Activated PI3 Kinase Delta Syndrome

Activated PI3 kinase delta syndrome is a rare inherited immune disorder that leaves people vulnerable to repeated infections and other serious health problems. First identified in 2013, this condition affects the immune system’s ability to fight bacteria and viruses, often leading to a complex pattern of symptoms that can vary widely from one person to another.

Table of contents

• Disease Identification and Classification
• What Is Activated PI3 Kinase Delta Syndrome?
• Genetic Causes and Inheritance
• Common Symptoms and Health Problems
• Diagnosis and Testing
• Treatment Options

Disease Identification and Classification

APDS, PASLI, p110δ-Activating Mutation Causing Senescent T Cells, Lymphadenopathy, and Immunodeficiency Disease, Activated Phosphoinositide 3-Kinase Delta Syndrome, PI3K Disease, Senescent T-cells-lymphadenopathy-immunodeficiency syndrome due to p110delta-activating mutation, Activated p110-delta syndrome

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D81.8

What Is Activated PI3 Kinase Delta Syndrome?

Activated PI3 kinase delta syndrome, often called APDS, is a disorder that weakens the immune system^[1]. The condition was first discovered in 2013 and is considered rare, though the exact number of people affected worldwide is unknown^[2]. Approximately 30 to 40 people in the United Kingdom are known to have the condition^[15].

People with APDS often have low numbers of white blood cells, particularly B cells and T cells, which are types of immune cells that normally recognize and attack bacteria and viruses to prevent infection^[2]. The severity of the condition varies widely. Some people may experience multiple severe infections while others show mild symptoms or none at all^[2].

Before APDS was identified, patients were sometimes given other diagnoses, such as Common Variable Immunodeficiency (CVID) or another antibody deficiency^[1]. Distinguishing between different immune disorders is often difficult because of the wide variety of symptoms patients experience^[1].

Genetic Causes and Inheritance

APDS is caused by changes, called variants or mutations, in genes that control an important enzyme called phosphatidylinositol 3-kinase delta (PI3K delta)^[2]. This enzyme is found in white blood cells and plays a vital role in helping these cells grow, divide, and mature into different types that each have distinct functions in the immune system^[2].

There are two types of APDS, each caused by changes in different genes. APDS type 1 (APDS1) is caused by variants in the PIK3CD gene, which provides instructions for making a protein called p110 delta^[2]. APDS type 2 (APDS2) is caused by variants in the PIK3R1 gene, which provides instructions for making a protein called p85 alpha^[2]. Both proteins are pieces of the PI3K delta enzyme^[2].

The genetic changes that cause APDS are classified as gain-of-function variants because they make the PI3K delta enzyme overactive—it is turned on too frequently^[2]. This overactivity disrupts the normal development and function of B cells and T cells, producing immune cells that cannot respond properly to infections and that die earlier than usual^[2].

APDS follows an autosomal dominant inheritance pattern, which means the condition can be inherited from just one affected parent^[10]. However, some cases develop due to a new genetic change that was not inherited from either parent, called a de novo variant^[14]. Because APDS is inherited, family members of a confirmed patient should be genetically tested, even if they do not have symptoms, as they may still carry the genetic variant and pass it on to their children^[1].

Common Symptoms and Health Problems

APDS is characterized by a spectrum of health problems involving the immune system. The most common symptoms include increased susceptibility to infections, abnormal growth of immune tissue, autoimmune problems, and an increased risk of certain cancers^[3].

The most common and often earliest reported symptoms of APDS are frequent and severe infections of the ears, sinuses, and upper and lower respiratory tracts^[1]. These infections typically begin in childhood, particularly in the lungs, sinuses, and ears^[2]. Studies show that between 96% and 100% of people with APDS experience these recurring respiratory infections^[14]. Over time, repeated respiratory tract infections can lead to a condition called bronchiectasis, which damages the airways leading from the windpipe to the lungs and can cause breathing problems^[2].

People with APDS may also have chronic active viral infections. These can include Epstein-Barr virus, herpes simplex virus, or cytomegalovirus infections^[2]. Herpes infections are commonly reported among patients with the condition^[1].

