X-Linked Immunodeficiency

What is X-Linked Immunodeficiency?

Primary immunodeficiencies (PID) are a collection of mostly inherited disorders, resulting from more than 400 different problems with the immune system. People with these conditions often experience regular and recurring infections as well as other symptoms such as autoimmunity, which is when the body’s immune system attacks its own cells, lymphoproliferation, an increased number of white blood cells, granulomas, small areas of inflammation, chronic lung diseases, and a higher risk of cancer.

There are seven types of immune system conditions that are passed down through the X chromosome – a type of gene that both males and females have. These are X-linked chronic granulomatous disease (X-CGD), X-linked immunodeficiency with hyper-IgM, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, X-linked severe combined immunodeficiency (X-SCID), X-linked agammaglobulinemia (XLA), and IPEX (immune deficiency, polyendocrinopathy, enteropathy, and X-linked expressions).

Even though these conditions are rare, they are associated with serious infections and can increase the risk of illness and death from an early age. This is because they cause a deficiency in cellular and/or humoral immunity, which means the body has a hard time fighting off harmful invaders like bacteria and viruses. Finding these genetic defects in the X chromosome can help identify people who carry these conditions. However, it can be really hard to identify these carriers if there’s no known family history of these conditions.

What Causes X-Linked Immunodeficiency?

Chronic granulomatous disease (CGD) is a condition inherited from your parents that can lead to serious bacterial and fungal infections. It can also cause small areas of inflammation throughout the body, known as granuloma formation.

Hyper immunoglobulin M syndrome is a wide-ranging condition caused by a defect in the process of class switch recombination (a process your body undertakes to create the best antibodies to fight infection). People with this syndrome often have normal or high levels of IgM (a type of antibody), but low levels of IgG and IgA (other types of antibodies). The most common form of the disease is linked to the X chromosome and is caused by a mutation in a specific gene (the CD40LG gene).

X-linked lymphoproliferative syndrome is generally characterized by an abnormal response of the immune system to the Epstein Barr virus – a common virus that most people get at some point in their lives. This disease can present with a condition called dysgammaglobulinemia (an abnormal amount of immunoglobulins), as well as lymphoma (a type of cancer) and severe mononucleosis (an infection caused by the Epstein-Barr virus).

The Wiskott-Aldrich syndrome is a disorder that people can inherit through the X chromosome, caused by a mutation in the gene that creates the Wiskott-Aldrich syndrome protein (WASp). People with this condition are prone to infections, a drop in the number of small platelets (causing microthrombocytopenia) which help with blood clotting, and eczema, a skin condition.

X-linked severe combined immunodeficiency (X-SCID) is a severe inherited immune system disorder. It involves a defect in a specific protein, causing life-threatening symptoms within the first two years of life if it is not treated.

X-linked agammaglobulinemia (XLA) is an inherited immune system disorder. This condition leads to a significant decrease in the number of antibodies (proteins that help the body to fight infections), a deficiency of antibodies, and an increased susceptibility to infections. Most commonly, boys from 3-18 months show symptoms of XLA. XLA is associated with a defect or absence of a specific protein, known as Bruton tyrosine kinase (BTK).

Lastly, IPEX stands for immune deficiency, polyendocrinopathy, enteropathy, and X-linked expressions. It’s a rare but fatal disorder linked to the X chromosome.

Risk Factors and Frequency for X-Linked Immunodeficiency

X-linked CGD is a disease that affects about 1 in 200,000 newborns. Since over half the mutations related to it are carried on the X chromosome, it’s more likely to affect males. Though the disease can occur at any age from infancy to late adolescence, most diagnoses occur in children under 5 years of age.

Hyper IgM syndrome is another disease that affects males. The symptoms usually start to show when a child is about one year old, with most presenting symptoms by the age of four.

XLP, a disease that affects between 1 to 3 in a million male births, can present clinical symptoms at an average age of 2.5. While this is the estimated number, the reality is likely higher as some conditions with similar symptoms are not considered XLP.

Wiskott-Aldrich syndrome (WAS) is a rare disease usually affecting males due to its X-linked nature. Its prevalence is estimated at one in 100,000 live births.

X-SCID is recognized as the most common form of severe combined immunodeficiency (SCID).

The incidence and prevalence of XLA disease are hard to estimate without population-wide screenings. But, based on United States registry system data, it’s approximated as 1 in every 190,000 male births.

