XLP almost exclusively affects males. XLP1 is estimated to affect about one to two individuals per million, while the rarer subtype, XLP2, is estimated to affect about one individual per five million.

The immune system is a complex system of many different cells, proteins, and other substances. Due to its complexity, the regulation of the immune system and proper communication between different immune cells is essential to its proper function. Two important immune cells are B cells and T cells, which collectively are called lymphocytes. 

XLP symptoms are often triggered after exposure to EBV. EBV is a common virus that causes a disease called mononucleosis which often leads to no long-term effects in otherwise healthy individuals. EBV can infect B cells by entering these immune cells and transforming their function. However, a healthy immune system eventually can identify and control the EBV-transformed B cells.

The gene responsible for XLP1 is SH2D1A. The protein product of this gene is involved in regulating the communication between B cells and T cells, facilitating the killing EBV-transformed B cells by T cells, and the development of a certain subset of T cells (natural killer T Cells or NKT). If the gene is defective, the unregulated communication between B cells and T cells leads to an overproduction of B cells and T cells in response to EBV, and the reduction of natural killer T cells hinders the proper containment of the infection. XLP2 is caused by a defect in the XIAP gene. The protein product of this gene inhibits apoptosis or programmed cell death. However, whether this function has a role in the development of XLP symptoms is not clear. 

 XLP is inherited in an X-linked recessive manner. Chromosomes are structures in human cells that carry the genetic material. Each person inherits one copy of each chromosome from each parent, leading to 23 pairs. One pair of chromosomes determines the sex of the individual; these two chromosomes are known as sex chromosomes which are denoted as X and Y. Females have two X chromosomes and no Y chromosome, while men have an X chromosome and a Y chromosome. The Y chromosome is much smaller than the X chromosome and has fewer genes. XLP is an X-linked condition which means the associated genes are present on the X chromosome. It is also a recessive condition, meaning that having a functional copy of the gene can make up for the defective copy. In an X-linked recessive condition like XLP, women are far less frequently affected because if they inherit a defective copy, the second X chromosome can compensate for the defective copy. However, since men only have one X chromosome, if that copy is defective, there are no functional genes to compensate for it which leads to XLP.

XLP symptoms usually present between the ages of 6 months to about 10 years. When individuals affected by XLP1 are infected with EBV, symptoms include fever, inflammation and soreness of the throat, and swelling in the lymph nodes. HLH is a life-threatening complication of XLP and may lead to the enlargement and inflammation of the liver, and enlargement of the spleen. The over-production of B cells and T cells may damage the bone marrow. The bone marrow is the site of the production of red blood cells, immune cells, and platelets. Platelets are cellular fragments that are responsible for appropriate blood clotting. Damage to bone marrow leads to aplastic anemia which is a reduction in all types of blood cells as a result of decreased production. If aplastic anemia is present, individuals may experience easy bruising or excessive bleeding since platelets cannot sufficiently form blood clots. Other symptoms include fatigue, shortness of breath, pale skin, rapid or irregular heartbeat, and recurrent infections. Kidneys, heart, and other organs may also be affected. Individuals affected by XLP may also have low levels of certain antibodies (gamma globulins) in the blood, a condition known as dysgammaglobulinemia. Individuals with dysgammaglobulinemia are susceptible to recurrent infections. In addition, some affected individuals may develop certain types of lymphomas after EBV exposure. Lymphomas are a group of cancers that start from lymphocytes (B cells and T cells). XLP1 may lead to B-cell lymphoma, most commonly in the intestines. Symptoms of B-cell lymphoma are abdominal swelling and pain, malabsorption of nutrients, weight loss, nausea, and vomiting.

XLP2 symptoms are similar to XLP1; however, lymphomas have not been observed in individuals with XLP2. Some cases of inflammatory bowel disease (IBD) have been observed in XLP2. IBD describes a group of conditions involving long-term inflammation of and damage to the intestines. XLP2 has been reported without exposure to EBV.

The diagnosis of XLP relies on clinical evaluation, the presence of physical symptoms, characteristic immune system abnormalities, as well as family history. If present in the family, XLP almost exclusively only affects males. Laboratory tests and findings, as well as molecular genetic testing, can confirm the diagnosis. In addition, individuals diagnosed with B-cell lymphoma in the region where small and large intestines connect can indicate XLP1. 

The most definitive diagnostic test is molecular genetic testing; however, this is not yet widely available. Other tests such as flow cytometry or western blood analysis can be performed to measure the levels of proteins encoded by SH2D1A and XIAP. Flow cytometry is a technique that measures and determines the physical and chemical characteristics of cells. Western blot is a technique that detects and measures a specific protein in a sample. Flow cytometry can also be used to measure the number of natural killer T (NKT) cells in the blood which is expected to be reduced in XLP1. NKT numbers, however, are normal in XLP2, thus, this has no diagnostic value in XLP2.

The only cure for XLP1 is allogeneic hematopoietic stem cell transplantation. In this procedure, blood-cell producing cells are taken from the bone marrow, umbilical cord, or blood of a donor to replace the defective cells in the bone marrow or immune system of the affected individual. This procedure is recommended in individuals affected by both symptomatic or asymptomatic XLP1. 

Additionally, depending on clinical presentation, other treatments can benefit individuals. If individuals affected by XLP are identified before exposure to EBV, they may benefit from the administration of antibodies against EBV to prevent life-threatening EBV infections. This is known is IVIG replacement therapy. This might also be helpful after EBV exposure to prevent future infections as a result of the weakened immune system. If individuals develop lymphomas, surgery, radiation, and chemotherapy may be helpful. Furthermore, in the presence of HLH or the overproduction of B cells and T cells, drugs that suppress the immune system such as steroids may be administered.

Since XLP2 is rarer than XLP1, treatments are less established. It is unclear whether allogeneic hematopoietic stem cell transplantation is effective in XLP2. If inflammatory bowel disease is present immunosuppressive drugs may be used to reduce inflammation and the associated symptoms.

XLP is a life-threatening condition. Without treatment individuals typically do not live past childhood or adolescence. Individuals affected by XLP2 have a slightly higher life expectancy than those affected by XLP1. Death in individuals affected by XLP is often due to HLH or the overproduction of B cells and T cells that can damage many organs in the body. Since HLH typically occurs after exposure to EBV, identifying individuals affected by XLP before EBV exposure is essential. If individuals are identified before EBV exposure, preventative measures can prevent, postpone, or reduce life-threatening complications and improve the prognosis.

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