PIK3CD gain-of-function disorder is a rare genetic disorder of the immune system. The disease is named after the genetic mutations that cause it. Sometimes, PIK3CD gain-of-function is abbreviated PIK3CD GOF or simply referred to as PIK3CD. This disorder also is sometimes called PASLI, which stands for p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency, or APS, which stands for activated PI3K syndrome.

People with this disorder have a weakened immune system, which puts them at risk for frequent infections starting in childhood. These include bacterial infections of the respiratory system and chronic viral infections such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV). People with PIK3CD disorder also have an increased risk of lymphoma, a type of cancer.

PIK3CD disorder is caused by “gain of-function” mutations in the gene PIK3CD. This gene produces a protein called p110 delta. These gain-of function mutations cause the p110 delta protein to become overactive. PIK3CD is turned on mainly in white blood cells and plays an important role in the immune system. Mutations in PIK3CD appear to affect the immune system by overactivating an important immune system signaling pathway. This leads to disruptions in the normal development of immune T cells, causing too many naïve T cells to become effector cells. These effector cells undergo a burst of proliferation and then become senescent, which means they stop growing and dividing. This results in lowered production of memory cells, increasing a person’s susceptibility to infection. Less frequently, mutations in other related genes cause similar versions of this disorder.

Normal Function

The PIK3CD gene provides instructions for making the p110 delta (p110δ) protein, which is one piece (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The version of PI3K that contains the p110δ subunit, called PI3K delta, is found in white blood cells, including immune system cells (lymphocytes) called B cells and T cells. These cells recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection.

PI3K delta functions as a kinase, which means that it adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K delta phosphorylates certain signaling molecules, which triggers a series of additional reactions that transmit chemical signals within cells. In lymphocytes, PI3K delta signaling is important for many cell activities, including cell growth and division (proliferation) and maturation (differentiation). PI3K delta helps direct B cells and T cells to differentiate into different types, each of which has a distinct function in the immune system.

Health Conditions Related to Genetic Changes

Activated PI3K-delta syndrome

Variants (also called mutations) in the PIK3CD gene have been found to cause an immune disorder called activated PI3K-delta syndrome. PIK3CD gene variants cause a form of the condition called activated PI3K-delta syndrome type 1. People with activated PI3K-delta syndrome type 1 typically have recurrent bacterial infections of the respiratory tract and chronic viral infections.

The PIK3CD gene variants that cause activated PI3K-delta syndrome type 1 change single protein building blocks (amino acids) in the p110δ protein. These variants are classified as gain-of-function variants because a PI3K-delta enzyme that contains the altered subunit is frequently turned on (overactive). Studies indicate that this overactive signaling causes T cells to mature and die too quickly. The excess signaling also blocks maturation of B cells at an early stage; the immature B cells cannot respond to foreign invaders and likely self-destruct. The lack of T cells and B cells makes it difficult for people with this disorder to fight off bacterial and viral infections. Overactive of PI3K-delta signaling can also stimulate the abnormal proliferation of lymphocytes, and accumulation of these cells can lead to enlarged lymph nodes (lymphadenopathy). Activated PI3K-delta syndrome type 1 is also associated with an increased risk of developing a form of blood cell cancer called lymphoma.

Autoimmune lymphoproliferative syndrome

MedlinePlus Genetics provides information about Autoimmune lymphoproliferative syndrome

Other Names for This Gene

• p110D
• P110DELTA
• phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit delta
• phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta
• phosphoinositide-3-kinase C
• PI3-kinase p110 subunit delta

Genomic Location

PIK3CD disorder is inherited in an autosomal dominant manner, which means that a person needs an abnormal gene from only one parent to have PIK3CD disorder. The abnormal PIK3CD gene dominates the normal PIK3CD gene from the other parent. Dominant inheritance also means that most families with PIK3CD disorder have affected relatives in each generation on the side of the family with the mutation. Importantly, however, not all people with the mutation have severe disease.

Unlike mutations that run in a family, some mutations occur as a result of a mutation in the egg or sperm of one of the parents or in the fertilized egg itself. These are called de novo, which means “new” mutations. In these cases, the patient does not have a family history of similar symptoms. De novo mutations can be passed on to children.

Children of a parent who carries a PIK3CD mutation have a 50 percent chance of inheriting the mutation. This means that, within a given family, each child’s risk of inheriting the mutated PIK3CD gene is independent of whether or not siblings have the mutation. For example, if the first three children in a family have the mutation, the fourth child has the same 50 percent risk of inheriting the mutation. Children who do not inherit the abnormal gene will not develop PIK3CD disorder or pass on the mutation.

PIK3CD disorder ranges in severity and can cause many different symptoms. Most of these symptoms can be successfully treated. PIK3CD disorder is characterized by recurrent respiratory infections, which can lead to progressive airway damage. People with PIK3CD disorder also may experience the following:

• Lymphoproliferation, or the buildup of immune cells called lymphocytes. This leads to enlarged lymph nodes and an enlarged spleen.
• Chronic viremia, or high levels of viruses such as EBV and CMV in the blood.
• Distinctive lymphoid nodules—small collections of lymph tissue—on mucosal surfaces such as the airways or gastrointestinal tract.
• Cytopenias, or reductions in the number of blood cells. Autoimmune cytopenias occur when the immune system attacks and destroys the body’s blood cells. Cytopenias can cause fatigue, increased risk of bleeding, and slow wound healing.
• EBV-driven B-cell lymphoma, a type of cancer associated with EBV infection.

Importantly, the severity of PIK3CD disorder varies. Some people with PIK3CD disorder have many medical problems, whereas others experience minimal symptoms. Some adults with the mutation may outgrow the symptoms that caused them problems as a child. This variation, called variable expressivity, can be striking, even within the same family. It may be explained by differences in lifestyle, exposures, treatments, or other genes.

The clinical symptoms of PIK3CD disorder are caused by immune system abnormalities. These include too few of some immune cell types and too many of other types. For example, people with PIK3CD disorder typically have too few of a type of memory cells and too many transitional B cells, effector T cells, and old T cells. Many patients also have differences in their immunoglobulin, or antibody, concentrations. For example, most have slightly elevated levels of the IgM subtype and reduced IgA.

Once a diagnosis is made, treatment for PIK3CD disorder is based on a person’s clinical condition. Researchers have had some success treating PIK3CD disorder with medications that inhibit the immune system pathway that is overactivated in people with the disease. In early studies, this strategy reduced swelling of the lymph nodes (lymphadenopathy), most likely by restoring the normal balance of naïve, effector, and memory cells in the patients’ immune systems. More research is needed to determine the most effective timing and dosage of this medication and to investigate other treatment options.

Living with PIK3CD disorder can be difficult not only for the person who has it but also for their family members. It is important for families to talk openly about PIK3CD disorder and about how the family is dealing with it so misconceptions can be identified and corrected and children can learn to identify and cope with their reactions.

Some children with PIK3CD disorder have to work hard to develop their self-confidence and sense of security. Children need to be reminded that they have many positive characteristics, especially when their appearance attracts attention (for example, because of enlarged lymph nodes in the neck). Some children who have siblings with PIK3CD disorder 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. Counseling also can help families cope with the challenges of PIK3CD disorder.

At the same time, many families say that PIK3CD disorder has brought them closer together. Through this disease, family members learn about controllable and uncontrollable aspects of life.