Immunodeficiency Congenital

Congenital immunodeficiency disorders are a group of inherited conditions where the immune system doesn’t work properly from birth, making it harder for the body to fight off infections and other health challenges.

Table of contents

• What is congenital immunodeficiency?
• Causes and inheritance
• Signs and symptoms
• Types of congenital immunodeficiency
• Diagnosis
• Complications
• Treatment options
• Prevention and management

What is congenital immunodeficiency?

primary immunodeficiency, primary immune disorders, primary immunodeficiency diseases, inborn errors of immunity

Congenital immunodeficiency, also known as primary immunodeficiency, refers to a group of inherited disorders where the immune system fails to work correctly from birth^[2]. These conditions are genetically determined, meaning they are caused by changes in genes that happen before a person is born^[3].

When the immune system doesn’t work properly, the body has difficulty fighting off germs like bacteria, viruses, and fungi that can cause infections. This makes people with congenital immunodeficiency more likely to get sick and to experience more serious complications from infections than others^[4].

There are more than 400 different types of congenital immunodeficiency disorders, involving changes in more than 430 genes^[11]. Some forms are mild and may not be noticed until adulthood, while others are severe and discovered soon after a baby is born^[2][6].

Around 1 in 2,000 people in America have a primary immunodeficiency disorder, though the actual number may be higher^[4]. These disorders can range from mild to life-threatening^[4].

Causes and inheritance

Congenital immunodeficiency disorders are caused by genetic changes that prevent the immune system from developing and working correctly^[4]. These genetic mistakes, called mutations, affect proteins necessary for the normal functioning of the immune system^[3].

The genetic changes that cause these conditions happen before birth, and you cannot control them. Which genes are changed will determine which specific disorder develops^[4]. The immune system may be less active than it should be, missing certain cells, or completely absent^[4].

Because these disorders are inherited, they often run in families. This means if your biological parents or siblings have a congenital immunodeficiency, you may be more likely to have one too^[4][6]. These disorders are more common in males^[4].

Knowing your family medical history is important. If someone in your family has been diagnosed with a congenital immunodeficiency, sharing this information with your healthcare provider can be crucial for your health and your children’s health, especially if you are pregnant or planning a pregnancy^[6].

Signs and symptoms

The most common sign of congenital immunodeficiency is getting infections more frequently than usual^[2][4]. People with these disorders catch infections more easily and may experience more severe symptoms or complications when they do get sick^[4].

Symptoms differ depending on the specific type of disorder and vary from person to person^[2]. Common symptoms include^[2][6]:

• Getting infections often, including pneumonia, bronchitis, sinus infections, ear infections, meningitis, or skin infections
• Infections that last longer than usual
• Infections that are harder to treat and don’t respond well to antibiotics
• Infections that are more severe and require hospitalization
• Infections that most people don’t get, called opportunistic infections
• Infections that go away and come back, even after treatment

Other symptoms can include^[2][4]:

• Inflammation and infection of internal organs
• Blood disorders, such as low platelet count or anemia (low red blood cell count)
• Digestive problems, including cramping, loss of appetite, nausea, and chronic diarrhea
• Delayed growth and development in children
• Enlarged spleen or swollen lymph nodes
• Unexplained weight loss or poor growth

Most people with congenital immunodeficiency experience symptoms before turning 20, but they can develop at any point in life^[4]. Some severe types are discovered soon after birth, while milder forms may not be noticed until adulthood^[3].

Types of congenital immunodeficiency

Congenital immunodeficiency disorders are classified based on which component of the immune system is deficient, absent, or defective^[3]. The main categories include disorders affecting B-cells (cells that produce antibodies), T-cells (cells that identify and attack invaders), or both^[3].

Some specific types of congenital immunodeficiency include^[3][4]:

• X-linked (Bruton) agammaglobulinemia: A condition where there is a complete deficiency of mature B-cells, leading to low levels of all classes of immunoglobulins (antibodies)
• Selective IgA deficiency: The most common primary immunodeficiency, where there are low levels of a specific type of antibody called IgA
• Common variable immunodeficiency (CVID): A condition where B-cells cannot properly differentiate into cells that produce antibodies, resulting in low levels of multiple types of immunoglobulins
• DiGeorge syndrome: A disorder caused by a genetic deletion that affects T-cell development and other body systems
• Severe combined immunodeficiency (SCID): One of the most severe types, where there is a combined absence of both T-cell and B-cell function
• Chronic granulomatous disease (CGD): A disorder affecting cells that fight infections
• Wiskott-Aldrich syndrome: A condition affecting multiple immune system components

Severe combined immunodeficiency (SCID) is particularly serious and life-threatening. Babies born with SCID lack functional T-cells, and because T-cells help B-cells produce antibodies, these children essentially lack a functional immune system^[7]. Without treatment, children with SCID typically do not survive past two years of age. However, if diagnosed and treated within the first few months of life before serious infections develop, their long-term survival rate is more than 90%^[7].

