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X-Linked Lymphoproliferative Disease 2 (XLP2) / XIAP Deficiency

What Is X-Linked Lymphoproliferative Disease 2 (XLP2) / XIAP Deficiency?

XLP2 is a type of X-linked lymphoproliferative disease. XLP2 typically affects boys. It can also occasionally affect girls. The condition was first described in 2006. Only about 100 boys have been diagnosed with it so far.

XIAP Deficiency Causes

XLP2 is caused by a change in the XIAP gene. This is sometimes called the BIRC4 gene.

The XIAP gene codes for the XIAP protein that the body needs to regulate the immune system. People with this genetic change either have problems with the XIAP protein, or they do not have the protein. Another name for this condition is XIAP deficiency. This is a unique disorder. The term we use is “XIAP deficiency.”

XIAP deficiency is an “X-linked” disease. This means that the genes that cause it are on the X chromosome. Boys have one X chromosome and one Y chromosome. Girls have two X chromosomes. If a boy has a changed XIAP gene on his X chromosome, he will develop XIAP deficiency.

For a girl to develop XIAP deficiency, she would need to have genetic changes on both X chromosomes. Another way she could develop XIAP deficiency would be by a “skewing” of X-chromosome inactivation. This causes many cells to be deficient in XIAP. Most girls with a genetic change are just carriers. They do not develop symptoms of XIAP / XLP2.

Girls that are affected by XIAP deficiency most commonly develop inflammatory bowel disease. But they can also develop other problems caused by XIAP deficiency. Girls who are affected or who are carriers can pass the disease on to their sons. The chance of this happening is 50%. They can also pass carrier status or, more rarely, the disease to their daughters.

XIAP Deficiency Signs, Symptoms and Other Problems

The symptoms for XIAP deficiency can vary from person to person. The symptoms can vary even within the same family. Children with XIAP deficiency are at risk for many diseases and health problems, including:

  • Hemophagocytic lymphohistiocytosis (HLH), a rare and life-threatening disorder of the immune system
  • Hypogammaglobulinemia, lower than normal levels of proteins called antibodies
  • Inflammatory bowel disease,swelling in the gastrointestinal (GI) tract
  • Enlarged spleen
  • Recurrent fever
  • Low blood counts
  • A severe response to the Epstein-Barr virus
  • Inflammatory complications such as arthritis (inflammation in the joints) or uveitis (inflammation in the eye)
  • Problems with infections

Children with the other type of X-linked lymphoproliferative disease, XLP1, are at increased risk for lymphoma, which is a type of blood cancer. Children with XLP2/XIAP deficiency do not develop lymphoma as a result of their condition.

XIAP Deficiency and Hemophagocytic Lymphohistiocytosis (HLH)

Between 67% and 90% of children with XIAP develop hemophagocytic lymphohistiocytosis (HLH). This is a potentially life-threatening disorder of the immune system that causes organ damage.

Signs and symptoms of HLH include:

  • Swollen lymph nodes (glands in the neck, under the arm or in the groin)
  • Enlarged liver and spleen
  • Liver, heart, spleen and kidney damage
  • Fever
  • Skin rash
  • Jaundice (yellowing of the eyes and skin)
  • Bone marrow problems
  • Anemia (not enough healthy red blood cells)
  • Thrombocytopenia (low platelets)
  • Neutropenia (low neutrophils)
  • Digestive problems, such as problems absorbing nutrients

Some children with XIAP deficiency develop some symptoms of HLH. These include fever, low blood counts and enlarged spleens. But they do not have the “full picture” of HLH. This is considered “incomplete HLH.”

XIAP Deficiency and Hypogammaglobulinemia

About one-quarter to one-third of children with XIAP deficiency develop lower-than-normal antibody levels or hypogammaglobulinemia.

Signs and symptoms include:

  • Repeating or serious infections
  • Cough
  • Cold symptoms
  • Stomach problems

XIAP Deficiency and Inflammatory Bowel Disease

Between 17% and 22% of children with XIAP develop inflammatory bowel disease. This condition leads to inflammation in the gastrointestinal tract. It causes symptoms such as:

  • Diarrhea
  • Abdominal pain
  • Weight loss
  • Fever

XIAP Deficiency Diagnosis

If your child develops symptoms of XIAP deficiency, your doctor may refer you to a hematologist, rheumatologist or immunologist. The doctor may provide:

  • A physical exam and symptom check
  • Blood tests to detect XIAP protein levels (XIAP levels may be low or zero in children with XIAP deficiency/XLP2) or XIAP function
  • Genetic tests to detect a genetic change in the XIAP gene

XIAP Deficiency Treatment

Currently, the only cure for XIAP deficiency is allogeneic hematopoietic stem cell transplantation. This is sometimes called a bone marrow transplant. These transplants replace diseased blood-forming stem cells with healthy ones. Not all patients with XIAP deficiency need a transplant.

If your child has XIAP deficiency, ongoing care from an experienced team of specialists is very important. The care team can provide an accurate diagnosis and comprehensive treatment plan to help your child have the best outcome possible. If needed, the care team can include specialists from many areas of medicine, such as a pediatric gastroenterologist.

Treatment for children with XIAP deficiency may include:

  • Steroids plus other immunosuppressant medicines or chemotherapy to help regulate the immune system
  • Biologic medicines to treat low antibody levels
  • Immunosuppressant medicines and diet changes for symptoms of inflammatory bowel syndrome
  • Antibiotics or antiviral medicines for children who develop repeated infections

Some children with XIAP deficiency should not have live virus vaccines because of their abnormal immune system. These vaccines include chickenpox/varicella; rotavirus; and measles, mumps and rubella (MMR).

Last Updated 02/2021

Reviewed By Rebecca Marsh, MD

Who treats this.

Cincinnati Children's specialists in the Immune Deficiency and Histiocytosis Program have extensive experience in diagnosing and managing rare immune deficiencies.