Duncan's Syndrome - Lymphoproliferative Disorder

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Duncan's Syndrome - Lymphoproliferative Disorder

Postby patoco » Sun Jun 11, 2006 3:08 pm

Duncan's Syndrome - Lymphoproliferative Disorder

X-Linked Lymphoproliferative Syndrome

Our Home Page: Lymphedema People

http://www.lymphedemapeople.com

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Lymphoproliferative disorders are characterized by as a disease in which the cells of the lymphatic system frow excessively. Quite the opposite to the hypoplaysia we experience with lymphedema. While most are infact malignancies such as lymphomas, some are not. Yet, they are often treated much like cancer; can be very life threatening
and are difficult not only to diagnose but to bring into a remission state.

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Duncan's Syndrome - X-Linked Lymphoproliferative Disease

How common is XLP?

XLP is extremely rare, and only about 100 families with XLP are known to exist worldwide. It is likely, however, that there are many more individuals whose disease is as yet unrecognised.

What are the features of the condition?

XLP can have many different symptoms, and we do not yet know what the full spectrum of the disease is. We think the immune system in XLP is unable to cope with some viral infections, in particular the Epstein Barr Virus (EBV). The immune system loses its normal tight regulation, and starts to malfunction.

About a third of patients have a very severe episode of glandular fever. Another third develop a cancer of their blood cells (lymphoma) and another third have low levels of immunoglobulins, the proteins in the blood that help fight infection. More rarely, patients may have a severe form of anaemia or inflammation of small blood vessels (vasculitis). It is common for one individual to have several different symptoms over the course of their illness.

What are the symptoms of the different features?

• Severe glandular fever • Lymphoma – patients may be tired, anaemic and develop swollen glands. • Hypogammaglobulinaemia (low levels of immunoglobulins) – patients may get frequent infections

What causes the condition?

The cause of the condition was only found in 1999, so there is much we do not understand about it.

It is caused by a mutation (mistake) in one of the genes on the X chromosome. This means the cell does not get the right instructions it needs to work properly. In most families, the mistake is in a gene called SH2D1A. This gene normally makes a protein called SAP. Mistakes in the gene cannot be found in a number of people with the disease, and we are working hard to find out which gene is responsible in these families.

How is the condition inherited?

The X chromosome is one of the not allowed chromosomes: females have two X chromosomes and males have one X and one Y. Each X chromosome carries one copy of the gene. If a male has a faulty gene on his X chromosome, he will have the disease. However, because the female has two X chromosomes, the normal gene on one X can compensate for the faulty one on the other. As a result, only males get the disease, although females may carry the disease but be unaffected. This is an X-linked disease and within a family tree you may be able to pick out other affected males.

For more information about genes and genetics, please see our leaflet Genetics and inheritance: information for families.

Are all children in the family affected?
No, if a mother carries the disease, each time she has a female child, there is a 50 per cent chance the child will be a carrier. Each time she has a male child, there is a 50 per cent chance the child will be affected by the disease.

How is XLP diagnosed?

The diagnosis will be suggested by the pattern of illness in a child and his family. In most children we can confirm the diagnosis using a blood test. This will check if the protein (SAP) that makes the cells work properly is present, and will also look for the ‘mistake’ in the gene. In some families there may not be a mistake in this particular gene, and the diagnosis can be made on the clinical story alone.

What treatment can be given for the condition?

Initially treatment will be given for your child’s symptoms, and may include anti-viral medicines, immunoglobulin therapy or steroids. Ongoing supportive treatments, such as immunoglobulin and antibiotics, will be given to keep them well in the short to medium term. Bone marrow transplantation is the definitive treatment of choice at the present time. This can be a difficult procedure, requiring a prolonged hospital stay.

What is the outlook for people with the condition?

Seventy per cent of individuals with XLP die by the age of 10 years without any treatment. However, as we are learning more about the disease we are identifying adults with milder forms of the condition.

Support group
The Primary Immunodeficiency Association offers advice and support for all families with immune deficiency in the UK.

Primary Immunodeficiency Association
Alliance House
12 Caxton Street
London SW1H 0QS
Helpline: 020 7976 7640
Website: www.pia.org.uk
Ref: 2003F134


Compiled by the Immunology Department in collaboration with the Child and Family Information Group

http://www.ich.ucl.ac.uk/factsheets/families/F030134/

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Lymphoproliferative Syndrome, X-linked

Last Updated: October 29, 2004

Synonyms and related keywords: XLP syndrome, Duncan syndrome, Duncan's syndrome, X-linked recessive progressive combined variable immunodeficiency syndrome, Epstein-Barr virus, EBV, infectious mononucleosis, hypogammaglobulinemia, lymphoma, lymphoproliferative diseases.

http://www.emedicine.com/med/topic1370.htm

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Understanding X Linked Lymphoproliferative Disorder

http://www.xlp.ca/

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David Roger's XLP Story

Hey there,

My name is David Rodgerson, I am 22 years old, and this is a brief introduction to my XLP story. For more information on XLP (also known as x-linked lymphoproliferative disease/disorder or Duncan's disease), visit the new web site that my sister and I have had made.