The prevalence and incidence of IPEX disease remain fairly undetermined. However, hindsight analyses indicate that this disease has likely been diagnosed and reported less frequently than expected.

Signs and Symptoms of X-Linked Immunodeficiency

X-linked Chronic Granulomatous Disease (CGD) often results in infections caused by certain types of microorganisms. These infections often appear in the lungs, skin, lymph nodes, and liver. Additionally, complications like formation of granulomas can cause issues in the lungs, gastrointestinal tract, and urinary system. Symptoms may include enlarged liver, spleen, and abnormal growth of lymph nodes. About 30% to 40% of patients with CGD can experience inflammation of the colon.

X-linked Hyper IgM syndrome’s effects can differ based on the exact genetic defect. This condition disrupts the function of the immune system cells leading to frequent and recurrent infections including serious lung infections. Patients may also experience increased risks of certain types of cancer including liver cancer and lymphoma.

The most common signs of X-linked Lymphoproliferative (XLP) disease include severe mononucleosis, lowered levels of certain antibodies, and abnormal growth of cells in the immune system. Patients typically show abnormal immune responses during certain infections, though their immune cell counts are often normal or raised.

If there are mutations in the Wiskott-Aldrich Syndrome (WAS) gene, the symptoms may vary and are typically not fully established until a child is over 2 years old. Classic WAS symptoms include bleeding disorders due to low platelet counts, recurrent infections, eczema, enlarged lymph nodes, and the spleen. Patients with WAS are also prone to autoimmune complications and cancer, which can result in early death.

X-linked Severe Combined Immunodeficiency (X-SCID) often results in recurrent infections, chronic diarrhea, oral thrush, ear infections, and slow growth during the first year of life. Diagnosis involves looking for the lack of certain immune system cells. Another name for this phenotype is T-B+NK-, which is mainly characterized by low or absent T-cells, dysfunctional B-cells, and fewer or even absent Natural Killer (NK) cells.

The primary physical symptom unique to X-linked Agammaglobulinemia (XLA) is the absence of secondary lymphoid tissues rich in B cells such as the tonsils and adenoids. Although diagnosis often happens early due to family history of the disease, many patients experience recurrent infections. The initial symptoms might not appear for the first few months due to the mother transferring immunity to the newborn.

For Immunodysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) syndrome in male patients, the symptoms are autoimmune-induced chronic diarrhea, endocrine disorders like neonatal type I diabetes or thyroiditis, severe skin inflammation, stunted growth, and food allergies. Some patients may also experience reduced blood cell count due to autoimmune reactions.

Testing for X-Linked Immunodeficiency

In X-linked CGD, a specific type of inherited disorder that affects the immune system, lab tests often show increased inflammation indicators. These include increased sedimentation rate, C-reactive protein, and hypergammaglobulinemia (an unusually high level of immune system components). Patients with gastrointestinal issues may also experience anemia (low red blood cell count) and low albumin (a protein made by the liver) due to chronic disease. Testing also often shows reduced memory B cell (a type of immune cell) and CD4 (+) T cells (a type of white blood cell).

For male patients who often have infections, especially abscesses and infections with certain types of pathogens, X-linked CGD could be the cause. In these cases, patients should be screened for neutrophil function, which is a type of white blood cell that fights off infection. If a problem is identified in the neutrophil function test, more specific and prompt testing is required. Additionally, for families with a history of CGD, it is very important to identify potential patients quickly with prenatal or neonatal screening programs.

Hyper IgM syndromes, a group of hereditary immunodeficiency disorders, are characterized by decreased levels of certain types of antibodies (IgG, IgM, and IgE). However, IgM levels can either be normal or high. Often, B-cell count is normal while memory B-cell count is low. In patients showing the right symptoms and with low levels of IgG and IgA, or elevated levels of IgM, Hyper IgM syndrome should be suspected and a test to identify genetic mutations should be done for diagnosis.

Wiskott-Aldrich syndrome (WAS), a rare X-linked recessive disease, often displays reduced T-cell count and function, response to vaccines, and abnormal immunoglobulin types. It should be suspected in male children with symptoms like small red spots on the skin (petechiae), skin discoloration due to bleeding (ecchymosis), and early-onset low platelets (thrombocytopenia). To confirm the diagnosis, a deletion mutation in the WAS gene must be shown.

