BENTA disease is a rare genetic disorder of the immune system caused by mutations in the gene CARD11. BENTA stands for “B-cell expansion with NF-jB and T-cell anergy.” The disease is characterized by high levels of certain immune cells starting in infancy, an enlarged spleen, enlarged lymph nodes, immunodeficiency, and an increased risk of lymphoma, a type of cancer. Breaking down the name, BENTA, helps explain the syndrome.

• A B cell is a type of immune cell from the bone marrow.

• Expansion means that the number of B cells is greater than normal.

• NF-jB is a protein complex involved in gene expression, or the degree to which certain genes are turned on or off.

• A T cell is a type of immune cell that matures in the thymus, a small organ located in the upper chest under the breastbone.

• Anergy refers to a “less-than-normal” (T cell) immune reaction to foreign substances.

BENTA disease is diagnosed based on clinical and laboratory findings as well as genetic testing.

BENTA disease is caused by “gain of-function” mutations in the gene CARD11, which provides instructions for production of the CARD11 protein. These gain-of-function mutations cause the CARD11 protein to be overactive. The CARD11 protein is required for activation of NF-jB in both B and T cells, which is essential for a healthy immune response. The development and differentiation of B cells might also be partially impaired in BENTA disease.

The gain-of-function CARD11 mutations associated with BENTA disease may also predispose patients to B-cell cancers. Importantly, overactivation of the NF-jB pathway, as occurs in BENTA disease, is frequently associated with B-cell cancers. Specifically, somatic (present only in some cells, such as cancer cells) gain-of-function CARD11 mutations are seen frequently in a type of cancer called diffuse large B-cell lymphoma. These mutations do not appear to be associated with T-cell cancers.

Normal Function

The CARD11 gene provides instructions for making a protein involved in the function of immune system cells called lymphocytes, particularly certain types called T cells and B cells. These cells identify foreign substances such as bacteria, viruses, and fungi and defend the body against infection. When T or B cells recognize a foreign substance, the CARD11 protein is turned on (activated) and attaches (binds) to two other proteins, BCL10 and MALT1, to form the CBM signalosome complex. This complex in turn activates other protein complexes called nuclear factor-kappa-B (NF-κB) and mTOR complex 1 (mTORC1), which are important for cellular signaling. NF-κB and mTORC1 signaling direct the development and function of T and B cells so they can support an immune response against foreign invaders.

Health Conditions Related to Genetic Changes

Atopic dermatitis

At least five CARD11 gene mutations have been identified in people with a skin disorder called atopic dermatitis (also known as atopic eczema). This condition is characterized by dry, itchy skin and red rashes. The word "atopic" indicates an association with allergies. While atopic dermatitis is not always due to an allergic reaction, it is commonly associated with other allergic disorders. People with atopic dermatitis caused by CARD11 gene mutations often have additional allergic disorders, such as asthma and environmental (such as pollen) or food allergies. Many of these individuals also have recurrent infections due to problems with the immune system (immunodeficiency).

Atopic dermatitis is generally thought of as a complex condition that is influenced by multiple genetic and environmental factors, which each contribute only a small amount to the overall risk of developing the condition. However, CARD11 gene mutations appear to cause atopic dermatitis without other factors. These mutations likely account for only a small percentage of cases of the condition.

A mutation in one of the two copies of the CARD11 gene in each cell is sufficient to cause atopic dermatitis. These mutations result in the production of an altered protein that does not function normally. The altered protein produced from the mutated copy of the gene interferes with the normal protein produced from the non-mutated copy of the gene (such mutations are described as "dominant-negative"), so the amount of functioning CARD11 protein in cells is reduced. These genetic changes are thought to prevent formation of the CBM signalosome complex, impairing signaling by NF-κB and mTORC1. Without these signals, T cells do not develop or function properly. The number of these cells is normal, but their response to foreign invaders is diminished, leading to recurrent infections.