In August of 2001 I discovered that I have a condition called XLP (X-Linked Lymphoproliferative Disease, or Duncan's disease). The disease is a genetic one and runs in my family. As well as myself, it was discovered that my nephew Aaron has it as well, as did my brother Glenn, who had passed away in 1988 from mononucleosis (an effect of having XLP). After extensive testing of my immediate and extended family, it was disovered that the only other carriers were my sister Cindy and my mother Barbara.

In April 2002, I had a stem cell transplant to "cure" me of this condition. While this does not fix the underlying genetics of the rest of my body, it has replaced my immune system with a new healthy one and thus removed the three problems caused by XLP. Since then I have had a little trouble with graft vs host disease (a complication often caused by transplants), but have otherwise been recovering wonderfully.

As it is an extremely rare condition, I have been looking for other people in the world who might share this condition and wish to talk with me. I'm looking for stories, information, or even just someone to say "I have this too."

With some help, my sister and I have completed a resource page for XLP, where people with this condition can do research to find out about the latest information on the disorder, and read other people's stories (with the people's permission to have them posted of course). The web site is intended as a resource but more importantly as a source of hope.

As for now, I'd like to hear from anyone interested in talking. You can reach me at the e-mail address below, or visit my personal web site.

God bless,

David Rodgerson

http://halifaxdavid.kicks-ass.net/~rodgerson/xlp/

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X-Linked Lymphoproliferative Syndrome

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


X-linked Lymphoproliferative Syndrome (XLP) is an extremely rare inherited (primary) immunodeficiency disorder characterized by a defective immune system response to infection with the Epstein-Barr virus (EBV).

This herpes virus is common among the general population and causes infectious mononucleosis (IM), usually with no long-lasting effects.

However, in individuals with X-Linked Lymphoproliferative Syndrome, exposure to EBV may result in severe, life-threatening infectious mononucleosis; 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 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 approximately six months to 10 years of age.

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.

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as defined at
http://www.emedicine.com/med/byname/lym ... linked.htm)

Background:

X-linked lymphoproliferative (XLP) syndrome is a rare immunodeficiency disease characterized by a predilection for fatal or near-fatal Epstein-Barr virus (EBV)–induced infectious mononucleosis (IM) in childhood, subsequent hypogammaglobulinemia, and a markedly increased risk of lymphoma or other lymphoproliferative diseases.

Pathophysiology:

In XLP syndrome, the most striking manifestation is that EBV triggers an initial episode of IM that causes death, usually by liver failure secondary to hepatic necrosis, in more than 50% of infected children.

In persons who survive the initial IM, immunodeficiency occurs secondarily, most likely due to virally induced cellular death of components of the immune system. This affects all lymphoid lines, including T lymphocytes, B lymphocytes, and natural killer cells. Hypogammaglobulinemia results, affecting all classes of immunoglobulins.

Approximately one third of patients develop lymphoma, usually B-cell non-Hodgkin histologies, although T-cell lymphomas have been reported. More rarely, aplastic anemia or a more benign lymphoproliferative disorder can result.

Frequency: In the US: The syndrome is rare. Fewer than 400 cases of XLP syndrome in fewer than 100 families have been reported.

Mortality/Morbidity: Fifty-six percent of patients develop fatal IM with ultimate fulminant liver failure. Other patients develop a fatal lymphoma, or they may die of recurrent IM. Few patients survive to adulthood.

Race: No specific ethnic distribution of this disease exists, although not enough patients have been identified internationally to fully evaluate this question.

not allowed:Because this is an X-linked disorder, all patients are male.

Age:The median age of onset is approximately 5 years.

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as defined at
X-linked lymphoproliferative syndrome registry report.
http://www.aegis.com/pubs/aidsline/1980 ... 70004.html

Abstract: Immune deficiency, especially to the Epstein-Barr virus, and increased susceptibility to fatal infectious mononucleosis, acquired agammoglobulinemia, and lymphoma are the cardinal features of the X-linked lymphoproliferative syndrome.

Since the establishment of the XLP Registry in September, 1978, 59 affected males in seven unrelated kindreds were comprehensively studied.

A spectrum of lymphoproliferative phenotypes was observed. Thirty-four patients (57%) died from infectious mononucleosis, eight (14%) had fatal infectious mononucleosis with lymphoma (immunoblastic sarcoma), nine (15%) had depressed immunity following EBV infection, and eight (14%) developed lymphoma. Several patients with XLP lacked EBV antibodies despite infection by EBV.

The results of this study suggest that EBV can be an oncogenic agent in patients who are immune deficient with XLP.

as defined at

http://www.unmc.edu/News/sumegixlp.htm

UNMC Researchers Identify Gene Causing Rare Fatal Immunological Problem in Males

An international team of scientists, including several University of Nebraska Medical Center researchers, has identified the gene involved in X-linked lymphoproliferative syndrome (XLP). The disorder, also known as Duncan's disease, is marked by an extreme vulnerability to the Epstein-Barr virus (EBV), a member of the herpes virus group that infects the majority of individuals by adulthood.

