Omenn syndrome is an inherited disorder of the immune system (immunodeficiency). Omenn syndrome is one of several forms of severe combined immunodeficiency (SCID), a group of disorders that cause individuals to have virtually no immune protection from bacteria, viruses, and fungi. Individuals with SCID are prone to repeated and persistent infections that can be very serious or life-threatening. Infants with Omenn syndrome typically experience pneumonia and chronic diarrhea. Often the organisms that cause infection in people with this disorder are described as opportunistic because they ordinarily do not cause illness in healthy people.

In addition to immunodeficiency, children with Omenn syndrome develop autoimmunity, in which the immune system attacks the body's own tissues and organs. This abnormal immune reaction can cause very red skin (erythroderma), hair loss (alopecia), and an enlarged liver and spleen (hepatosplenomegaly). In addition, affected individuals have enlargement of tissues that produce infection-fighting white blood cells called lymphocytes. These include the thymus, which is a gland located behind the breastbone, and lymph nodes, which are found throughout the body.

If not treated in a way that restores immune function, children with Omenn syndrome usually survive only until age 1 or 2.

Mutations in several genes involved in immune system function can cause Omenn syndrome. The two most frequent causes are mutations in the RAG1 and RAG2 genes. These genes provide instructions for making proteins that are active in two types of lymphocytes called B cells and T cells. To help fight infections, B cells and T cells have special proteins on their surface that help them recognize foreign invaders; these proteins must be somewhat different from each other to be able to recognize a wide variety of substances. The RAG1 and RAG2 proteins help increase the diversity of proteins that are on the surface of these cells.

RAG1 and RAG2 gene mutations that cause Omenn syndrome drastically reduce the respective protein's function. As a result, the diversity of proteins on the surface of B cells and T cells is severely limited, impairing the cells' ability to recognize foreign invaders and fight infections. The abnormal B cells and T cells result in the frequent, life-threatening infections of Omenn syndrome. The decrease in lymphocyte function leads to a reduction in the numbers of B cells. The number of T cells is typically normal, although they are highly similar because they are derived from just a few functional precursor cells. The abnormal T cells attack the body's own cells and tissues, accounting for the autoimmune features of Omenn syndrome.

Normal Function

The RAG1 gene provides instructions for making a member of a group of proteins called the RAG complex. This complex is active in immune system cells (lymphocytes) called B cells and T cells. These cells have special proteins on their surface that recognize foreign invaders and help protect the body from infection. These proteins need to be diverse to be able to recognize a wide variety of substances. The genes from which these proteins are made contain segments known as variable (V), diversity (D), and joining (J) segments. During protein production within lymphocytes, these gene segments are rearranged in different combinations to increase variability of the resulting proteins. The RAG complex is involved in this process, which is known as V(D)J recombination.

During V(D)J recombination, the RAG complex attaches (binds) to a section of DNA called a recombination signal sequence (RSS), which is next to a V, D, or J segment. The RAG complex makes small cuts in the DNA between the segment and the RSS so the segment can be separated and moved to a different area in the gene. This process of DNA rearrangement within B cells and T cells is repeated multiple times in different areas so that the V, D, and J segments are arranged in various combinations. The variety of proteins produced throughout life following V(D)J recombination provides greater recognition of foreign invaders and allows the body to fight infection efficiently.

Health Conditions Related to Genetic Changes

Omenn syndrome

At least 70 mutations in the RAG1 gene have been found to cause an immune system disorder called Omenn syndrome. This condition is a type of severe combined immunodeficiency (SCID), which is a group of disorders characterized by an almost total lack of immune protection from foreign invaders such as bacteria, viruses, and fungi. Omenn syndrome is characterized by a reduced ability to fight infections and autoimmunity, in which the immune system attacks the body's own tissues and organs. Without treatment, Omenn syndrome is often fatal in infancy.

Most of the RAG1 gene mutations that cause Omenn syndrome change single protein building blocks (amino acids) in the RAG1 protein. These changes can impair RAG complex formation and function, including its ability to bind to DNA. As a result, V(D)J recombination is diminished and the diversity of proteins on the surface of B cells and T cell is severely limited, impairing the cells' ability to recognize foreign invaders and fight infections. The abnormal B and T cells result in the frequent, life-threatening infections of Omenn syndrome. The decrease in lymphocyte function leads to a reduction in the numbers of B cells, but the number of T cells is typically normal. The abnormal T cells attack the body's own cells and tissues, accounting for the autoimmune features of Omenn syndrome.