It is not clear how the immune dysfunction caused by CARD11 gene mutations leads to atopic dermatitis and allergic disorders. Atopic dermatitis is not initially caused by an allergic reaction, although sometimes substances that can cause allergic reactions (allergens) are thought to contribute to flare-ups of the rashes.

Omenn syndrome

MedlinePlus Genetics provides information about Omenn syndrome

Other disorders

CARD11 gene mutations can cause other immune system disorders. At least 3 mutations in the gene have been found to cause a type of severe combined immunodeficiency (SCID) known as immunodeficiency 11. SCID is a group of disorders characterized by an almost total lack of immune protection from foreign invaders. Immunodeficiency 11 is characterized by recurrent severe infections in the respiratory tract, particularly pneumonia caused by a fungus known as Pneumocystis jirovecii. Immunodeficiency 11 occurs when both copies of the CARD11 gene are mutated. The mutations are described as "loss of function" because they lead to production of an abnormally short, nonfunctional CARD11 protein. The lack of CARD11 function diminishes T cells' ability to fight foreign invaders, despite normal numbers of the cells, leading to recurrent infections. Individuals with immunodeficiency 11 do not appear to have an increased risk of atopic dermatitis (described above) or allergies.

At least four mutations in the CARD11 gene cause another immune cell disorder called B-cell expansion with NF-κB and T-cell anergy (BENTA). This condition is characterized by an excess of immune system cells called B cells (B-cell lymphocytosis), an increased risk of B-cell lymphoma, and susceptibility to infection. The mutations that cause BENTA are inherited and occur in one copy of the CARD11 gene. Like those involved in B-cell and T-cell cancers (described above), the genetic changes that cause BENTA are "gain-of-function" mutations; they lead to production of an altered CARD11 protein that is always turned on, resulting in constant NF-κB signaling. Overactive NF-κB promotes the proliferation of B cells, which can lead to B-cell lymphoma. These abnormal cells, however, cannot respond to infections. T cells are also abnormal and unable to fight foreign invaders (a phenomenon known as anergy). These immune cell problems lead to the increased risk of infection in people with BENTA.

Cancers

Mutations in the CARD11 gene are also associated with cancers of B cells (primarily diffuse large B-cell lymphoma) and T cells (adult T-cell leukemia/lymphoma). These mutations are not inherited; instead, they arise during a person's lifetime and are found only in B or T cells that give rise to cancer. These genetic changes are called "gain-of-function" mutations because they lead to production of an altered CARD11 protein that is always turned on, even without recognition of foreign substances by the B or T cell. As a result, NF-κB is constantly activated. Unregulated NF-κB signaling allows these cells to grow and divide without control, contributing to the development of cancer.

Other Names for This Gene

• bcl10-interacting maguk protein 3
• BENTA
• BIMP3
• CARD-containing MAGUK protein 1
• carma 1
• CARMA1
• caspase recruitment domain-containing protein 11
• IMD11
• IMD11A
• PPBL

Genomic Location

BENTA disease is inherited in an autosomal dominant manner. “Autosomal” refers to the fact that every person has two copies of the CARD11 gene, one inherited from each parent. Only one of the two copies of CARD11 needs to be abnormal for a person to have BENTA disease. “Dominant” indicates that the abnormal copy of the gene from one parent dominates the matching, normal gene copy from the other parent. Autosomal dominant inheritance means that most families with BENTA disease have affected relatives on the side of the family with the mutation.

Children of a parent who carries a CARD11 mutation have a 50 percent chance of inheriting the mutation. In a family, each child’s risk of inheriting a mutated copy of the CARD11 gene is independent of whether his or her siblings inherited the mutation. For example, if the first four children in a family have the mutation, the next child has the same 50 percent risk of inheriting the mutation. Children who do not inherit the mutation will not develop BENTA disease or pass on the mutation to their children. In this example, a man with an autosomal dominant disorder has two affected children and two unaffected children. Women also can pass on the mutation.