The discovery, which is reported in the Oct. 1 edition of Nature Genetics, is significant, as it will allow males at risk for XLP to be diagnosed earlier, so that therapy can be given before it is too late. In addition, it will permit the direct diagnosis of XLP in families with a single affected male.

The team of scientists was headed locally by two professors in the UNMC Department of Pathology and Microbiology -- Janos Sumegi, M.D., Ph.D., and Thomas A. Seemayer, M.D. It included researchers from Boston University School of Medicine as well as researchers from laboratories in France, Germany, Great Britain and Italy.

XLP was first observed in 1969 by the late David T. Purtilo, M.D., former professor and chairman of pathology and microbiology at UNMC who died in 1992. Males with XLP inherit a mutant gene in the X chromosome, leaving them incapable of withstanding EBV. This immune deficiency passes from unaffected women who are carriers to some of their male children.

By the time they are adults, more than 90 percent of Americans are silently infected with EBV, a virus more common than chicken pox. However, most infected people develop antibodies to fight the infection and have little more than a sore throat or a slight fever.

Today, more than 88 unrelated families and 297 males are registered in the XLP Registry at UNMC. Dr. Purtilo established the registry in 1978 to provide a central facility for coordinating research and serving as a resource for diagnostic and therapeutic strategies. Dr. Seemayer is now in charge of maintaining the XLP Registry.

Although XLP is a rare disorder occurring only as a genetic accident with a frequency of one in every 1 million live births, it currently is believed to be under diagnosed, Dr. Sumegi said.

After becoming infected with EBV, males born with XLP succumb to either one or a combination of four diseases -- mononucleosis, aplastic anemia (bone marrow failure), lymphoma or hypogammaglobulinemia (the inability to produce antibodies). About 75 percent of males with XLP die by age 10. No one has lived past age 44.

Previous genetic, cytogenetic and physical mapping studies conducted at UNMC and Boston University School of Medicine narrowed the search for the XLP gene to a small region on the X chromosome, said Dr. Sumegi, who spearheaded this work at UNMC. A variety of techniques, including DNA sequencing and computer-based analysis, was used to isolate the gene, known as SH2D1A.

Presently, the only curative therapy for XLP is allogenic stem cell transplantation. Age at the time of transplant appears to be critical, Dr. Seemayer said. Of 13 boys transplanted, nine are alive and well without recurrent disease, and all were under 15 years of age at the time of the transplant. The four non-survivors were all over 15 years of age when they were transplanted.

UNMC is the only public academic health science center in the state. Through its commitment to research, education and patient care, UNMC has established itself as one of the country's leading centers for cancer research and treatment and solid organ transplantation. More than $34 million in research grants and contracts are awarded to UNMC scientists annually. In addition, UNMC's educational programs are responsible for training more health professionals practicing in Nebraska than any other institution.

For more information, contact:
Tom O'Connor, UNMC Public Affairs
Phone: (402) 559-4353
October 1, 1998

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as defined at

http://www.wtajtv.com/health/cordbxlp.html

Cord Blood for XLP

X-Linked Lymphoproliferative Syndrome (XLP)

X-Linked Lymphoproliferative Syndrome (XLP) is a rare condition which causes serious illness after infection with Epstein-Barr virus (EBV, the virus that causes infectious mononucleosis). EBV is very common and 90 percent of people carry it in their body – constantly keeping the virus in check. Patients with XLP have an immune system that doesn’t properly respond to the virus. So EBV multiplies uncontrollably, causing life-threatening symptoms, such as fever, inflamed and sore throat, swollen lymph glands, enlargement of the spleen or liver, and/or jaundice. In some patients, the immune system produces abnormally high numbers of certain white blood cells that can damage the liver and bone marrow cells. XLP is caused by a faulty gene on the X chromosome. It almost exclusively affects males. The most common age at the start of EBV symptoms is between two and three, with a range of onset between six months and 10 years.

Cord Blood Stem Cell Transplants for XLP

Currently, there aren’t any adequate treatments for XLP and roughly 75 percent of patients die by age 10. But some doctors are successfully treating patients with stem cell transplants. Stem cells are the basic building blocks for blood. They act like baby blood cells, growing into whatever specific blood cells are needed by the body in a particular moment of time (red cells, white cells, or platelets). Patients getting a stem cell transplant receive high doses of chemotherapy to destroy their body’s ability to reject the new stem cells. After a few days, the donor stem cells are transfused into the recipient through an intravenous line. The cells find their way into the bone marrow where they grow and rebuild the patient’s immune system.

Within the body, stem cells are mostly found in the bone marrow. The cells are harvested through a surgical procedure with the donor under general anesthesia. Another source of stem cells is umbilical cord blood. After a baby is born, the umbilical cord is clamped and the blood is removed and frozen.

