Information on the following diseases can be found in the Related Disorders section of this report:

• Associated Congenital Disorders (General)
• .

X-linked lymphoproliferative syndrome (XLP), an extremely rare inherited disorder, is characterized by a range of symptoms and findings that occur due to a defective immune system response to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and usually infects "silently," causing no apparent symptoms (asymptomatic). In some other cases, particularly during adolescence, EBV infection may cause infectious mononucleosis (IM), usually with no long-lasting effects (benign, self-limited IM). However, males with XLP who are exposed to Epstein-Barr virus may develop severe, life-threatening hepatic (liver) form infectious mononucleosis and hepatitis, abnormally low levels of antibodies or immunoglobulins (hypogammaglobulinemia) in the blood and body secretions, malignancies of certain types of lymphoid tissue (B-cell lymphomas), or other abnormalities.

Approximately half of individuals with X-linked lymphoproliferative syndrome experience severe, life-threatening mononucleosis characterized by fever, inflammation and soreness of the throat (pharyngitis), swollen lymph glands, enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly), and/or abnormal functioning of the liver, resulting in yellowing of the skin, mucous membranes, and whites of the eyes (jaundice or icterus). In some cases, individuals who experience life-threatening mononucleosis infection may subsequently have an abnormal increase (i.e., proliferation) of certain white blood cells (lymphocytes and histiocytes) in particular organs, severe liver damage and/or failure, damage to the blood-cell generating bone marrow (hematopoietic marrow cells) that may result in aplastic anemia, and/or other symptoms that may result in life-threatening complications in affected children or adults. Aplastic anemia is characterized by a marked deficiency of all types of blood cells (pancytopenia) including low levels of red blood cells, certain white blood cells, and platelets, specialized red blood cells that function to assist appropriate blood clotting. In individuals with XLP, a decrease in platelets (thrombocytopenia) results in increased susceptibility to bruising and excessive bleeding (hemorrhaging). Because X-linked lymphoproliferative syndrome is inherited as an X-linked recessive genetic trait, the disorder is usually fully expressed in males only.

X-linked lymphoproliferative syndrome is considered a rare primary immunodeficiency disorder; one of a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms). The T-cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B-cell system (humoral immune response) fights infection caused by other viruses and bacteria by secreting immune factors called antibodies or immunoglobulins into the blood and body secretions (e.g., saliva). Antibodies can kill microorganisms or "coat" them so they are more easily destroyed by certain white blood cells. White blood cells (leukocytes) are part of the body's immune system, playing an essential role in protecting against infection as well as fighting infection once it occurs. In addition, antibodies are produced following vaccination, providing protection from infectious diseases like polio, measles, and tetanus. The immune deficiency in XLP affects both T-cell and B-cell immune responses and therefore is classified as a "combined immunodeficiency."

According to the medical literature, either directly after EBV exposure or following infectious mononucleosis, approximately one third of males with XLP may begin to exhibit abnormally low levels of antibodies (immunoglobulins) in the blood and body secretions (acquired hypogammaglobulinemia). As with bone marrow suppression, low levels of protective antibodies in the blood and body secretions may result in an increased susceptibility to various "opportunistic" infections.

In addition, approximately one fourth of males with XLP may develop malignancies of certain types of lymphoid tissue (B-cell lymphomas) subsequent to EBV exposure or development of infectious mononucleosis. Such lymphomas are characterized by malignant transformation of abnormally proliferating B cells. Burkitt's Lymphoma involving the area where the small intestine joins the large intestine (ileocecal area) is the most commonly reported B-cell lymphoma among affected males. Symptoms and findings associated with Burkitt's Lymphoma involving the intestines may include abdominal swelling (distention) and discomfort, impaired absorption of nutrients by the gastrointestinal (GI) tract (malabsorption), nausea, vomiting, changes in bowel habits, weakness, and/or weight loss.