BENTA disease can also arise spontaneously in a patient as the result of a de novo mutation in CARD11. De novo mutations are not inherited but occur as a result of a mutation in the egg or sperm of one of the parents or in the fertilized egg itself. A patient with a de novo mutation can pass on the mutation to his or her children.

People with BENTA disease have polyclonal B-cell lymphocytosis (elevated levels of certain types of B cells) that develops in infancy, splenomegaly (enlarged spleen), and lymphadenopathy (enlarged lymph nodes). These features, as well as laboratory findings characteristic of BENTA disease, likely contribute to the mild immunodeficiency seen in people with BENTA disease. People with BENTA disease are susceptible to recurrent sinus and lung infections, as well as infections with viruses such as molluscum contagiosum virus, Epstein-Barr virus, or BK virus.

People with BENTA disease must be closely monitored for any signs of a B-cell cancer. A diagnosis of leukemia can generally be ruled out in people with BENTA disease based on the unremarkable appearance of their resting lymphocytes, or white blood cells. However, at least one patient with BENTA disease developed B-cell chronic lymphocytic leukemia as an adult. Cancer symptoms may include fatigue, loss of appetite, weight loss, or night sweats.

There are a few notable patterns that doctors can observe in the blood of a person with BENTA disease. The majority of BENTA patient blood cells are naïve, mature B cells, with elevated levels of a subtype of B cells called transitional B cells. Laboratory studies also have shown poor B-cell differentiation and immunoglobulin, or antibody, secretion. Serum IgM, a type of antibody, is low in most patients, and total IgG and IgA are typically on the low end of normal. Some patients have poor immune responses to certain vaccines. T-cell counts in people with BENTA disease are within or just above the normal range, although the T cells may be poorly responsive to certain foreign pathogens, hence inclusion of the word “anergy” as part of the BENTA acronym.

Currently, minimal treatment options are available for people with BENTA disease. Doctors closely monitor BENTA patients for infections and for signs of development of B-cell cancers. Splenectomy, or spleen removal, potentially could help reduce the B-cell burden in patients with BENTA disease. However, according to two published reports, B-cell counts increased dramatically in two patients who underwent the procedure. It remains to be determined whether immunosuppressive drugs, including B-cell-depleting drugs such as rituximab, are effective for treating BENTA disease.

Living with BENTA disease can be difficult not only for the person who has it but for their family members as well. It is important for families to talk openly about BENTA disease and about how the family is dealing with it so misconceptions can be corrected and children can learn to cope with their reactions. Some children with BENTA disease have to work hard to develop their self-confidence and sense of security. Everyone needs to be reminded that they have many positive characteristics, especially when their appearance attracts attention (for example, due to large spleen and lymph nodes). Some children with BENTA disease are asked to wear special “spleen guards,” which can be cumbersome, to protect against serious injuries when playing sports.

Some children who have siblings with BENTA disease worry about their brother or sister being in pain or dying from the disease. Some think that they may develop symptoms because they look or act like a sibling who has the disease or that the disease is contagious. Some children struggle with how much time their parents spend with their sick sibling. Many families benefit from meeting or talking to other families affected by the same rare disease. Patient organizations such as the Immune Deficiency Foundation (www.primaryimmune.org) are great resources for providing useful information and support. The BENTA disease Wikipedia page (en.wikipedia.org/wiki/BENTA_disease) also provides simple information about the disease. Counseling can also help families cope with the challenges of BENTA disease.

At the same time, many families say that BENTA disease has brought them closer together. Family members learn about controllable and uncontrollable aspects of life. Although certain aspects of the disorder cannot be controlled, how a family responds to the stress of any illness is controllable and an important aspect of managing BENTA disease. Children also learn who they can turn to for support and how to solve problems. Acknowledging both the challenges and opportunities that BENTA disease presents helps children develop resilience.