There are at least 20 different genetic variants that can cause SCID. The most common type is caused by a problem in a gene found on the X chromosome and affects only males^[3][7].

Diagnosis

Diagnosing congenital immunodeficiency requires specialized knowledge and experience. A healthcare provider will make a diagnosis based on your medical history, family history, physical examination, and various tests^[4][9].

If you have a history of repeated or unusual infections, your provider may refer you to a clinical immunologist, a healthcare provider who specializes in the immune system^[6].

Common diagnostic tests include^[3][9]:

• Blood tests: These can measure levels of infection-fighting proteins called immunoglobulins, count different types of blood cells and immune system cells, and assess whether the immune system is responding properly
• Differential white blood cell count: Determines the types and numbers of white blood cells present
• Absolute lymphocyte count: Measures the number of lymphocytes (a type of white blood cell)
• Quantitative immunoglobulin measurements: Measures levels of different types of antibodies
• Antibody titer tests: Checks whether your immune system produces antibodies in response to vaccines or infections

All states in the United States now include testing for severe combined immunodeficiency (SCID) as part of newborn screening^[6][7]. This simple blood test can show if a baby has a low number of T-cells, a sign that the baby may have SCID. Thanks to newborn screening, most babies with SCID are diagnosed before they develop health problems^[7].

For families with a previously affected child, prenatal testing can be performed before the baby is born if the genetic variant responsible for the condition has been identified^[7][9].

Complications

People with congenital immunodeficiency face several potential complications beyond frequent infections. They are more likely to develop autoimmune disorders, conditions where the immune system mistakenly attacks the body’s own tissues^[2][6].

People with these disorders also have an increased risk of certain blood disorders and cancers. Because the immune system normally protects the body against cancer, a weakened immune system increases the likelihood of developing certain types of cancer^[6].

If left untreated, some types of congenital immunodeficiency can result in serious health problems, including permanent organ damage and death^[6]. Chronic infections can lead to complications such as bronchiectasis (permanent damage to the airways)^[3].

Living with congenital immunodeficiency can also impact mental health. The stress of managing frequent infections, the unpredictability of the condition, chronic fatigue, fear of infection, and social isolation can all contribute to anxiety and depression^[26].

Treatment options

Treatments for congenital immunodeficiency aim to prevent and treat infections, boost the immune system, and in some cases, treat the underlying cause of the disorder^[9][11].

Managing infections is a key part of treatment. This includes^[9][11]:

• Fast and aggressive treatment with antibiotics when infections occur
• Prophylactic antibiotics (antibiotics taken regularly to prevent infections)
• Anti-fungal and anti-viral medications when needed

Immunoglobulin replacement therapy is one of the main treatments for people with severe antibody deficiency. This treatment provides the antibodies that the body cannot make on its own, helping to prevent infections^[11][12]. In 2020-2021, over 7,000 people with immunodeficiency in the UK were prescribed immunoglobulin therapy^[18].

For some of the most serious congenital immunodeficiency disorders, curative treatments are available^[11]:

Hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant, can completely cure some types of congenital immunodeficiency by replacing the defective immune system with a healthy one^[11][12]. This treatment is especially important for severe combined immunodeficiency. Advances in HSCT management over recent decades have improved survival rates with less toxicity and fewer complications^[15].

Gene therapy is a newer treatment option that is currently being tested in clinical trials for several types of congenital immunodeficiency. It offers an alternative to stem cell transplantation when a suitable donor is not available^[11][12]. Gene therapy involves correcting the genetic defect that causes the immune deficiency.

Some congenital immunodeficiencies can be managed with specific medications targeted at the affected immune pathway, particularly for autoimmune or autoinflammatory processes associated with the condition^[11].

Prevention and management

Early diagnosis is crucial and can help prevent or delay many of the health problems caused by congenital immunodeficiency^[6]. Even with treatment, most types do not have a cure, so ongoing management is essential^[6].

Taking steps to prevent infection is very important if you have congenital immunodeficiency. These steps include^[6][20]:

• Washing your hands properly for 20 seconds with soap and water
• Using hand sanitizer and bacterial wipes between handwashing
• Avoiding touching your eyes, nose, and mouth
• Taking good care of your teeth and keeping up with dental visits
• Maintaining healthy habits, including being physically active, eating healthy, and getting enough sleep
• Avoiding crowds and exposure to people who are sick
• Wearing a mask in certain situations
• Showering and bathing regularly

It’s important to talk to your healthcare provider about which vaccinations are safe for you. In some cases, people with congenital immunodeficiency cannot receive live vaccines such as rotavirus, chickenpox, oral polio, and measles, mumps, rubella^[6]. Newborn screening for SCID helps identify babies with this condition early, before they receive these vaccines^[6].

If you need to travel, proper planning and precautions can help you travel safely. This is important because traveling can increase the risk of exposure to infections^[19].

Living with congenital immunodeficiency can be challenging, but with the right support and resources, many people with these disorders lead full and active lives^[19]. It’s important to seek support for your mental health, as the stress and isolation of living with a chronic condition can take a toll on emotional well-being^[26].