X-linked lymphoproliferative syndromes: brothers or distant cousins?

• Published in: Blood Vol. 116; no. 18; pp. 3398 - 3408
• Main Authors: Filipovich, Alexandra H., Zhang, Kejian, Snow, Andrew L., Marsh, Rebecca A.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 04-11-2010; Americain Society of Hematology; American Society of Hematology
• Series: Review Article
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; Biological and medical sciences; Epstein-Barr virus; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoproliferative Disorders - genetics; Lymphoproliferative Disorders - immunology; Lymphoproliferative Disorders - pathology; Lymphoproliferative Disorders - therapy; Medical sciences; Metabolic diseases; Miscellaneous; Other metabolic disorders; Phenotype; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Review; Signaling Lymphocytic Activation Molecule Family Member 1; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - immunology; Endocrinopathy; Sex linked character; Hematology; Lymphoproliferative syndrome; Metabolic diseases; Cardiovascular disease; Hemopathy; X-Chromosome; Sibling; Metabolic syndrome
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-03-275909

X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecule-associated protein (SAP; encoded by SH2D1A) is mutated in XLP1, and X-linked inhibitor of apoptosis (XIAP; encoded by BIRC4) is mutated in XLP2. XLP1 is a disease with multiple and variable clinical consequences, including fatal hemophagocytic lymphohistiocytosis (HLH) triggered predominantly by Epstein-Barr virus, lymphomas, antibody deficiency, and rarer consequences of immune dysregulation. To date, XLP2 has been found to cause HLH with and without exposure to Epstein-Barr virus, and HLH is commonly recurrent in these patients. For both forms of XLP, the only curative therapy at present is allogeneic hematopoietic cell transplantation. Beyond their common X-linked locus and their requirement for normal immune responses to certain viral infections, SAP and XIAP demonstrate no obvious structural or functional similarity, are not coordinately regulated with respect to their expression, and do not appear to directly interact. In this review, we describe the genetic, clinical, and immunopathologic features of these 2 disorders and discuss current diagnostic and therapeutic strategies.