When possible, doctors often prefer stem cells obtained from cord blood. Stem cells obtained from bone marrow must be matched to the recipient. There is also a risk for a potentially dangerous condition called graft-versus-host disease (GVHD), in which the infused cells react to the recipient’s body. Cord blood is less likely to be contaminated with viruses, doesn’t need to be perfectly matched, and is less likely to cause GVHD. There is one limit to using cord blood for stem cell transplants. Doctors need to have a sufficient number of stem cells to rebuild the patient’s immune system. Since the amount of cord blood is very limited, the procedure is generally used for small children (up to about age 10).

More Information

Cord Blood Registry, 888-CORDBLOOD (267-3256), www.cordblood.com

American Cord Blood Program
University of Massachusetts Medical Center
19 N. Quinsigamond Ave.
Shresburg, MA 01545 USA
http://www.americancordblood.com

Cord Blood Donor Foundation
1200 Bayhill Drive, Suite 301
San Bruno, CA 94066 USA
http://www.cordblooddonor.org

National Marrow Donor Program, http://www.marrow.org

*** Article at: http://www.icomm.ca/geneinfo/xlp.htm ***

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UNMC Researchers Identify Gene Causing Rare Fatal Immunological Problem in Males - X Linked Lymphoproliferative Disorder - Duncan's Syndrome

An international team of scientists, including several University of Nebraska Medical Center researchers, has identified the gene involved in X-linked lymphoproliferative syndrome (XLP). The disorder, also known as Duncan's disease, is marked by an extreme vulnerability to the Epstein-Barr virus (EBV), a member of the herpes virus group that infects the majority of individuals by adulthood.

The discovery, which is reported in the Oct. 1 edition of Nature Genetics, is significant, as it will allow males at risk for XLP to be diagnosed earlier, so that therapy can be given before it is too late. In addition, it will permit the direct diagnosis of XLP in families with a single affected male.

The team of scientists was headed locally by two professors in the UNMC Department of Pathology and Microbiology -- Janos Sumegi, M.D., Ph.D., and Thomas A. Seemayer, M.D. It included researchers from Boston University School of Medicine as well as researchers from laboratories in France, Germany, Great Britain and Italy.

XLP was first observed in 1969 by the late David T. Purtilo, M.D., former professor and chairman of pathology and microbiology at UNMC who died in 1992. Males with XLP inherit a mutant gene in the X chromosome, leaving them incapable of withstanding EBV. This immune deficiency passes from unaffected women who are carriers to some of their male children.

By the time they are adults, more than 90 percent of Americans are silently infected with EBV, a virus more common than chicken pox. However, most infected people develop antibodies to fight the infection and have little more than a sore throat or a slight fever.

Today, more than 88 unrelated families and 297 males are registered in the XLP Registry at UNMC. Dr. Purtilo established the registry in 1978 to provide a central facility for coordinating research and serving as a resource for diagnostic and therapeutic strategies. Dr. Seemayer is now in charge of maintaining the XLP Registry.

Although XLP is a rare disorder occurring only as a genetic accident with a frequency of one in every 1 million live births, it currently is believed to be under diagnosed, Dr. Sumegi said.

After becoming infected with EBV, males born with XLP succumb to either one or a combination of four diseases -- mononucleosis, aplastic anemia (bone marrow failure), lymphoma or hypogammaglobulinemia (the inability to produce antibodies). About 75 percent of males with XLP die by age 10. No one has lived past age 44.

Previous genetic, cytogenetic and physical mapping studies conducted at UNMC and Boston University School of Medicine narrowed the search for the XLP gene to a small region on the X chromosome, said Dr. Sumegi, who spearheaded this work at UNMC. A variety of techniques, including DNA sequencing and computer-based analysis, was used to isolate the gene, known as SH2D1A.

Presently, the only curative therapy for XLP is allogenic stem cell transplantation. Age at the time of transplant appears to be critical, Dr. Seemayer said. Of 13 boys transplanted, nine are alive and well without recurrent disease, and all were under 15 years of age at the time of the transplant. The four non-survivors were all over 15 years of age when they were transplanted.

UNMC is the only public academic health science center in the state. Through its commitment to research, education and patient care, UNMC has established itself as one of the country's leading centers for cancer research and treatment and solid organ transplantation. More than $34 million in research grants and contracts are awarded to UNMC scientists annually. In addition, UNMC's educational programs are responsible for training more health professionals practicing in Nebraska than any other institution.

http://www.unmc.edu/News/sumegixlp.htm

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SAP: The gene responsible for X-linked lymphoproliferative disease

Ornella PAROLINI
Walter KNAPP
(Institute for immunology University Vienna)

The phenotype of X linked lymphoproliferative (XLP) disease presents us with heterogeneous and relatively non-specific clinical findings. Affected patients often die suddenly with few signs of warning. One of the most intriguing aspects of XLP syndrome is the association with Epstein Barr virus (EBV).

