X-Linked Lymphoproliferative (XLP) Syndrome?

X-linked lymphoproliferative syndrome (XLP), or Duncan’s syndrome, is a rare genetic condition where the immune system does not work properly. The immune system is made up of special cells, proteins, tissues and organs, which work together to protect our bodies from the detrimental effects of pathogens, including bacteria, viruses and fungi.

Most of the time, the immune system does a great job of keeping people healthy and preventing infections. However, in individuals with X-linked lymphoproliferative syndrome, the immune system does not always respond as it should to specific challenges.

It is possible that the main title of the report X linked Lymphoproliferative Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

X-linked lymphoproliferative disease (also known as XLP1, Purtilo syndrome, OMIM #308240) was initially identified as “Duncan’s disease” in recognition of a large kindred reported by David Purtilo and colleagues in 1975. In the Duncan kindred, maternally related male individuals developed what are now recognized as the classic manifestations of disease, including Epstein-Barr virus (EBV)-induced hemophagocyticlymphohistiocytosis (HLH), B cell lymphomas, and hypo- or dysgammaglobulinemia.

1 Boys infected with EBV exhibited known manifestations of HLH, including fever, jaundice, convulsions, hepatosplenomegaly, lymphadenopathy, and cytopenias, with evidence of lymphohistiocytic infiltrates and hemophagocytosis in biopsy specimens of affected tissues. One male individual developed complications of hypogammaglobulinemia, including pneumonia, otitis media, and sinusitis.

Two other male members developed lymphomas of the abdomen and central nervous system. In the Duncan kindred, females did not develop disease and EBV was proven or suspected to be a contributing factor to illness in most affected boys. Affected boys ranged in age from 23 months to 19 years, and all died by the time of the initial report, illustrating the life-threatening nature of this disorder.

Additional early reports supported the conclusion that Duncan’s disease was a distinct X-linked disorder characterized by the onset of HLH, lymphoma, and humoral immune defects, often occurring in the setting of EBV.2–4 The search for the causative gene ended in 1998, when three laboratories simultaneously reported that Duncan’s disease was due to inactivating mutations in the Src Homology 2 (SH2) Domain Containing Gene 1A (SH2D1A), which resides at the Xq25 chromosomal locus.

In 2006, Rigaud and colleagues reported that a subset of families with similar clinical phenotypes, but no mutations in SH2D1A, harbored mutations instead in a second gene known as X-linked Inhibitor of Apoptosis (XIAP; previously Baculovirus Inhibitor of Apoptosis Repeat-Containing 4 [BIRC4], OMIM #300635), which lies in the vicinity of SH2D1A.8 Within XIAP mutant kindreds there was a high incidence of HLH, with 11 of 12 (92%) male individuals affected. Four patients also developed hypo- or dysgammaglobulinemia.

 In contrast to patients with SH2D1A mutations, XIAP-deficient individuals often exhibited recurring episodes of HLH and disease was not always secondary to EBV infection. In this initial report, no XIAP-deficient patients were affected by lymphoma; however, two developed a hemorrhagic colitis. Based on its clinical similarity to XLP1 and localization to the X chromosome, Rigaud and colleagues named this condition XLP2.

Discovery of the genes mutated in SLAM-associated protein (SAP) and XIAP deficiencies has allowed for improved understanding of XLP pathogenesis and facilitated development of precise immunologic and genetic tests. As a consequence, it is now possible to rapidly identify affected individuals and initiate appropriate treatments.

Together, these interventions have improved patient outcomes. The ability to make a definitive diagnosis has also enabled experience to be gathered specific to each disorder. Analysis of current data reveals that while SAP deficiency and XIAP deficiency share susceptibility to HLH and humoral immune defects, they represent clinically and pathologically distinct disorders.

General Discussion

X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited (primary) immunodeficiency disorder characterized by a defective immune system that is powerfully responsive to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects.

