Lymphoproliferative Syndrome, X-Linked

Alternative Names

  • XLP1
  • XLP
  • Lymphoproliferative Disease, X-Linked
  • XLPD
  • LYP
  • Duncan Disease
  • Epstein-Barr Virus Infection, Familial Fatal
  • EBV Infection, Severe, Susceptibility to
  • EBVS
  • Infectious Mononucleosis, Severe, Susceptibility to
  • Immunodeficiency, X-Linked Progressive Combined Variable
  • Immunodeficiency 5
  • IMD5
  • Purtilo Syndrome
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Certain disorders involving the immune mechanism

OMIM Number

308240

Mode of Inheritance

X-linked recessive

Gene Map Locus

Xq25

Description

X-linked Lymphoproliferative Syndrome (XLP), or Duncan disease, is an extremely rare genetic disorder of the immune system that causes a defective immune system response to some viral infections, in particular the Epstein-Barr virus (EBV). Defective immune response to those viral infections can be either underactive response (immunodeficiency), or overactive response that leads to many complications. EBV is a herpes virus that causes infectious mononucleosis (IM) and normally it has no long-lasting effects. However, patients with XLP cannot properly attack the virus and that will result in severe, life-threatening IM; glandular fever (in 1/3 of the patients); hypogammaglobulinemia with increased susceptibility to various infections (in 1/3 of the patients); lymphomas especially B-cell lymphoma (in 1/3 of the patients); and/or other abnormalities that vary from one patient to another. Rarely, severe anemia, thrombocytopenia, and inflammation of the blood vessels may also present in those patients. Onset of symptoms ranges from six months to 10 years of age.

There are only 100 families all over the world suffering from XLP, however, unrecognized cases do definitely exist in many countries. Diagnosis relies mainly on blood test that identifies mutations in the corresponding gene or detects the defects in the gene-produced protein known as SAP (Signaling lymphocytic activation molecule - Associated Protein). Supportive treatment is recommended by antibiotics, that prevent other infections, and by immunoglobulin supplements, however, bone marrow transplantation remains the best choice of treatment. About 70% of untreated cases die by the age of 10 years.

Molecular Genetics

Since XLP is transmitted as an X-linked recessive genetic trait, the disorder is usually fully expressed in males only. In most families with XLP, mutations in the SH2 domain protein 1A (SH2D1A) gene have been found to cause the disease. Normally, SH2D1A gene is encoding SAP protein that functions as a regulator of the signal transduction pathways. On the other hand, the causative gene cannot be identified in some families with XLP and research is ongoing to find out which gene is responsible in these families.

Epidemiology in the Arab World

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Other Reports

Bahrain

Al-Mukharraq (1997) described a 49-month-old Bahraini boy who presented at the age of six months with history of upper respiratory tract infection, pallor, generalized lymphadenopathy, hepatosplenomegaly, and delayed milestones. The patient had two dead male siblings, one of them died with a progressive CNS lymphoma at three years and the other died at the age of seven months with a fulminant course of febrile infectious disease. Utlrasonography showed marked enlargement of the spleen and the paraortic lymph node. Bone marrow aspiration biopsy revealed erythroid hyperplasia granulocytopoieses. The marrow had a rapid proliferation with early B-cell population. Cytogenetics 46 X Y of the 11 cell examined showed normal male karyotype in ten cells and an abnormal count of 58 chromosomes in one cell. Fine needle aspiration biopsy of cervical lymph node displayed non-specific reactive lymphadenitis. Immunophenotyping of the bone marrow and axillary mesenteric lymph node showed that 80% were of T-cell type. At the age of four years and nine months he was admitted for meningitis and sepsis and he developed disseminated intravascular coagulation. His condition worsened rapidly and died within the 24 hours of his admission. The blood and CSF cultures grew Streptococcus pneumonia.

Saudi Arabia

Alangari et al. (2006) described a 7-year old Saudi boy with XLP and growth hormone deficiency.  The patients had a history of recurrent infections and growth failure.  His parents were distantly related, and he had seven other healthy siblings.  Upon examination, he was found to be below the 5th centile for both height and weight, and had finger clubbing.  CBC analysis showed low immunoglobulin levels, and elevated WBC and total lymphocyte levels.  In addition, growth hormone levels after stimulation were found to be low.  He was started on immunoglobulin replacement therapy.  Biopsy of a progressive left cervical lymph node enlargement identified diffuse large B-cell non-Hodgkin’s lymphoma.  This raised the suspicion of XLP, which was confirmed by mutation analysis of the SH2D1A gene.  The patient underwent a bone-marrow transplant from an HLA identical sister, but died of post-transplant complications.

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