X-SCID, a severe genetic disorder, should be suspected in all male patients exhibiting a certain pattern of immune markers. The diagnosis can be confirmed by identifying a certain mutation through next-generation sequencing.

In XLA, an immune system disorder, tests often show low immunoglobulins (proteins that function as antibodies) or none at all, insufficient response to vaccines, and low or zero B cell count. To confirm such a diagnosis, mature B-cell rate must be below 2% and no immune cells should be seen in various body tissues.

In IPEX, a rare autoimmune disorder, it should be suspected in all male patients showing symptoms such as persistent diarrhea, growth issues, and/or infant-type diabetes. Other signs like skin inflammation, low blood cells due to an autoimmune reaction, or thyroid inflammation are supportive of the diagnosis but are not required. Confirmation comes from genetic testing to identify mutations in a specific gene (FOXP3).

Treatment Options for X-Linked Immunodeficiency

The treatment for X-linked Chronic Granulomatous Disease (CGD) revolves around fighting and preventing infections, early diagnosis of infections, and aggressively managing any complications that may arise from these infections. Patients with this condition are often advised to take antibiotics and antifungal medications throughout their life. These medications include Trimethoprim-sulfamethoxazole for bacterial infections and itraconazole for fungal infections. Immunomodulatory therapy, which is designed to modify or regulate the immune system’s functions, may also be used based on each patient’s specific symptoms. Interferon-gamma treatment, which boosts the immune system, can also be added to this treatment regimen. Oral glucocorticoids, a type of steroid, are commonly used to manage disease-related inflammation. If necessary, additional anti-inflammatory medications like azathioprine and sulfasalazine may be used to counteract any long-term adverse effects from the steroids. The definitive cure for X-linked CGD is Hematopoietic Cell Transplantation (HCT), which involves transplanting blood stem cells.

For patients with X-linked Hyper IgM syndrome, immunoglobulin replacement, a treatment which supplements the body with antibodies it cannot produce, is necessary. Also, these patients should have their liver function checked every six months. Doctors should look for the presence of cryptosporidium and microsporidium, two types of parasites, and if found, patients should be treated with azithromycin or nitazoxanide, which are types of antibiotics. HCT is the sole curative treatment for this disease.

The treatment of X-linked Lymphoproliferative Disease (XLP) involves managing acute disease symptoms, preventing possible complications, and providing curative treatment. Anti-viral medications and immunoglobulin therapy are helpful for treating active disease symptoms. Another alternative treatment is B-cell treatment with rituximab, which attacks a type of white blood cell that has turned into a cancer cell. Immunoglobulin treatment can also be used to prevent primary infections and the reactivation of the Epstein-Barr virus, however, the effectiveness of this treatment in this regard is still not clear. Gene therapy looks promising, but the only curative treatment for XLP is HCT.

In Wiskott-Aldrich Syndrome (WAS), treatment typically involves general precautions to protect against infections, intravenous immunoglobulin therapy, and low-dose IL-2 treatment, a type of immunotherapy. In more serious cases, splenectomy (surgical removal of the spleen) and stem cell transplantation with immunosuppressive therapy may be necessary. Gene therapy is also a promising treatment approach for this condition.

The definitive treatment for X-linked Severe Combined Immunodeficiency (X-SCID) is Hematopoietic Cell Transplantation (HCT). Gene therapy is still at the clinical research stage for this condition. With HCT, it’s important that T-cell, B-cell, and NK cell (three types of white blood cells) transplantation occurs to ensure that the patient’s immune system functions fully. If only T-cell transplantation occurs, patients may require ongoing immunoglobulin replacement therapy due to their B cells’ underperformance.

The treatment for Immunodeficiency with Thymoma involves replacing immunoglobulin, a protein that helps fight infections. Also, general precautions such as avoiding infections and using inactive vaccines for immunization are recommended. The immunoglobulin replacement therapy reduces the risk of infection and the need for hospital admissions. It also helps in preventing the development of long-term respiratory illness and reduces risk of systemic enteroviral infection, a severe whole-body infection caused by enteroviruses.

