Generalized pustular psoriasis (GPP) is a severe form of a skin disorder called psoriasis. GPP and other forms of psoriasis are caused by abnormal inflammation. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). However, when inflammation is abnormal and uncontrolled, it can damage the body's tissues and organs. Individuals with GPP have repeated episodes in which large areas of skin become red and inflamed and develop small pus-filled blisters (pustules). The skin problems can be accompanied by fever, extreme tiredness (fatigue), muscle weakness, an increased number of white blood cells, and other signs of inflammation throughout the body (systemic inflammation). The inflammation problems subside and reappear often. Episodes can be triggered by infection, exposure to or withdrawal from certain medications, menstruation, or pregnancy, although the trigger is often unknown. GPP can be life-threatening if not treated.

While many affected individuals have features only of GPP (called GPP alone), some develop features of another skin condition called psoriasis vulgaris (PV), either before or after GPP appears. PV, the most common form of psoriasis, is characterized by red, scaly patches of skin (plaques) on parts of the body.

GPP is the rarest form of psoriasis. Although the worldwide prevalence of GPP is unknown, the condition is estimated to affect 2 per million people in Europe. It also occurs in approximately 0.6 per million people each year in Japan.

Mutations in several genes, including IL36RN and CARD14, increase the risk of developing GPP. These two genes provide instructions for making proteins that play roles in regulating inflammation, particularly in the skin. The IL-36Ra protein, produced from the IL36RN gene, blocks the activity of specific proteins that trigger signaling pathways to promote skin inflammation. IL36RN gene mutations involved in GPP reduce the amount of IL-36Ra protein in the skin. Without control by IL-36Ra, signaling pathways that promote inflammation are overly active.

Conversely, the CARD14 protein normally turns on inflammation signaling. The CARD14 gene mutations associated with GPP increase the activity of the CARD14 protein, leading to uncontrolled inflammation signaling in the skin. Enhancement of these signaling pathways results in abnormal inflammatory reactions, which contribute to the skin problems and systemic inflammation characteristic of GPP.

IL36RN gene mutations are most often associated with GPP alone and are only rarely found in individuals who also have PV. Mutations in this gene appear to be the most common genetic risk factor for GPP alone. CARD14 gene mutations are more frequently found in individuals with both GPP and PV, although changes in this gene have also been found in individuals with GPP alone.

Many people with GPP do not have a mutation in the IL36RN or CARD14 gene. Mutations in other genes, some of which have not been identified, may also be associated with the condition. Having a gene mutation in one of the associated genes does not mean an individual will have GPP. Researchers suspect that environmental or other genetic factors help determine whether an individual will develop the condition.

Normal Function

The CARD14 gene provides instructions for making a protein that turns on (activates) a group of interacting proteins known as nuclear factor-kappa-B (NF-κB). The NF-κB protein complex regulates the activity of multiple genes, including genes that control the body's immune responses and inflammatory reactions. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). The NF-κB protein complex also protects cells from certain signals that would otherwise cause them to self-destruct (undergo apoptosis).

The CARD14 protein is found in many of the body's tissues, but it is particularly abundant in the skin. NF-κB signaling appears to play important roles in regulating inflammatory reactions in the skin and in promoting the survival of skin cells.

Health Conditions Related to Genetic Changes

Generalized pustular psoriasis

At least three CARD14 gene mutations have been found in people with generalized pustular psoriasis (GPP), a rare and severe form of an inflammatory skin disorder called psoriasis. Individuals with GPP have repeated episodes in which large areas of skin become red and inflamed and develop small pus-filled blisters (pustules). The skin problems can be accompanied by fever and other signs of inflammation throughout the body (systemic inflammation). The episodes are thought to be triggered by infections, certain medications, pregnancy, or other stresses on the body. Most people with CARD14-associated GPP also have symptoms of the most common form of psoriasis called psoriasis vulgaris (PV), which is characterized by red, scaly patches of skin (plaques).

The CARD14 gene mutations associated with GPP (including GPP with PV) lead to production of an altered CARD14 protein that more readily turns on NF-κB. Overactive NF-κB signaling increases the activity of genes involved in the body's inflammatory response. The resulting abnormal inflammation contributes to the skin problems characteristic of GPP and PV.

CARD14 gene mutations increase the risk of developing GPP. Not everyone with a mutation in this gene has the characteristic problems with inflammation. This complex condition is thought to arise from a combination of genetic and environmental factors.

Familial pityriasis rubra pilaris

At least three mutations in the CARD14 gene have been identified in people with familial pityriasis rubra pilaris, a rare hereditary skin condition characterized by a patchy, salmon-colored skin rash covered in fine scales. These mutations lead to overactivation of NF-κB signaling, which triggers an abnormal inflammatory response in the skin. Researchers are working to determine how these changes lead to the specific features of familial pityriasis rubra pilaris.