However, in individuals with XLP, exposure to EBV may result in severe, life-threatening fulminant hepatitis; abnormally low levels of antibodies in the blood and body secretions (hypogammaglobulinemia), resulting in increased susceptibility to various infections; malignancies of certain types of lymphoid tissue (B-cell lymphomas); and/or other abnormalities. The range of symptoms and findings associated with XLP may vary considerably from case to case. In addition, the range of effects may change in an affected individual over time. In most cases, individuals with XLP experience an onset of symptoms anytime from ages about 6 months to 10 years of age.

Synonyms

The syndrome is usually asymptomatic until EBV infection develops. Then, most patients develop fulminating or fatal infectious mononucleosis with liver failure (caused by cytotoxic T cells that react to EBV-infected B or other tissue cells). Survivors of initial infection develop B-cell lymphomas, aplastic anemia, hypogammaglobulinemia (resembling that in common variable immunodeficiency), splenomegaly, or a combination.

• Duncan Disease
• EBV Susceptibility (EBVS)
• Epstein-Barr Virus-Induced Lymphoproliferative Disease in Males
• Immunodeficiency-5 (IMD5)
• X-Linked Progressive Combined Variable Immunodeficiency
• Purtilo Syndrome
• XLP

Diagnosis

A Pan-American Group (PAGID) and the European Society for Immunodeficiencies (ESID) has published diagnostic criteria for XLP. Definitive diagnostic criteria include a male patient with lymphoma/Hodgkin’s disease, fatal EBV infection, immunodeficiency, aplastic anaemia, or lymphohistiocytic disorder and who has a mutation in SH2D1A.

Using antibodies to SAP, Western blot techniques are now available to screen peripheral blood mononuclear cells from suspected XLP patients for SAP protein. Although there are only limited data, it is anticipated that this will identify about 90% of cases.

Mutation screening can then be undertaken in those with absent protein, and in the rare cases with SAP protein production who have a typical family history of XLP. It is important to identify other affected males and female carriers in the family; the latter can then be offered prenatal diagnosis or arrangements made to screen male infants at birth.

• Genetic testing

The diagnosis of XLP should be considered in young males who have severe EBV infection, HLH, a suggestive family history, or other common manifestations.

Genetic testing is the gold standard test for confirming the diagnosis (before and after EBV infection and symptoms develop) as well as the carrier state. However, genetic testing can take weeks to complete, so other testing is done if the diagnosis must be made earlier (eg, flow cytometry to assess SH2D1A protein expression).

Suggestive findings include

• Decreased antibody responses to antigens (particularly to EBV nuclear antigen)
• Impaired T-cell proliferative responses to mitogens
• Decreased NK-cell function
• An inverted CD4:CD8 ratio

These findings are typical before and after EBV infection. A bone marrow biopsy can help confirm HLH.

In survivors, laboratory and imaging tests are done yearly to check for lymphoma and anemia.

Genetic testing is done in relatives when a case or carrier is identified in a family. Prenatal screening is recommended for people if a mutation that causes XLP has been identified in their family.

Causes

X-linked lymphoproliferative syndrome is caused by alterations, also known as “mutations,” at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.

X-linked lymphoproliferative syndrome develops as the result of a mutation in one of two different genes, SH2D1A or XIAP (also known as BIRC4), both of which are located on the X chromosome. When XLP is due to mutations in the SH2D1A gene, it is sometimes referred to as “XLP1.” When XLP is due to mutations in the XIAP gene, it is sometimes referred to as “XLP2.”

The SH2D1A gene produces a protein called SAP, which regulates how white blood cells combat infections such as Epstein-Barr virus and controls how they produce antibodies and other immunoregulatory molecules. When alterations in the SH2D1A gene are present, usually less SAP protein is produced. Occasionally, an abnormal protein is produced, but it is unable to function properly.

The XIAP gene produces a protein known as X-linked inhibitor of apoptosis (XIAP), which functions to prevent cell death. When alterations in the XIAP gene are present, usually less XIAP protein is produced, which is believed to result in decreased numbers of specific types of white blood cells. It is not yet understood how this causes the features of X-linked lymphoproliferative syndrome.

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.

