histocompatibility complex enhancer-binding protein MAD3
• NF-kappa-B inhibitor alpha
• NFKBI
• nuclear factor of kappa light chain gene enhancer in B-cells
• nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha

Genomic Location

When EDA-ID is caused by variants in the IKBKG gene, it is inherited in an X-linked recessive pattern. The IKBKG gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a variant would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of the IKBKG gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

When EDA-ID is caused by variants in the NFKBIA gene, the condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new variants in the gene and occur in people with no history of the disorder in their family.

The prevalence of the X-linked recessive type of EDA-ID is estimated to be 1 in 250,000 individuals. Only a few cases of the autosomal dominant form have been described in the scientific literature.