It is well known that EBV infection is associated with other forms of lymphoproliferation and diseases such as acute infectious mononucleosis (IM), sporadic fatal infectious mononucleosis (SFIM), lymphoproliferative disorders in immunologically compromised individuals (LPD), Hodgkin's disease (HD), chronic active EBV infection (CAEBV), and virus-associated hemophagocytic syndrome (VAHS). In addition there are EBV-associated diseases such as EBV genome-positive Burkitt's lymphoma (BL), and undifferentiated nasopharyngeal carcinoma (NPC).

Although the involvement of EBV with the above mentioned pathologies is well defined, the general mechanisms controlling the normal immune response to EBV and the reasons underlying the progression of EBV infection into this wide variety of human disorders are largely unclear. Interestingly, some of the above mentioned pathologies resemble the characteristic overshooting but ineffective T-cell response observed in XLP patients.

In 1998 three groups reported the identification of the gene that is abnormal in XLP. The gene has been called SH2D1A, SAP and DHSP, and encodes a 128 amino acid protein consisting only of an SH2 domain with 5 aminoacids at the aminoterminus and 25 amino acids at the carboxyterminus. The gene is predominantly expressed in T-cells. The expression in other cell types and the regulation of this gene during T-cell activation is still controversial.

Therefore our aims are:

to get better insights into SAP gene expression and regulation
to define at genetic and at functional level the involvement of SAP and its binding partner SLAM (signaling lymphocyte activation molecule) genes in some of the mentioned diseases.

Accomplished tasks

During this year we have tried to establish the required tools for the performance of the entire project and started addressing some key questions of the project itself:

1. In order to study regulation and expression of the gene it is necessary to produce a monoclonal antibody. We have already obtained an SAP recombinant fusion protein. We have employed two different strategies, using both E.coli and S.Cerevisiae expression systems. The production of anti SAP monoclonal antibody is in progress.

2. We have successfully established a mutation analysis test for SAP, the gene defective in XLP, and SLAM, the protein that binds to SAP. The method is based on a screening method such as SSCP (single strand conformation polymorphism) analysis and direct sequencing of both SAP and SLAM genes.

The test has been applied to suspected XLP patients coming from the St. Anna Kinderspital and other pediatric centers (a total of 7 patients has been evaluated, however only two were confirmed to have a mutation in the SAP gene).

3. Concerning the specific question about the involvement of the SAP gene in other EBV related disorders, we have applied mutation analysis to the following samples: hemophagocytic syndrome, Burkitt type lymphoma, Hodgkin´s disease. The samples were collected at the St. Anna Kinderspital and the Hematology Unit of the AKH. A total number of 35 samples has been evaluated. So far no DNA alteration in the SAP gene has been detected in any of the above mentioned group of patients. We have identified a polymorphism in the 5’ non coding region at position —349. If this polymorphism has any functional relevance, it still needs to be investigated and requires an extensive analysis of the gene in normal controls.

Future directions

Beside the analysis of DNA alterations in the SAP gene in patients with other forms of EBV related diseases, functional studies on T-cell lines derived from these patients will be performed in order to clarify the functional involvement of SAP and/or SLAM in the above mentioned EBV related pathologies. This information will have a strong impact on the understanding of the mechanisms underlying the pathogenesis of other EBV associated diseases beside XLP.

Concerning suspected XLP patients, we will continue with SAP molecular diagnosis. Finally, we intend to complete SAP expression and regulation studies both at mRNA and protein level since these results are essential for any approach in genetic correction.

http://www.ccri.at/english/externa_4.html

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SH2D1Abase mutation publications (SAP Gene)

http://bioinf.uta.fi/SH2D1Abase/sh2d1apubs.html

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#308240
LYMPHOPROLIFERATIVE SYNDROME, X-LINKED

Alternative titles; symbols

XLP
LYMPHOPROLIFERATIVE DISEASE, X-LINKED; XLPD
LYP
DUNCAN DISEASE
EPSTEIN-BARR VIRUS INFECTION, FAMILIAL FATAL
EBV SUSCEPTIBILITY; EBVS
INFECTIOUS MONONUCLEOSIS, SUSCEPTIBILITY TO
IMMUNODEFICIENCY, X-LINKED PROGRESSIVE COMBINED VARIABLE
IMMUNODEFICIENCY 5; IMD5
PURTILO SYNDROME

Gene map locus Xq25

TEXT

A number sign (#) is used with this entry because X-linked lymphoproliferative syndrome is caused by mutation in the gene encoding the SH2 domain protein-1A (300490).

DESCRIPTION

X-linked lymphoproliferative syndrome, or Duncan disease, is characterized by extreme sensitivity to infection with Epstein-Barr virus, which results in a complex phenotype manifested by severe or fatal mononucleosis, acquired hypogammaglobulinema, and malignant lymphoma. Other features may include aplastic anemia, red cell aplasia, and lymphomatoid granulomatosis (Purtilo et al., 1977; Purtilo, 1981; Purtilo and Grierson, 1991; Coffey et al., 1998).

