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National Institute of Allergy and Infectious Diseases | health information 

BENTA Disease

What Is BENTA Disease?

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.

Genetics and Function

BENTA disease is caused by “gainof-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.

Genetics primer: All the cells in the body contain instructions on how to do 

their job. These instructions are packaged into chromosomes, each of which 

contains many genes, which are made up of DNA. Errors, or mutations, in the 

genes can cause diseases such as BENTA disease. Credit: NIAID

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of Allergy and Infectious Diseases
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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.

Inheritance

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. Credit: U.S. National Library of 

Medicine

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.

Clinical Symptoms

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.
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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.

Laboratory Findings

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.

Treatment

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.

BENTA Disease and Your Family

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 
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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.
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Glossary

Anergy—A lacking or weak immune system response.

Autosomal dominant—A pattern of inheritance in which an 

affected person has one mutated copy of a gene and one 

normal copy.

B cell—A type of immune cell that comes from the bone marrow. 

B cells present antigens, or foreign substances, to T cells and 

produce antibodies, or immunoglobulins.

BK virus—A common virus that typically only causes problems 

for those with immune deficiency.

Cell—The basic unit of living organisms. Human cells consist of 

a nucleus (control center) and cellular organs, called organelles, 

enclosed by a membrane. Groups of cells with similar structure 

and function form tissues.

Chromosome—A thread-like structure made up of DNA that is 

tightly coiled around supporting proteins. Chromosomes reside 

in the control center, or nucleus, of a cell. 

De novo mutation—A gene mutation that occurs in the egg or 

sperm of one of the parents or in the fertilized egg itself.

Differentiation—The process by which a cell changes from one 

cell type to another or acquires a different set of functions.

DNA (deoxyribonucleic acid)—A self-replicating material 

present in nearly all living organisms. It is the carrier of genetic 

information.

Epstein-Barr virus—A ubiquitous, usually harmless, virus that 

sometimes is associated with lymphoma and other cancers. 

Also known as EBV.

Gain-of-function mutation—A type of gene mutation that causes 

the protein produced from the gene to be overactive.

Gene—A unit of heredity that is transferred from parent to child. 

Genes are made up of DNA. 

Germline—Part of a person’s genetic makeup that is present in 

every cell of the body and can be transmitted to offspring.

Immune system—A system of biological structures and processes 

within the body that protects it against “foreign” threats such as 

bacteria or viruses.

Immunosuppressive medications—Medications that are used 

to suppress an overactive immune system.

Leukemia—Cancer that starts in blood-forming tissue, such as 

the bone marrow, and causes large numbers of abnormal blood 

cells to be produced and enter the bloodstream.

Lymphadenopathy—Enlarged lymph nodes.

Lymphocytes—A class of white blood cells that are part of the 

immune system.

Lymphocytosis—A disorder involving abnormally high lymphocyte counts.

Lymphoma—Cancer that begins in cells of the immune system.

Molluscum contagiosum—A viral skin infection that results in 

round, firm, painless bumps.

Mutation—A change in the DNA sequence that is associated 

with disease or susceptibility to disease.

NF-κB—A protein complex involved in gene expression, or 

the degree to which certain genes are turned on or off. NF-κB 

controls many genes required for cell growth, survival, and 

cell function in the immune system.

Rituximab—An antibody-based drug that destroys B cells and 

is used to treat diseases characterized by excessive numbers 

of B cells, overactive B cells, or B cells that do not function 

properly.

Splenectomy—Removal of the spleen, a fist-sized organ that 

sits above the stomach and is part of the lymphatic system.

Splenomegaly—Enlargement of the spleen.

T cell—A lymphocyte produced in the thymus (a small organ 

located in the upper chest under the breastbone) that is actively 

involved in the immune response.

July 2015

www.niaid.nih.gov