X-linked lymphoproliferative syndrome (XLP) is inherited as an X-linked recessive genetic trait. The gene map location of the altered (mutated) has been tracked to a site at Xq25. The genetic trait is transmitted in an X-linked recessive mode as a result of which it is nearly always fatal to the male fetus or to male babies.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq25” refers to band 25 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consan-guineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off’ and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

The gene responsible for XLP is called "SH2D1A." Certain abnormal changes (mutations) in or deletions of material from the gene may result in X-linked lymphoproliferative syndrome in affected individuals. Researchers have determined that the gene encodes a unique protein called "SAP" that regulates another protein known as "SLAM." SLAM, which stands for "signaling lymphocyte activation molecule," controls communication between B cells and T cells. It is suspected that, in individuals with XLP, uncontrolled functioning of the SLAM protein causes improper communication between these immune cells, resulting in an abnormal immune response following EBV infection.

There have been a few reports in the medical literature in which females have symptoms and physical findings that appear very similar to those seen in males with XLP. In such cases, the underlying genetic and immunological causes are not known and are under investigation. Therefore, the implications of such findings are not yet understood.

X-linked lymphoproliferative syndrome is an extremely rare disorder that is usually fully expressed in males only. About 400± cases affecting males in more than 80 multigenerational families (kindreds) from several different countries have been reported in the medical literature. Researchers estimate that approximately one to two in every one million males are affected by XLP.

Symptoms of the following disorders may be similar to those of X-linked lymphoproliferative syndrome. Comparisons may be useful for a differential diagnosis:

There are additional congenital disorders that may be characterized by impairment of the T-lymphocyte and/or B-lymphocyte systems, resulting in abnormally low levels of antibodies or immunoglobulins (hypogamma-globulinemia) in the blood and body secretions, increased susceptibility to certain infections such as severe infection with Epstein-Barr virus, liver dysfunction, aplastic anemia, and/or other symptoms and findings similar to those occurring in association with X-linked lymphoproliferative syndrome. Such disorders usually have other physical features that may differentiate them from XLP. (For more information on these disorders, choose the disease name in question as your search term in the Rare Disease Database.)

Diagnosis
Because gene mutations that cause X-linked lymphoproliferative syndrome (XLP) have been identified, precise genetic testing may now be possible. However, such testing may only be available through research laboratories with a special interest in this disease.

Therefore, in many cases, XLP is diagnosed when affected males become symptomatic, which is typically anytime from approximately six months to 10 years of age. Diagnosis of X-linked lymphoproliferative syndrome may be based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, and a pattern of immune system defects detected by specialized laboratory testing on blood from affected individuals. Diagnosis is most easily established when a clear family history is present.

In individuals with severe infectious mononucleosis or fulminant hepatitis, specialized imaging tests may reveal abnormal enlargement of the liver and spleen (hepatosplenomegaly) and/or other findings. After EBV exposure or following infectious mononucleosis, specialized laboratory tests may reveal abnormally high concentrations of certain lymphocytes in the blood (lymphocytosis), deficient or absent antibody response to EBV antigens (e.g., EBV nuclear antigen), and, in some cases, abnormally low levels of all classes of immunoglobulins (acquired hypogammaglobulinemia) in the blood and body secretions. In some affected individuals, laboratory testing may also reveal abnormal liver function and/or a marked deficiency of all types of blood cells (pancytopenia), suggesting aplastic anemia. In some cases, specialized laboratory and imaging tests may also reveal additional findings associated with XLP.

According to the medical literature, in families with males affected by X-linked lymphoproliferative syndrome, other male family members who have not yet been exposed to EBV (EBV seronegative) should be considered at risk for XLP. Because exposure to EBV may result in life-threatening complications in those with the disorder, it is essential that a diagnosis of XLP be confirmed or excluded in such family members before EBV exposure occurs.