An autosomal form of susceptibility to EBV has also been suggested (see 226990).

CLINICAL FEATURES

Purtilo et al. (1974, 1975) reported a kindred by the name of Duncan in which 6 males died between the ages of 2 and 19 years from a lymphoproliferative disease. The subtle, progressive combined variable immunodeficiency disease was characterized by benign or malignant proliferation of lymphocytes and histiocytosis, as well as alterations in concentrations of serum immunoglobulins. In at least 3 of 6 boys, infectious mononucleosis occurred during or preceding the terminal events. Fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, atypical lymphocytosis, and a spectrum ranging from agammaglobulinemia to polyclonal hypergammaglobulinemia occurred. At necropsy, the thymus glands and thymic-dependent areas in the lymph nodes and spleen were depleted of lymphocytes. Hematopoietic organs, viscera, and central nervous system were diffusely infiltrated by lymphocytes, plasma cells, and histiocytes, some containing erythrocytes. Two of the 6 males, half sibs, had lymphomas of the ileum and central nervous system. The authors raised the possibility that 'the Epstein-Barr virus or other viruses triggered the fatal proliferation of lymphocytes and that progressive attrition of T-cell function allowed uncontrolled lymphoproliferation.' In addition to the kindred described by Purtilo and his colleagues, the kindred in which 4 young male cousins died of infectious mononucleosis, as reported by Bar et al. (1974), and the kindred with agammaglobulinemia developing after infectious mononucleosis in 3 maternal male cousins, as reported by Provisor et al. (1975), may be examples of Duncan disease.

Hamilton et al. (1980) abbreviated the designation of this disease to XLP (X-linked lymphoproliferative) syndrome. They reported studies of 59 affected males in 7 unrelated kindreds ascertained through an XLP registry. Thirty-four patients died of infectious mononucleosis, 8 had fatal infectious mononucleosis with immunoblastic sarcoma, 9 had depressed immunity following Epstein-Barr virus infection, and 8 developed lymphoma.

Purtilo et al. (1982) reviewed 100 cases of XLP in 25 kindreds, and suggested 4 major interrelated phenotypes: infectious mononucleosis (IM), malignant B-cell lymphoma (ML), aplastic anemia (AA), and hypogammaglobulinemia (HGG). Eighty-one of the patients died; 2 were asymptomatic but showed immunodeficiency to EBV; 75 had IM and, concurrently, 17 of this group had AA; all with AA died within a week. On the other hand, AA did not accompany HGG or ML. In 9, IM appeared to evolve into ML; however, most patients with ML showed no obvious antecedent IM. In 1, IM occurred after recurrent ML. Twenty-six of 35 lymphomas were in the terminal ileum. Heterozygous women (mothers of boys with XLP) showed abnormally elevated titers of antibodies to EBV.

Sullivan et al. (1980) found deficient activity of natural killer (NK) cells from patients with XLP. Sullivan et al. (1983) studied 2 males with XLP before and during acute fatal Epstein-Barr virus infection. Before EBV infection, both showed normal cellular and humoral immunity. Death in both cases was caused by liver failure: one developed extensive hepatic necrosis; the other developed massive infiltration of the liver with EBV-infected immunoblasts after aggressive immunosuppressive therapy. Sullivan et al. (1983) proposed that an aberrant immune response triggered by acute EBV infection results in unregulated anomalous killer and natural killer cell activity against EBV infected and uninfected cells. They further suggested that the global cellular immune defects in males with XLP who survive EBV infection represent an epiphenomenon.

Purtilo and Grierson (1991) reported that during the previous decade 240 males with XLP within 59 unrelated kindreds had been identified worldwide. One-half of the patients had developed fatal infectious mononucleosis at an average age of about 2.5 years, and death occurred on average only 33 days following onset of illness. About one-third had acquired hypogammaglobulinemia and another one-fourth had developed malignant lymphoma, most of which were of the Burkitt type involving the ileocecal region. Although hypogammaglobulinemia and malignant lymphoma were associated with longer survivals, no patient had been documented as living into the fifth decade of life.

Seemayer et al. (1995) reviewed XLP 25 years after Purtilo's first observations in 1969. Purtilo established a registry in 1980 to serve as a worldwide resource for the diagnosis, treatment, and research of this condition. After Purtilo's death in late 1992, the registry and research unit continued to function as a worldwide consultative service. By 1995, some 272 affected members of 80 kindreds had been identified. Approximately 10% of the boys who inherited the mutated XLP gene were immunologically abnormal, even before evidence of EBV exposure.

Coffey et al. (1998) noted that the average age of disease onset in XLP is 2.5 years, with 100% mortality by the age of 40 years. Following infection with EBV, patients mount a vigorous, uncontrolled polyclonal expansion of T and B cells. The primary cause of death is hepatic necrosis and bone marrow failure. The extensive tissue destruction of the liver and bone marrow appears to stem from the uncontrolled cytotoxic T-cell response.