Management of Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is divided into managing acute and long-term symptoms. Patients may experience severe dehydration or metabolic imbalances due to early-onset diabetes or diarrhea caused by enteropathy before or after diagnosis. Flare-ups may occur due to infections, vaccinations, diet changes, or other unknown triggers. Managing these immediate complications necessitates a multi-disciplinary approach. Long-term management includes diet and nutrition modifications to avoid intense immunosuppression and food allergens. HCT is the only definitive cure for the disease. However, post-transplantation, endocrine disorders may persist due to end-organ damage.

When trying to diagnose different medical conditions that are linked to the X-chromosome, doctors need to take into account a range of other possible conditions that may present similar symptoms. These include:

For X-linked CGD (Chronic Granulomatous Disease):

Cystic fibrosis
Hyper IgE syndrome
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Glutathione synthetase deficiency
Crohn’s disease

For X-linked hyper IgM:

PI3K-delta syndrome
Ataxia telangiectasis
Nijmegen breakage syndrome
Common variable immune deficiency (CVID)
Congenital rubella
Phenytoin use
T-cell leukemia
Lymphoma
Nephrotic syndrome

For XLP (X-Linked Lymphoproliferative Disease):

Hemophagocytic lymphohistiocytosis
CVID
Chediak-Higashi syndrome
Griscelli syndrome
X-linked inhibitor of apoptosis (XIAP) deficiency
Serious infectious mononucleosis in male patients
Lymphoma

For WAS (Wiskott-Aldrich Syndrome):

Eczema such as Omenn syndrome, IPEX, Netherton syndrome
Hyper IgE syndrome
DOCK8 deficiency
Atopic dermatitis

For X-SCID (X-Linked Severe Combined Immunodeficiency):

JAK3 deficiency with autosomal recessive transitions causing other T-B + NK- SCID phenotypes

For XLA (X-linked Agammaglobulinemia):

Transient hypogammaglobulinemia of infants
CVID
Autosomal recessive agammaglobulinemia
Combined agammaglobulinemia with T and B-cell failure

For IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome):

IPEX-like syndromes
Neonatal enteropathy
Eosinophilic enteropathies
Severe combined immune deficiencies

Only genetic tests can differentiate between some of these conditions.

What to expect with X-Linked Immunodeficiency

Survival rates are typically higher in patients of a younger age with a condition called X-linked CGD, a genetic disorder affecting the immune system. While this disease was initially considered fatal in childhood, improvements in treatment have greatly improved survival rates. Today, with preventive antibiotic and immune system-modifying treatments, patients can often live beyond 40 years of age.

X-linked hyper IgM syndrome, another immune disorder, often results in severe infections, diseases of the liver or bile ducts, and cancers. These complications are the primary causes of death in patients with this condition. However, survival rates have greatly increased with Hematopoietic Cell Transplant (HCT), which is a procedure to replace damaged or destroyed cells in the bone marrow. Patients can now often live beyond 20 years, with 90% reaching this age. Early transplantation can also prevent the development of liver failure.

In the case of X-linked Lymphoproliferative (XLP), a very rare inherited immune system disorder, the mortality rate is high. Without treatment, 70% of patients might not live past their 10th birthday, and by age 40, mortality is 100%. However, treatments like Rituximab (a medication to treat certain types of cancer), Intravenous Immunoglobulin (a solution of antibodies given through a vein), and HCT have helped lower the long-term mortality rates to below 30%.

For Wiskott-Aldrich syndrome (WAS), another rare genetic disorder that affects the immune system and blood clotting, life expectancy is typically reduced if patients are not treated with Hematopoietic Cell Transplantation (an operation that replaces diseased blood-forming cells in the bone marrow) or gene therapy. The main cause of death in these patients is severe bleeding.

Lastly, for X-linked Agammaglobulinemia (XLA), an inherited immune system disorder, the age of diagnosis has notably dropped over the last 50 years. Thanks to advancements in treatments like Immunoglobulin therapy (medication that boosts the immune system), patients with XLA have been able to reach adulthood more easily in recent decades.

In contrast, infants with Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome, a rare autoimmune disorder, may unfortunately not survive infancy if left untreated. Despite improvements in prognosis with Hematopoietic Cell Transplantation and immune-suppressing treatments over the years, the overall outlook for this disease remains poor.

