X-linked lymphoproliferative disease

X-linked lymphoproliferative disease (also known as "Duncan's disease"[1]:86 or "Purtilo syndrome"[2]) is a lymphoproliferative disorder.[3]

X-linked lymphoproliferative disease
SpecialtyHematology 

Presentation

Strangely, in boys with X-linked lymphoproliferative disorder, there is an inability to mount an immune response to the Epstein-Barr virus (EBV),[4] which often leads to death from bone marrow failure, irreversible hepatitis, and malignant lymphoma. However, the connection between EBV and X-linked lymphoproliferative disorder is yet to be determined.[5]

Patients produce insufficient numbers of CD27 memory B cells.[6]

Cause

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.[7]

The SAP protein is important in the signalling events that activate T- and NK-cells[8] 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.[9]

Some sources recommend classifying this condition as "X-linked familial hemophagocytic lymphohistiocytosis" instead of X-linked lymphoproliferative disease.[10]

Diagnosis

Treatment

Eponym

It is also known as Duncan Disease, after 6 of 18 males in the Duncan family died of lymphoproliferative disease, including fulminant infectious mononucleosis and lymphoma [11]. It is also called "Purtilo's Syndrome", after Dr. David Theodore Purtilo (1939–1992), a pioneering Pathologist and Immunologist at the American Army Center for Pathology in Washington, who discovered it in the early 1970s. A native of Duluth, Minnesota, he pioneered the research for this condition after discovering it in one of his patients. In the late 1980s, he resided in Omaha, Nebraska and died on September 28, 1992 in Florida, after suffering a stroke before he could deliver a speech to a forum.[12]

References
  1. James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
  2. http://ghr.nlm.nih.gov/condition/x-linked-lymphoproliferative-disease
  3. Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 808. ISBN 1-4160-2999-0.
  4. Kumar, Vinay; Cotran, Ramzi S.; Robbins, Stanley L. (2003). Robbins Basic Pathology (7th ed.). Philadelphia: Elsevier. p. 418. ISBN 1-4160-2534-0.
  5. Lymphoproliferative Disorders at eMedicine
  6. Ma CS, Pittaluga S, Avery DT, et al. (February 2006). "Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease". J. Clin. Invest. 116 (2): 322–33. doi:10.1172/JCI25720. PMC 1332028. PMID 16424938.
  7. Abbas, A.K; Lichtman, A.H. (2005). Cellular and Molecular Immunology (5th ed.). Philadelphia: Elsevier Saunders.
  8. X-linked Lymphoproliferative Syndrome at Merck Manual of Diagnosis and Therapy Professional Edition
  9. Rigaud S, Fondanèche MC, Lambert N, et al. (November 2006). "XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome". Nature. 444 (7115): 110–4. doi:10.1038/nature05257. PMID 17080092.
  10. Marsh RA, Madden L, Kitchen BJ, et al. (August 2010). "XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease". Blood. 116 (7): 1079–82. doi:10.1182/blood-2010-01-256099. PMC 2938130. PMID 20489057.
  11. 1.Purtilo DT, Cassel C, Yang JP. Letter: Fatal infectious mononucleosis in familial lymphohistiocytosis. N Engl J Med 1974; 291:736.
  12. https://www.nytimes.com/1992/10/03/us/david-t-purtilo-53-a-specialist-in-disorders-of-the-immune-system.html
Classification
External resources


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