Systemic vasculitis is an uncommon manifestation of XLP. Dutz et al. (2001) described a patient who died as a result of chronic systemic vasculitis and fulfilled clinical criteria for the diagnosis of XLP. Sequencing of the SH2D1A gene revealed a novel point mutation affecting the SH2 domain. The patient presented with virus-associated hemophagocytic syndrome, and later chorioretinitis, bronchiectasis, and hypogammaglobulinemia developed. He further developed mononeuritis and fatal respiratory failure. Evidence of widespread small and medium vessel vasculitis was noted at autopsy with involvement of retinal, cerebral, and coronary arteries as well as the segmental vessels of the kidneys, testes, and pancreas. Immunohistochemical analysis showed that the vessel wall infiltrates consisted primarily of CD8+ T cells, implying a cytotoxic T-lymphocyte response to antigen. Epstein-Barr virus DNA was detected by PCR in arterial wall tissue microdissected from infiltrated vessels, suggesting that the CD8+ T cells were targeting EBV antigens within the endothelium. Dutz et al. (2001) proposed that functional inactivation of the SH2D1A gene impairs the immunologic response to EBV, resulting in systemic vasculitis.

DIAGNOSIS

Purtilo and Grierson (1991) concluded that the diagnosis of XLP in affected males and female carriers was 99% accurate based on results of linkage to DXS42 RFLPs (lod = 19.4) and 95% accurate with RFLP probes to DXS37 (lod = 11.8). By linkage analysis, they detected males with the XLP gene before EBV infection occurred.

Using RFLP analysis, Grierson et al. (1993) evaluated 10 families in which a single male had died of infectious mononucleosis. The authors suggested that, in such families, Epstein-Barr virus-seronegative males must be considered at risk for XLP and should be identified pre-EBV infection in order to maximize survival. One family in the study was determined to have XLP; 3 other families in the study had carriers of XLP, and 3 families were determined not to have XLP.

Prenatal Diagnosis

Skare et al. (1992) made the diagnosis of XLP prenatally by analyzing closely linked RFLP markers of cells obtained at amniocentesis at 15 weeks' gestation. By use of DNA markers applied to chorionic villus sampling (CVS) material, Mulley et al. (1992) identified with high reliability an unaffected male fetus, brother of an affected male. By HLA-DR typing of the CVS, they also showed that the fetus was DR-identical to the affected sib.

CLINICAL MANAGEMENT

Williams et al. (1993) reported successful bone marrow transplantation in an 11-year-old boy with Duncan syndrome, with restoration of an apparently normal host immune response to EBV. They presented this as evidence that the primary abnormality in this disorder resides in bone marrow-derived cells.

Vowels et al. (1993) described a boy with this disorder in whom transplantation of cord-blood stem cells from an HLA-identical sib resulted in correction of the genetic defect and the hypogammaglobulinemia. Cord blood collected at birth contains 5 to 10 times more marrow progenitor cells than the peripheral blood of older infants or children, and the volume of blood and nucleated cells that can be collected is substantial. The authors noted that cord blood had successfully been transplanted into patients with aplastic anemia and leukemia, resulting in repopulation of the bone marrow and immune systems.

Arkwright et al. (1998) reported a sibship of 4 males born to unrelated parents, 3 of whom had X-linked lymphoproliferative disease. The proband was born at 33 weeks' gestation and developed neonatal varicella zoster infection complicated by tibial osteomyelitis. At 18 months of age, he developed infectious mononucleosis complicated by hepatitis and aplastic anemia. The latter responded well to oral corticosteroids, broad-spectrum antibiotics, and acyclovir. He later developed hypoglobulinemia and required regular intravenous infusions of immunoglobulin. An older brother was healthy until the age of 7, when he developed a fulminant cytomegalovirus infection (hemophagocytic lymphohistiocytosis). This responded to etoposide-based chemotherapy and a successful allogenic bone marrow transplant from his normal sib. At 4 months of age, another brother was shown by RFLP and microsatellite markers flanking the XLP locus to have inherited the high-risk haplotype. Although healthy, he was receiving prophylactic intravenous immunoglobulin infusions. This sibship demonstrated the varied clinical manifestations of X-linked lymphoproliferative disease.

Schuster and Kreth (1999) stated that the only means available to prevent EBV- and non-EBV-related complications in later life is early transplantation of allogeneic hematopoietic stem cells, i.e., cord blood or bone marrow (Vowels et al., 1993; Williams et al., 1993). The age of the patient at the time of transplantation appeared to be critical. Whereas 4 of 8 XLPD patients who underwent stem cell transplantation before the age of 15 years were alive and well for more than 2 years posttransplantation, all 4 boys older than 15 years of age at the time of transplantation died within 90 days of complications.