Possible Complications When Diagnosed with X-Linked Immunodeficiency

In chronic granulomatous disease, various parts of the body, including the lungs, skin, lymph nodes, and liver, can become infected. Without proper detection and treatment, complications can arise, such as abscesses on the skin, lungs, and organs, pus-filled swollen glands, bone infections, pneumonia, and surface-level skin infections.

The X-linked Hyper IgM syndrome can lead to several health problems if it is not identified and treated early. These include bronchiectasis which is a condition where the airways in the lungs become damaged due to recurring infections, various diseases affecting the gallbladder and bile ducts, liver disease and bile duct cancer caused by the cytomegalovirus (CMV).

On the other hand, patients with X-linked Lymphoproliferative Syndrome (XLP) may encounter serious complications like severe infectious mononucleosis, lymphoma (a type of blood cancer), inflammation of blood vessels (lymphocytic vasculitis), and aplastic anemia where the body stops producing enough new blood cells.

Lastly, a severe condition known as the classic Wiskott-Aldrich Syndrome (WAS), can escalate to lymphoma associated with the Epstein-Barr virus. Interestingly, autoimmune reactions have also been detected in around half of the classic WAS cases.

Complications of Main Conditions:

Abscesses in skin, lungs, and organs (Chronic granulomatous disease)
Pus-filled swollen glands (Chronic granulomatous disease)
Bone infections (Chronic granulomatous disease)
Pneumonia (Chronic granulomatous disease)
Surface-level skin infections (Chronic granulomatous disease)
Bronchiectasis (X-linked Hyper IgM syndrome)
Gallbladder and bile duct diseases (X-linked Hyper IgM syndrome)
CMV-related liver disease and bile duct cancer (X-linked Hyper IgM syndrome)
Severe infectious mononucleosis (X-linked Lymphoproliferative Syndrome)
Lyphoma (X-linked Lymphoproliferative Syndrome)
Inflammation of blood vessels (X-linked Lymphoproliferative Syndrome)
Aplastic anemia (X-linked Lymphoproliferative Syndrome)
Epstein-Barr virus-associated lymphoma (Wiskott-Aldrich Syndrome)
Autoimmune reactions (Wiskott-Aldrich Syndrome)

Preventing X-Linked Immunodeficiency

Finding flaws in genes located on the X chromosome helps identify who may carry these genes. However, this can be tough if there isn’t any known history of these genes in the family. That’s why it’s critical to screen based on previously diagnosed cases. The screening can help spot individuals who may not yet show symptoms or unborn children who might inherit these genes.

Frequently asked questions

X-Linked Immunodeficiency is a type of immune system condition that is passed down through the X chromosome. It is associated with serious infections and can increase the risk of illness and death from an early age. It causes a deficiency in cellular and/or humoral immunity, making it difficult for the body to fight off harmful invaders like bacteria and viruses.

The prevalence and incidence of X-Linked Immunodeficiency are hard to estimate without population-wide screenings.

The signs and symptoms of X-Linked Immunodeficiency can vary depending on the specific condition. Here are the signs and symptoms of different X-Linked Immunodeficiency disorders: 1. X-Linked Chronic Granulomatous Disease (CGD): - Infections in the lungs, skin, lymph nodes, and liver - Formation of granulomas causing issues in the lungs, gastrointestinal tract, and urinary system - Enlarged liver, spleen, and abnormal growth of lymph nodes - Inflammation of the colon in 30% to 40% of patients 2. X-Linked Hyper IgM Syndrome: - Frequent and recurrent infections, including serious lung infections - Increased risks of certain types of cancer, such as liver cancer and lymphoma 3. X-Linked Lymphoproliferative (XLP) Disease: - Severe mononucleosis - Lowered levels of certain antibodies - Abnormal growth of cells in the immune system - Abnormal immune responses during certain infections 4. Wiskott-Aldrich Syndrome (WAS): - Bleeding disorders due to low platelet counts - Recurrent infections - Eczema - Enlarged lymph nodes and spleen - Prone to autoimmune complications and cancer 5. X-Linked Severe Combined Immunodeficiency (X-SCID): - Recurrent infections - Chronic diarrhea - Oral thrush - Ear infections - Slow growth during the first year of life - Lack of certain immune system cells (T-B+NK- phenotype) 6. X-Linked Agammaglobulinemia (XLA): - Absence of secondary lymphoid tissues rich in B cells (e.g., tonsils and adenoids) - Recurrent infections - Initial symptoms may not appear for the first few months 7. Immunodysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) Syndrome: - Autoimmune-induced chronic diarrhea - Endocrine disorders like neonatal type I diabetes or thyroiditis - Severe skin inflammation - Stunted growth - Food allergies - Reduced blood cell count due to autoimmune reactions It's important to note that these are just some of the signs and symptoms associated with X-Linked Immunodeficiency, and the specific symptoms can vary among individuals.