Other disorders

RAG1 gene mutations can cause other disorders of the immune system (immunodeficiencies). Mutations that completely eliminate the production or function of the RAG1 protein cause a form of SCID that is associated with few or no B cells and T cells. Individuals with this form of SCID have recurrent, persistent infections beginning in infancy, which are usually fatal within the first year of life.

RAG1 gene mutations that result in the production of RAG1 proteins that retain some normal function cause another form of immunodeficiency. This condition is characterized by somewhat reduced numbers of B and T cells, but affected individuals typically do not develop severe infections until late childhood. People with this form of immunodeficiency may also have areas of inflammation (granulomas) in various tissues that can cause tissue damage.

Other Names for This Gene

• MGC43321
• RAG-1
• recombination activating gene 1
• recombination activating protein 1
• RING finger protein 74
• RNF74
• V(D)J recombination-activating protein 1

Genomic Location

Normal Function

The RAG2 gene provides instructions for making a member of a group of proteins called the RAG complex. This complex is active in immune system cells (lymphocytes) called B cells and T cells. These cells have special proteins on their surface that recognize foreign invaders and help protect the body from infection. These proteins need to be diverse to be able to recognize a wide variety of substances. The genes from which these proteins are made contain segments known as variable (V), diversity (D), and joining (J) segments. During protein production within lymphocytes, these gene segments are rearranged in different combinations to increase variability of the resulting proteins. The RAG complex is involved in this process, which is known as V(D)J recombination.

During V(D)J recombination, the RAG complex attaches (binds) to a section of DNA called a recombination signal sequence (RSS), which is next to a V, D, or J segment. The RAG complex makes small cuts in the DNA between the segment and the RSS so the segment can be separated and moved to a different area in the gene. This process of DNA rearrangement within B cells and T cells is repeated multiple times in different areas so that the V, D, and J segments are arranged in various combinations. The variety of proteins produced throughout life following V(D)J recombination provides greater recognition of foreign invaders and allows the body to fight infection efficiently.

Health Conditions Related to Genetic Changes

Omenn syndrome

More than 20 mutations in the RAG2 gene have been found to cause an immune system disorder called Omenn syndrome. This condition is a type of severe combined immunodeficiency (SCID), which is a group of disorders characterized by an almost total lack of immune protection from foreign invaders such as bacteria, viruses, and fungi. Omenn syndrome is characterized by a reduced ability to fight infections and autoimmunity, in which the immune system attacks the body's own tissues and organs. Without treatment, Omenn syndrome is often fatal in infancy.

Most of the RAG2 gene mutations that cause Omenn syndrome change single protein building blocks (amino acids) in the RAG2 protein. These changes can impair RAG complex formation and function, including its ability to bind to DNA. As a result, V(D)J recombination is diminished and the diversity of proteins on the surface of B cells and T cell is severely limited, impairing the cells' ability to recognize foreign invaders and fight infections. The abnormal B and T cells result in the frequent, life-threatening infections of Omenn syndrome. The decrease in lymphocyte function leads to a reduction in the numbers of B cells, but the number of T cells is typically normal. The abnormal T cells attack the body's own cells and tissues, accounting for the autoimmune features of Omenn syndrome.

Other disorders

RAG2 gene mutations can cause other disorders of the immune system (immunodeficiencies). Mutations that completely eliminate the production or function of the RAG2 protein cause a form of SCID that is associated with few or no B cells or T cells. Individuals with this form of SCID have recurrent, persistent infections beginning in infancy, which are usually fatal within the first year of life.

RAG2 gene mutations that result in the production of RAG2 proteins that retain some normal function cause another form of immunodeficiency. This condition is characterized by somewhat reduced numbers of B and T cells, but affected individuals typically do not develop severe infections until late childhood. People with this form of immunodeficiency may also have areas of inflammation (granulomas) in various tissues that can cause tissue damage.

Other Names for This Gene

• RAG-2
• recombination activating gene 2
• V(D)J recombination-activating protein 2

Genomic Location

This condition is 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, but they typically do not show signs and symptoms of the condition.

The standard treatment for Omenn syndrome is bone marrow transplantation or cord blood stem cell transplantation. General care for any patient with severe combined immunodeficiency (SCID), including Omenn syndrome, includes isolation to prevent infection and meticulous skin and mucosal hygienic practices while the patient is awaiting stem cell reconstitution. Broad-spectrum antibiotics may be administered parenterally while cultures and body fluid analyses are in progress. Parenteral nutrition may also be provided as therapy for diarrhea and failure to thrive.

Overall, the various forms of SCID are estimated to affect 1 in 75,000 to 100,000 newborns. The exact prevalence of Omenn syndrome is unknown.