Psoriatic arthritis

MedlinePlus Genetics provides information about Psoriatic arthritis

Other disorders

Changes in the CARD14 gene may also contribute to other forms of psoriasis. At least two mutations have been identified in families with psoriasis. Several other rare variants of the CARD14 gene have been associated with an increased risk of psoriasis in people without a family history of the disorder. Studies suggest that these genetic changes enhance activation of NF-κB, resulting in abnormal inflammation, which is a characteristic feature of psoriasis. However, CARD14 gene mutations appear to be an uncommon risk factor for this condition. Additional factors in combination with the particular CARD14 gene mutation may help determine which form of skin inflammation develops.

Other Names for This Gene

• bcl10-interacting maguk protein 2
• BIMP2
• CAR14_HUMAN
• CARD-containing MAGUK protein 2
• card-maguk protein 2
• carma 2
• CARMA2
• caspase recruitment domain family, member 14
• caspase recruitment domain-containing protein 14

Genomic Location

Normal Function

The IL36RN gene provides instructions for making a protein called interleukin 36 receptor antagonist (IL-36Ra). This protein is primarily found in the skin where it helps regulate inflammation, part of the body's early immune response. Inflammation in the skin is stimulated when other proteins called IL-36 alpha (α), IL-36 beta (β), or IL-36 gamma (γ) attach to (bind) a specific receptor protein. This binding turns on (activates) signaling pathways that promote inflammation, namely the NF-κB and MAPK pathways. To control inflammatory reactions, the IL-36Ra protein binds to the receptor protein so that IL-36α, IL-36β, and IL-36γ cannot. In this way, the IL-36Ra protein blocks (antagonizes) the receptor's activity.

Health Conditions Related to Genetic Changes

Generalized pustular psoriasis

More than a dozen IL36RN gene mutations have been found to increase susceptibility to a serious skin disorder called generalized pustular psoriasis (GPP). Individuals with this condition have repeated episodes in which large areas of skin become red and inflamed and develop small pus-filled blisters (pustules). The skin problems can be accompanied by fever and other signs of inflammation throughout the body (systemic inflammation). The episodes are thought to be triggered by infections, certain medications, menstruation, pregnancy, or other stresses on the body.

The IL36RN gene mutations associated with GPP reduce the amount of IL-36Ra protein in the skin or eliminate it altogether. Without control by IL-36Ra, signaling pathways that promote inflammation are overly active, resulting in uncontrolled inflammation, particularly in the skin.

IL36RN gene mutations increase the risk of developing GPP. Not everyone with mutations in this gene has the characteristic problems with inflammation. This complex condition is thought to arise from a combination of genetic and environmental factors.

Other disorders

IL36RN gene mutations are also associated with other inflammatory skin conditions that involve pustule formation. Like GPP (described above), acute generalized exanthematous pustulosis (AGEP), is characterized by a rash and pustules over a large area of the body, typically triggered by antibiotics or other medications. (Certain features of the inflamed skin differentiate AGEP and GPP.) Other IL36RN-associated conditions are classified as forms of localized pustular psoriasis because the blisters are found in limited regions of the body. For example, palmoplantar pustulosis affects the hands and feet, and acrodermatitis continua of Hallopeau affects the tips of the fingers and toes. It is unclear how mutations in the same gene cause these different conditions.

IL36RN gene mutations have been found in individuals with a condition called geographic tongue, in which the top and sides of the tongue have irregular patches that resemble a map. The patches are not linked to infections or other health problems. Some people with GPP have geographic tongue, but the abnormality can also occur without features of other conditions.

Other Names for This Gene

• FIL1
• FIL1(DELTA)
• FIL1D
• IL-1 related protein 3
• IL-1F5
• IL-36Ra
• IL1F5
• IL1HY1
• IL1L1
• IL1RP3
• IL36RA
• interleukin 1 family, member 5 (delta)
• interleukin-1 HY1
• interleukin-1 receptor antagonist homolog 1
• interleukin-1-like protein 1
• interleukin-36 receptor antagonist protein
• MGC29840
• PSORP
• PSORS14

Genomic Location

When associated with IL36RN gene mutations, risk of GPP is typically inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene.

When associated with CARD14 gene mutations, GPP risk is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of the disorder. In some cases, an affected person inherits the mutation from one parent. Other cases result from new (de novo) mutations in the gene.

People with mutations in either the IL36RN or CARD14 gene inherit an increased risk of GPP, not the condition itself. Not all people with this condition have mutations in one of these genes, and not all people with a mutation in one of these genes will develop the disorder.