Activated PI3K-delta syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Activated PI3K-delta syndrome (also known as APDS) is a disorder that impairs the immune system. Individuals with this condition often have low numbers of white blood cells (lymphopenia), particularly B cells and T cells. Normally, these cells recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The severity of activated PI3K-delta syndrome varies widely. Some people may have multiple, severe infections while others show mild symptoms to none at all.

Most commonly, people with activated PI3K-delta syndrome develop recurrent infections that begin in childhood, particularly in the lungs, sinuses, and ears. Over time, recurrent respiratory tract infections can lead to a condition called bronchiectasis, which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. People with activated PI3K-delta syndrome may also have chronic active viral infections, such as Epstein-Barr virus, herpes simplex virus, or cytomegalovirus infections.

Another possible feature of activated PI3K-delta syndrome is abnormal clumping of white blood cells. These clumps can lead to enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly). The white blood cells can also build up to form solid masses (nodular lymphoid hyperplasia), usually in the moist lining of the airways or intestines. While nodular lymphoid hyperplasia is not cancerous (benign), activated PI3K-delta syndrome increases the risk of developing forms of blood cancer called Hodgkin lymphoma and non-Hodgkin lymphoma.

Some people with activated PI3K-delta syndrome develop autoimmunity, which occurs when the body attacks its own tissues and organs by mistake.

There are two types of activated PI3K-delta syndrome, each with different genetic causes.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Activated PI3K-delta syndrome is caused by variants (also called mutations) in the PIK3CD gene and the PIK3R1 gene. Activated PI3K-delta syndrome type 1 is caused by variants in the PIK3CD gene, which provides instructions for making a protein called p110 delta (p110δ). Activated PI3K-delta syndrome type 2 is caused by variants in the PIK3R1 gene. This gene provides instructions for making slightly different versions of another protein; the most common version is called p85 alpha (p85α).

Both p110δ and p85α are pieces (subunits) of an enzyme called phosphatidylinositol 3-kinase (PI3K), which turns on signaling pathways within cells. The version of PI3K that contains the p110δ and p85α subunits is called PI3K delta. PI3K delta is found in white blood cells, including B cells and T cells. PI3K-delta signaling is involved in the growth and division (proliferation) of white blood cells, and it helps direct B cells and T cells to mature (differentiate) into different types, each of which has a distinct function in the immune system.

The PIK3CD gene variants that cause activated PI3K-delta syndrome lead to the production of an altered p110δ protein. PIK3R1 gene variants lead to an altered p85α protein, sometimes causing it to be abnormally short. These variants are classified as gain-of-function variants because a PI3K-delta enzyme that contains either of the altered subunits is frequently turned on (overactive).

Studies indicate that overactive PI3K-delta signaling alters the differentiation of B cells and T cells, producing cells that cannot respond to infections and that die earlier than usual. The lack of functioning B cells and T cells makes it difficult for people with activated PI3K-delta syndrome to fight off bacterial and viral infections. Overactive PI3K-delta signaling can also stimulate the abnormal proliferation of white blood cells, leading to lymphadenopathy and nodular lymphoid hyperplasia in some affected individuals. An increase in B cell proliferation in combination with reduced immune system function may contribute to the development of lymphoma in people with activated PI3K-delta syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Activated PI3K-delta syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Activated PI3K-delta syndrome is considered a rare disorder, but its exact prevalence is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Pneumonia · Very frequent (99-80%)

Inflammation of any part of the lung parenchyma.

Recurrent upper and lower respiratory tract infections · Very frequent (99-80%)

Increased susceptibility to upper and lower respiratory tract infections as manifested by recurrent episodes of upper and lower respiratory tract infections.

Autoimmunity · Frequent (79-30%)

The occurrence of an immune reaction against the organism's own cells or tissues.

Bronchiectasis · Frequent (79-30%)

Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.

Chronic sinusitis · Frequent (79-30%)

A chronic form of sinusitis.

Decreased circulating antibody level · Frequent (79-30%)

An abnormally decreased level of immunoglobulin in blood.

Decreased total B cell count · Frequent (79-30%)

The absolute number of B cells in the blood, per microlitre is below the lower limit of normal of the reference range for the appropriate sex and age-group.

Hepatomegaly · Frequent (79-30%)

Abnormally increased size of the liver.

Other findings in the same source

From: Orphanet

Additional reported features include Increased circulating IgM level (Frequent (79-30%)); Intestinal lymphoid nodular hyperplasia (Frequent (79-30%)); Lymphadenopathy (Frequent (79-30%)); Recurrent otitis media (Frequent (79-30%)); Splenomegaly (Frequent (79-30%)); Abnormal intestine morphology (Occasional (29-5%)); Arthritis (Occasional (29-5%)); Failure to thrive (Occasional (29-5%)); Hearing impairment (Occasional (29-5%)); Lymphoma (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Activated PI3K-delta syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Activated PI3K-delta syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.