XLP1

There is a mutation on the X-chromosome that has been found to be associated with a T- and NK-cell lymphoproliferative disorder. The mutation is on the long arm of the chromosome, at position 25, which is denoted as Xq25. At this position, there is a deletion in the SH2D1A gene, which codes for an SH2 domain on a signal transducing protein called SLAM-associated protein (SAP).

The term “SH2” domain stands for src-homology 2 domain, which is a three-dimensional domain structure of about 100 amino acid residues. These domains are present in many signalling proteins because they permit specific, non-covalent bonding to proteins that contain phosphotyrosines. The amino acid residues adjacent to the phosphotyrosine on the target protein are what determine the unique binding specificity.

The SAP protein is important in the signalling events that activate T- and NK-cells. due to its adaptor function. Normally, the SAP protein is expressed in the cytoplasm of T- and NK-cells, where it binds to the cytoplasmic domain of the surface receptor called signaling lymphocyte activation molecule (SLAM).

This binding initiates a signal transduction pathway, which results in the modulation of IFN-γ. A deletion in the SH2D1A gene leads to a non-functional SH2 domain on the SAP protein, making it unable to bind to SLAM. This leads to aberrant IFN-γ modulation, causing uncontrolled cell proliferation.

XLP2

A second form is associated with XIAP.

Some sources recommend classifying this condition as “X-linked familial hemophagocyticlymphohistiocytosis” instead of X-linked lymphoproliferative disease.

Inheritance

This condition is generally inherited in an X-linked recessive pattern. The genes associated with this condition are located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of an associated gene in each cell is sufficient to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Except for egg and sperm cells, the other cells in our body have 46 chromosomes containing our genes in the form of DNA. For the most part, each cell has two copies of every chromosome, one inherited from the mother and one from the father. This rule is different when applied to the sex chromosomes, which are also known as “X” and “Y.” Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. Since the SH2D1A genes are located on the X chromosome, females have two copies of each of these genes, while males have only one copy.

In females (who have two X chromosomes), a mutation usually has to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of an associated gene, males are affected by X-linked recessive disorders much more frequently than females. However, in rare cases a female carrying one altered copy of the SH2D1A or XIAP gene in each cell may develop signs and symptoms of this condition.

Treatment

Allogeneic bone marrow transplantation (BMT) from an MHC-matched sibling following conditioning with etoposide, busulfan and cyclophosphamide has been successful in curing the disease, as has BMT from matched-unrelated donors (MUD). If an MHC-matched sibling donor is not available, the disease should be treated with some form of etoposide-containing regimen while the search for a MUD bone marrow donor is underway.

Because of the overall poor prognosis, many paediatricians are now recommending BMT in infants diagnosed during family screening before signs of the disease appear. However, some affected individuals have remarkably benign disease, and more information is needed on the frequency of life-threatening complications so that families can be adequately counselled on the risks and benefits of BMT.

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.

The SH2D1A and XIAP genes affect females and males differently

Because of this feature, an alteration in the SH2D1A or XIAP gene will affect female and male individuals differently. If a woman has one X chromosome with an alteration in SH2D1A or XIAP and her other X chromosome has a normal SH2D1A or XIAP gene, she is said to be a “carrier” of the gene mutation.

Despite having a mutation in one of her two gene copies, the normal SH2D1A or XIAP gene will produce enough protein so she does not develop X-linked lymphoproliferative syndrome. This normal copy provides a protective effect for a female X-linked lymphoproliferative syndrome carrier. This female carrier, however, can pass her X chromosome with the SH2D1A or XIAP alteration to a proportion of her future children. Thus, a female carrier can transmit the trait to develop X-linked lymphoproliferative syndrome.

Since males have a single X-chromosome, they have only one copy of the SH2D1A and XIAP genes. Therefore, when a male has an alteration in SH2D1A or XIAP, he will develop clinical signs of X-linked lymphoproliferative syndrome. This is because he does not have an extra normal copy of SH2D1A or XIAP on his Y chromosome to compensate by making normal SAP or XIAP protein.  The Y chromosome in males does not contain the same genes that are carried on the X chromosome.