Another possible feature of APDS is abnormal clumping of white blood cells. These clumps can lead to enlarged lymph nodes, a condition called lymphadenopathy, or an enlarged spleen, known as splenomegaly^[2]. White blood cells can also build up to form solid masses called nodular lymphoid hyperplasia, usually in the moist lining of the airways or intestines^[2]. While nodular lymphoid hyperplasia is not cancerous, APDS increases the risk of developing blood cancers called Hodgkin lymphoma and non-Hodgkin lymphoma^[2].

Some people with APDS develop autoimmunity, which occurs when the body attacks its own tissues and organs by mistake^[2]. Autoimmune problems can include autoimmune cytopenias (low numbers of blood cells), juvenile arthritis, glomerulonephritis, and sclerosing cholangitis^[5].

Gastrointestinal problems are also common, including digestive tract issues that can resemble Crohn-like colitis and a condition called intussusception^[3]. Other reported symptoms include chronic cough, enlarged tonsils, developmental delays, and short stature or growth delays^[1][3]. The key clinical differences between APDS type 1 and APDS type 2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2^[3].

Diagnosis and Testing

Making a correct diagnosis of APDS is crucial and can change the course of treatment and outcomes for patients^[1]. Genetic testing is the only way to definitively diagnose APDS^[1]. The clinical diagnosis can be established based on suggestive symptoms, or the molecular diagnosis can be confirmed by finding a pathogenic variant in either the PIK3CD gene (for APDS1) or PIK3R1 gene (for APDS2) through molecular genetic testing^[3].

Before genetic testing confirms APDS, doctors may find atypical levels of immunoglobulins (antibodies) in laboratory tests^[4]. Immunophenotyping may show variable degrees of low antibody levels with increased IgM levels, increased circulating transitional B cells, and decreased naïve CD4 and CD8 T-cells with increased CD8 effector/memory T cells^[5].

It is vital that patients take note of their symptoms and their frequency and share this information with their doctor^[1]. The first step in managing APDS is recognizing it, as symptoms can be progressive and lead to damage to organs over time^[10]. Patients with two or more symptoms consistent with APDS are excellent candidates for genetic testing^[10].

Treatment Options

Treatment of APDS varies considerably depending on the severity of symptoms, ranging from simple observation to more intensive interventions^[6]. Current treatment options include conventional therapies to support the immune system, targeted medications that address the root cause, and in severe cases, stem cell transplantation.

Targeted Therapies

Leniolisib (brand name Joenja) is a selective PI3K delta inhibitor that was approved for medical use in the United States in March 2023^[4]. It is the first approved drug in the United States specifically for activated PI3K delta syndrome^[4]. Leniolisib has shown promise in clinical trials by directly targeting the overactive PI3K delta signaling pathway, which is the hallmark of the condition^[3]. It is recommended as a first-line treatment for significant lymphoproliferative disease, including lymphadenopathy and splenomegaly^[3]. The medication is approved for patients aged 12 and older^[1].

Sirolimus, an inhibitor of a protein pathway called mTOR (mammalian target of rapamycin), is recommended for individuals with lymphoproliferative disease or enlarged organs when leniolisib is unavailable^[3]. It is used off-label due to its immunosuppressive and antiproliferative properties^[3].

Supportive Care

Regular immunoglobulin replacement therapy, given either intravenously or subcutaneously, is used to prevent recurrent bacterial infections and improve immune function^[3]. This is one of the conventional treatments for immunodeficiency^[6].

Long-term prophylactic antibiotics can be considered to reduce the frequency of bacterial infections^[3]. Bacterial infections should be treated rapidly with antibiotics^[4]. Individuals with recurrent herpes simplex or herpes zoster virus can receive prophylactic antiviral medications such as acyclovir or valganciclovir^[3].

Glucocorticoids may be used for acute management of certain symptoms^[3]. Lifestyle modifications, including minimizing exposure to infectious agents, are also recommended^[4].

Hematopoietic Stem Cell Transplantation

Allogenic hematopoietic stem cell transplant (HSCT) is reserved for individuals with severe or treatment-refractory APDS^[3]. This option is considered for patients with progressive organ damage, recurrent infections that do not respond to treatment, or severe immune dysregulation that does not respond to pharmacologic therapy^[3]. HSCT has been used in childhood for patients with profound immunodeficiency or those suffering from lymphoproliferation and malignancy^[6].