X-Linked Immunodeficiency can be inherited through the X chromosome.

The doctor needs to rule out the following conditions when diagnosing X-Linked Immunodeficiency: - Cystic fibrosis - Hyper IgE syndrome - Glucose-6-phosphate dehydrogenase (G6PD) deficiency - Glutathione synthetase deficiency - Crohn's disease - PI3K-delta syndrome - Ataxia telangiectasis - Nijmegen breakage syndrome - Common variable immune deficiency (CVID) - Congenital rubella - Phenytoin use - T-cell leukemia - Lymphoma - Nephrotic syndrome - Hemophagocytic lymphohistiocytosis - Chediak-Higashi syndrome - Griscelli syndrome - X-linked inhibitor of apoptosis (XIAP) deficiency - Serious infectious mononucleosis in male patients - Eczema such as Omenn syndrome, IPEX, Netherton syndrome - DOCK8 deficiency - Atopic dermatitis - JAK3 deficiency with autosomal recessive transitions causing other T-B + NK- SCID phenotypes - Transient hypogammaglobulinemia of infants - Autosomal recessive agammaglobulinemia - Combined agammaglobulinemia with T and B-cell failure - IPEX-like syndromes - Neonatal enteropathy - Eosinophilic enteropathies - Severe combined immune deficiencies

The types of tests needed for X-Linked Immunodeficiency include: 1. Lab tests to measure inflammation indicators such as sedimentation rate, C-reactive protein, and hypergammaglobulinemia. 2. Testing for neutrophil function to screen for potential problems in white blood cell function. 3. Genetic testing to identify specific mutations in genes associated with X-Linked Immunodeficiency. 4. Screening programs for prenatal or neonatal testing in families with a history of X-Linked Immunodeficiency.

X-Linked Immunodeficiency is treated through Hematopoietic Cell Transplantation (HCT), which involves transplanting blood stem cells. This is the definitive cure for the disease.

When treating X-Linked Immunodeficiency, there can be several side effects and complications. These include: - Abscesses in the skin, lungs, and organs - Pus-filled swollen glands - Bone infections - Pneumonia - Surface-level skin infections - Bronchiectasis (in X-linked Hyper IgM syndrome) - Gallbladder and bile duct diseases (in X-linked Hyper IgM syndrome) - CMV-related liver disease and bile duct cancer (in X-linked Hyper IgM syndrome) - Severe infectious mononucleosis (in X-linked Lymphoproliferative Syndrome) - Lymphoma (in X-linked Lymphoproliferative Syndrome) - Inflammation of blood vessels (in X-linked Lymphoproliferative Syndrome) - Aplastic anemia (in X-linked Lymphoproliferative Syndrome) - Epstein-Barr virus-associated lymphoma (in Wiskott-Aldrich Syndrome) - Autoimmune reactions (in Wiskott-Aldrich Syndrome)

The prognosis for X-Linked Immunodeficiency varies depending on the specific condition. Here are the prognoses for some of the X-Linked Immunodeficiency disorders mentioned in the text: - X-linked CGD: With improved treatment, patients can often live beyond 40 years of age. - Hyper IgM syndrome: Survival rates have greatly increased with Hematopoietic Cell Transplant (HCT), and patients can now often live beyond 20 years, with 90% reaching this age. - XLP: Without treatment, the mortality rate is high, but with treatments like Rituximab, Intravenous Immunoglobulin, and HCT, the long-term mortality rates have been lowered to below 30%. - WAS: Life expectancy is typically reduced if patients are not treated with Hematopoietic Cell Transplantation or gene therapy. The main cause of death in these patients is severe bleeding. - XLA: Thanks to advancements in treatments like Immunoglobulin therapy, patients with XLA have been able to reach adulthood more easily in recent decades. - IPEX syndrome: The overall outlook for this disease remains poor, and infants may not survive infancy if left untreated.

An immunologist or an immunology specialist.