Autoimmune Lymphoproliferative Syndrome: Causes, Inheritance Pattern, Symptoms, Diagnosis, and Treatment

Introduction:

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which the body cannot regulate the number of immune system cells known as lymphocytes. In this condition, there is abnormal production of a large number of lymphocytes (lymphoproliferation) due to abnormal lymphocyte apoptosis (a form of programmed cell death). This accumulation of excessive lymphocytes results in various complications, such as enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly), and the spleen (splenomegaly).

What Causes Autoimmune Lymphoproliferative Syndrome?

Autoimmune lymphoproliferative syndrome results from genetic mutations in one of many genes controlling how lymphocytes work. FAS is the most commonly affected gene, which keeps the immune system active even when no infection is present. This can be found in 75 % of the affected individuals.

Many lymphocytes are produced when the immune system is activated to fight a large infection. In normal conditions, these lymphocytes undergo apoptosis (programmed cell death) when they are no longer required. Mutation in the FAS gene can interfere with apoptosis causing excess lymphocytes in the body tissues and organs, leading to autoimmune disorders. Any interference with the process of apoptosis causes the multiplication of cells without control leading to lymphomas (cancer of the lymphatic system).

What Is the Inheritance Pattern in Autoimmune Lymphoproliferative Syndrome?

Most of the people affected with the autoimmune lymphoproliferative syndrome follow the autosomal dominant inheritance pattern. In this, a copy of a faulty gene is passed on from one parent and a copy of the normal gene from another parent. However, not all people with faulty copies of the gene get ALPS. In around 40 percent of cases, no symptoms appear therefore, parents may not realize they carry the gene.

In some cases, new gene defects can still occur with no history of the disorder in their family. If genetic changes occur at the time of conception (in egg or sperm), it is termed sporadic and can be passed to the next generation. If the change occurs later during the development of the embryo, then only the blood cells get affected, and is called a somatic variant that cannot be passed to future generations.

In rare cases, ALPS can also be inherited in an autosomal recessive pattern, meaning both parents pass the defective gene to their child but do not show any symptoms.

What Are the Clinical Features of Autoimmune Lymphoproliferative Syndrome?

ALPS usually manifests in the early years of life. The most common clinical manifestations are noninfectious nonmalignant enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly), and the spleen (splenomegaly). Autoimmune disorders and lymphoma is a late complications of ALPS. All the disease manifestations appear more commonly in males than females. These clinical features of ALPS appear in different forms in life, which include -

• Lymphoproliferation - This affects the spleen and lymph nodes during childhood causing lymphadenopathy and splenomegaly. Therefore parents might notice enlarged glands in the neck, armpits, or groin of the child.

• Autoimmune Disease - Patients with ALPS are at higher risk of autoimmune disease in which the immune system malfunctions and starts to attack its own tissues of the body. Autoimmune disease related to ALPS occurs when antibodies get formed that attacks the red blood cells causing hemolytic anemia (type of anemia occurring when red blood cells are getting destroyed faster than they can be replaced) and platelets, leading to thrombocytopenia (low number of platelets), causing symptoms like tiredness, pallor, easy bleeding, and bruising.

• Lymphoma - Autoimmune lymphoproliferative syndrome is associated with an increased risk of cancer of white blood cells in adulthood. However, this is not present in every case. Lymphoma can lead to symptoms like fever, fatigue, weight loss, loss of appetite, and enlargement of one or more lymph nodes.

According to various studies, the chances of clinical features in ALPS include -

• Lymphadenopathy - 96 %.

• Splenomegaly - 95 %

• Hepatomegaly - 72 %

• Splenectomy - 49 %

• Autoimmune hemolytic anemia - 29 %

• Immune-mediated thrombocytopenia - 23 %

• Neutropenia - 19 %

• Glomerulonephritis - 10 %

• Liver dysfunction - 5 %

• Infiltrative lung lesions - 4 %

• Eye lesions - 0.7 %

How Is Autoimmune Lymphoproliferative Syndrome Diagnosed?

The diagnosis of autoimmune lymphoproliferative syndrome depends upon the clinical features and the blood tests assessing different types of lymphocytes, also called double-negative T lymphocytes. Various conditions show similar symptoms compared to ALPS, so it is important to evaluate the clinical features to exclude any of these carefully. Moreover, special test such as genetic test is a gold standard for diagnosing autoimmune lymphoproliferative syndrome.

In addition, ALPS complications may need to be evaluated by scans or further blood tests. If lymphoma is suspected, a small biopsy of one of the lymph nodes is performed to confirm the diagnosis.

According to different studies, revised diagnostic criteria for ALPS were developed at the first international ALPS workshop in 2009, which include -

Required Criteria -

1. Chronic (more than six months), nonmalignant, noninfectious lymphadenopathy, or splenomegaly

2. Elevated CD3+ TCRαβ+CD4−CD8− DNT cells (> 1.5 % of total lymphocytes or > 2.5 % of CD3+ lymphocytes) in normal or elevated lymphocyte counts.

Additional Criteria -

A. Primary

1. Defective lymphocyte apoptosis in two separate assays.

2. Somatic or germline pathogenic mutation in FAS, FASLG, or CASP10.

B. Secondary

1. Elevated plasma sFASL levels (more than 200 pg/mL), plasma IL-10 levels (more than 20 pg/mL), serum or plasma vitamin B12 levels (more than 1500 ng/L) or plasma IL-18 levels more than 500 pg/mL.

2. Typical immunohistologic findings as reviewed by a hematopathologist.

3. Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) with elevated IgG levels (polyclonal hypergammaglobulinemia)

4. Family history of a nonmalignant or noninfectious lymphoproliferation with or without autoimmunity.

Definitive Diagnosis - Both required criteria plus one primary accessory criterion.

Probable Diagnosis - Both required criteria plus one secondary accessory criterion.

How Is Autoimmune Lymphoproliferative Syndrome Treated?

In the majority of cases, treatment is not required, but the size and number of blood cells have to be monitored regularly by taking a blood sample. However, in some patients, medication may be required to control the overgrowth of lymphocytes or autoimmune complications.

The patient and family should be educated about the risks associated with ALPS, such as anemia, thrombocytopenia, and other autoimmune diseases that can also develop and may require immediate attention. For severe cases, replacement of the abnormal lymphocytes by hematopoietic stem cell transplantation might be considered, but this is rare.

In a case with enlargement of the lymph nodes in children with ALPS can lead to anxiety in patients and families as the swellings can be clinically seen on the neck, arm, or groin areas. Therefore, clinicians may treat these patients for cosmetic purposes alone. Medications like corticosteroids or immunosuppressive drugs such as Azathioprine, Cyclosporine, or Mycophenolate mofetil can be used to shrink the size of abnormally growing organs. However, these are contraindicated in patients who are solely treated for cosmetic purposes.

The surgery is limited to only lymph node biopsies. Splenectomy (surgical removal of the spleen) should be avoided in case of splenomegaly (enlarged spleen), as the spleen is an essential organ that helps in protecting the body from serious infections.

Conclusion:

An autoimmune lymphoproliferative syndrome is a rare disease that usually affects children. Symptoms usually improve by their own after puberty. Genetic counseling is advised for parents and family members to find the cause and prepare them to manage this condition.