Chances of passing the SH2D1A or XIAP gene mutation to your children

A female carrier of an SH2D1A or XIAP gene mutation has a 50 percent chance that she will pass this mutation onto each of her future children. Provided that the male partner of a female carrier does not himself have X-linked lymphoproliferative syndrome (XLP), a female child inheriting the alteration will also be a carrier like her mother and not show symptoms of X-linked lymphoproliferative syndrome. This is because she will have one X chromosome with an alteration in the SH2D1A or XIAP gene (inherited from her mother) and one X chromosome with a normal copy of the SH2D1A and XIAP genes (inherited from her father).

It is also possible that a female child could inherit the normal copy of SH2D1A and XIAP from both her carrier mother and her father. This child would not be a carrier of X-linked lymphoproliferative syndrome and therefore, she could not pass the SH2D1A or XIAP alteration to her future children.

A male child will always receive an X chromosome from his mother and a Y chromosome from his father. Thus, if the child born to a female X-linked lymphoproliferative syndrome carrier is a male, there is a 50 percent chance that he will inherit the X chromosome carrying the SH2D1A or XIAP alteration. If this were the case, the child would have X-linked lymphoproliferative syndrome. Similarly there is a 50 percent chance that he will inherit the X chromosome with the normal SH2D1A or XIAP gene copy. In this case, the male child would not have X-linked lymphoproliferative syndrome.

If a man with X-linked lymphoproliferative syndrome (and hence an SH2D1A or XIAP mutation) has children with a female partner who does not carry an alteration in SH2D1A or XIAP, he will either pass on a Y chromosome to his sons (who will therefore be unaffected by the syndrome) or he will pass the X chromosome with the SH2D1A or XIAPalteration to his daughters (who will be X-linked lymphoproliferative syndrome carriers). This type of inheritance of XLP follows an “X-linked” or “sex-linked” recessive pattern.

Reproductive options

There are several reproductive options for an individual with an alteration in SH2D1A or XIAP who does not want to pass this alteration onto his or her future children.

Prenatal genetic diagnosis

The usual procedure is to first determine the sex of the developing baby by performing chromosome analysis through the isolation of DNA from its cells. This can be done though one of two procedures — chorionic villus sampling (CVS) or amniocentesis — which are offered at a different time during the pregnancy. If one of these tests reveals that the baby is a boy, DNA from his fetal cells can be analyzed for presence or absence of the SH2D1A or XIAP gene mutation.

Preimplantation genetic diagnosis (PGD)

This reproductive technology is available to individuals who are known to have a genetic alteration that causes a condition such as X-linked lymphoproliferative syndrome. PGD is performed in combination with in vitro fertilization (IVF) and offers a way to test patient’s embryos for genetic disorders before transferring them into the uterus.

The procedure is particularly useful for patients with a serious inherited disorder such as X-linked lymphoproliferative syndrome, who wish to avoid passing the disorder to their children. For best results, the SH2D1A or XIAP mutation carried by the mother must be identified before either prenatal testing or PGD can be performed.

Cancer risks

It is estimated that 30 percent of patients with XLP1 develop lymphoma, an aggressive but usually curable cancer of a type of immune cell known as lymphocyte. Most of the time, lymphomas develop in XLP1 patients who have previously been infected with Epstein-Barr virus. However, in some cases, boys or young men with XLP1 can develop lymphoma without ever having had Epstein-Barr virus infection. The average age of lymphoma onset in XLP1 is estimated to be 6 years, but tumors can present at any age and anywhere in the body. To date, no patients with XLP2 have developed lymphoma.

Cancer screening protocol for children with XLP

It is not yet clear whether surveillance testing for lymphoma is useful in X-linked lymphoproliferative syndrome (XLP1) patients since it is difficult to predict when and where lymphoma will occur in the body. Instead, boys and men with XLP1 should be seen on a regular basis by their physicians and remain aware of the signs and symptoms of lymphoma, such as development of one or more firm and/or enlarged lymph nodes, fatigue, fever, weight loss, night sweats and shortness of breath. If any of these symptoms should occur and cannot otherwise be easily explained, an XLP1 patient should undergo prompt evaluation.

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