In addition, if males are diagnosed with Burkitt's Lymphoma involving the area where the small intestine joins the large intestine (i.e., the ileocecal area), they and their male family members should receive testing for XLP. If XLP is confirmed, carrier testing may also be considered for female family members.

Treatment
The treatment of X-linked lymphoproliferative syndrome may require the coordinated efforts of a team of specialists who need to plan, systematically and comprehensively, an affected individual's treatment. Such specialists may include pediatricians and/or internists, specialists in the functioning of the immune system (immunologists), physicians specializing in the diagnosis and treatment of blood disorders (hematologists) or cancers (oncologists), and/or other health care specialists.

Because of the life-threatening implications of this disorder, it is important to identify those males with XLP as soon as possible. If affected individuals are identified before EBV exposure, infusion with immunoglobulins (intravenous gammaglobulin) with EBV antibodies may be recommended to help prevent life-threatening infectious mononucleosis and the onset of other symptoms and findings potentially associated with XLP.

In affected individuals who are diagnosed with XLP subsequent to EBV exposure, treatment may include therapies to help prevent opportunistic infections associated with XLP such as the administration of antibiotic medications (prophylactic antibiotic therapy) and/or intravenous gammaglobulin therapy.

Affected individuals who develop B-cell lymphoma such as Burkitt's lymphoma may be treated with surgery, radiation, and/or chemotherapy.

Genetic counseling will be of benefit for affected males and their family members. Other treatment is symptomatic and supportive.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

Two clinical trials involving the transplantation of a patient’s own stem cells are currently underway, and sponsored by the same principal investigator, K. Scott Baker, MD, at the University of Minnesota. Dr. Baker may be contacted at: (612) 625-9428 or baker084@umn.edu.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Lymphoproliferative Syndrome, X-Linked, Entry Number; 308240: Last Edit Date; 7/20/2005.

TEXTBOOKS
Kobayashi RH. X-Linked Lymphoproliferative Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:400.

Janeway CAJr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 6th ed. Garland Science Publishing. New York, NY; 2005:486-87.

Frank MM, Austen KF, Claman HN, et al. Eds. Samter’s Immunological Diseases. 5th ed. Little Brown and Company, Boston, MA; 1995:407.

JOURNAL ARTICLES
Bhat R, Eissmann P, Endt J, Hoffmann S, Watzl C. Fine-tuning of immune responses to SLAM-related receptors. J Leukoc Biol. 2006;79:417-24.

Erdos M, Uzvolgyi E, Nemes Z, Torok O, et al. Characterization of a new disease-causing mutation of SH2D1A in a family with X-linked proliferative disease. Hum Mutat. 2005;25:506.

Tabata Y, Villanueva J, Lee SM, Zhang K, et al. Rapid detection of intracellular SH2D1A protein in cytotoxic lymphocytes from patients with X-linked lymphoproliferative disease and their family members. Blood. 2005;105:3066-71.

Latour S, Veillette A. The SAP family of adaptors in immune regulation. Semin Immunol. 2004;16:409-19.

Engel P, Eck MJ, Terhorst C. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat Rev Immunol. 2003;3:813-21.

FROM THE INTERNET
X-linked Lymphoproliferative Disease. Great Ormond Street Hospital for Children NHS Trust. Information Sheet. nd. 3pp.
www.teamhartley.co.uk/whatis.asp

X-Linked Lymphproliferative Syndrome. Primary Immunodeficiency Diseases. Primary Immunodeficiency Resource Center. 2006 Jeffrey Modell Foundation. 4pp.
www.info4pi.org

What is XLP? XLP Canada. nd. 1p.
www.xlp.ca/what.html

Saville MW. Lymphproliferative Syndrome, X-Linked. emedicine. Last Updated: October 29, 2004. 5pp.
www.emedicine.com/med/topic1370.htm

Winter SS. Lymphoproliferative Disorders. emedicine. Last Updated: April 7, 2006. 5pp.
www.emedicine.com/ped/topic1345.htm