MAPPING

Skare et al. (1987, 1987) demonstrated linkage of XLP with marker DXS42, which maps to Xq24-q27 (lod score of 5.26). Haplotype analysis refined the XLP locus distal to DXS42 and proximal to DXS99. Skare et al. (1989) extended the linkage information on the family they reported in 1987 and studied 6 additional families, all of which corroborated the close linkage to DXS42 (1% recombination; lod = 17.5) and DXS37 (maximum lod = 13.3 at theta = 0.0.)

Hayoz et al. (1988) identified a large, extensively affected Swiss family with XLP, ascertained through a patient with acquired hypogammaglobulinemia associated with a mononucleosis syndrome at the age of 18 years; the patient died at 19. In this family, a new mutation for hemophilia A (306700) had occurred, resulting in a woman who was a carrier of both genes. She had a son with hemophilia, a daughter who was a carrier of both disorders, and a son who was free of both disorders. The doubly-heterozygous daughter had 1 son with XLPD and 1 son who was doubly affected. The observations suggested that the hemophilia A locus and the XLPD locus are far apart, a conclusion that was supported by other mapping data.

Harris et al. (1988) excluded linkage of XLP to 28 X-linked probes. Harris and Docherty (1988) found no particular chromosomal abnormalities in this disorder. One of their patients was found to have the Klinefelter syndrome, having inherited 2 copies of his maternal XLPD-carrying X chromosome. Wyandt et al. (1989) found deletion of part of band Xq25 in a male with this disorder; others found the same deletion in the mother and a sister. Skare et al. (1989) reported family linkage studies of the XLP-causing gene with several Xq DNA markers. They also reported 1 male of 14 unrelated affected persons who had a deletion in Xq which was thought to involve about one-half of Xq25. This male retained sequences at all 5 loci that had been found to be closely linked to XLP, but lacked DXS6 which by somatic hybrid mapping had been assigned to Xq26-qter. In a large Swiss family with XLP, Sylla et al. (1989) demonstrated linkage of XLP to marker DXS37, which is located in Xq25-q26. Multipoint linkage analysis showed that the XLP locus is distal to DXS11 but proximal to HPRT (308000). Sanger et al. (1990) demonstrated an interstitial deletion involving a portion of Xq25 in an affected male as well as in 1 sister and their mother. Using blot hybridization, Skare et al. (1993) identified 3 XLP males with deletions of Xq25 encompassing marker DXS739.

MOLECULAR GENETICS

In 9 unrelated patients with X-linked lymphoproliferative syndrome, Coffey et al. (1998) identified mutations in the SH2D1A gene (300490.0001-300490.0009).

In 2 brothers with early-onset non-Hodgkin lymphoma, but no clinical or laboratory evidence of EBV infection, Brandau et al. (1999) identified a deletion of exon 1 of the SH2D1A gene (300490.0010). Other SH2D1A mutations were identified in 2 additional unrelated patients without evidence of EBV infection; 1 had non-Hodgkin lymphoma and 1 had signs of dysgammaglobulinemia. Development of dysgammaglobulinemia and lymphoma without evidence of prior EBV infection in 4 patients suggested that EBV is unrelated to these particular phenotypes, in contrast to fulminant or fatal infectious mononucleosis. No SH2D1A mutations were found in 3 families in which clinical features were suggestive of XLP.

Sumegi et al. (1999) reviewed the molecular basis of Duncan disease. They tabulated 15 mutations in the SH2D1A gene.

HISTORY

Schuster and Kreth (1999) attributed the first report of a family with XLP to Hambleton and Cottom (1969), who described a family in which 2 brothers suffered from hypogammaglobulinemia and malignant lymphoma following infectious mononucleosis.

SEE ALSO

Levine et al. (1982); Loeffel et al. (1985); Lyon and Loutit (1983); Purtilo (1976); Purtilo et al. (1978); Purtilo et al. (1977); Skare et al. (1989); Steinherz et al. (1985)

CONTRIBUTORS

Cassandra L. Kniffin - reorganized : 5/26/2004
Marla J. F. O'Neill - updated : 4/5/2004
Paul J. Converse - updated : 9/10/2003

http://www.ncbi.nlm.nih.gov/entrez/disp ... ?id=308240

.........

Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP)

http://hmg.oupjournals.org/cgi/content/full/8/13/2407

.........

Mapping the X-linked lymphoproliferative syndrome.

J C Skare, A Milunsky, K S Byron, and J L Sullivan

http://www.pubmedcentral.nih.gov/articl ... id=2882515

.........

Lymphocytic vasculitis in X-linked lymphoproliferative disease

Jan P. Dutz, Loralyn Benoit, Xiaoxia Wang, Douglas J. Demetrick, Anne Junker, Derek de Sa, and Rusung Tan

From the Departments of Medicine, Pathology & Laboratory Medicine and Pediatrics, University of British Columbia and British Columbia's Children's Hospital; and the Department of Pathology, University of Calgary, Alberta, Canada.

http://www.bloodjournal.org/cgi/content/full/97/1/95
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