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At a glance

Genetic disorder linked to the long arm of the X-chromosome characterized by the clinical triad of increased susceptibility to primary Epstein-Barr virus (EBV) infection, dysgammaglobulinemia, and lymphoma.

Synonyms

Duncan Disease (named after the last name of a common ancestor of the first described boy by Purtilo); Purtilo Syndrome; Epstein Barr Virus Susceptibility Syndrome.

Incidence

About 350 cases have been described.

Genetic inheritance

X-linked recessive, with gene locus mapping to Xq25. The responsible gene is called SAP/SH2D1A and seems to have a key function in T/B-cell homeostasis. (SAP is the abbreviation for SLAM [signaling lymphocytic activation molecule]-associated protein, and SH2D1A refers to Src homology 2 domain protein 1A.)

Pathophysiology

In more than half of these patients, the infection with EBV triggers an infectious mononucleosis that (usually) within a month after onset results in lethal liver failure as a result of fulminant hepatitis with extensive hepatic necrosis. EBV-induced lymphoblasts trigger an abnormal T- and B-cell proliferation, resulting in diffuse infiltration of multiple organs, leading not only to fulminant hepatitis, but also to bone marrow failure with hemophagocytic components. Survivors of this infection initially develop a state of immunodeficiency that can affect all immune cell lines and immunoglobulins and put the patients at high risk for bacterial infections, or develop a malignant lymphoma (see “Clinical aspects” below) later in life. However, newer studies indicate that dysgammaglobulinemia and lymphoma may occur in these patients even in the absence of a prior EBV infection (sero- and PCR-negative), pointing to a fundamental role of the SAP/SH2D1A gene in the pathogenesis of this syndrome. It has been hypothesized that XLP may be a progressive immunodeficiency disease with manifestation particularly after viral infections.

Diagnosis

Based on clinical criteria, family history, fatal EBV infection, immunodeficiency, aplastic anemia, genotype analysis (SAP/SH2D1A gene), and serology (although not necessarily positive for EBV). Deoxyribonucleic acid (DNA) probes can reveal the carrier state in females. The definitive diagnosis is made when two or more maternally related males manifest an XLP phenotype following EBV infection. Hyperimmunoglobulinemia A or M (before EBV infection), hyperimmunoglobulinemia G1 or G3 (before EBV infection), and inadequate response to EBV infection are considered minor criteria for the diagnosis.

Clinical aspects

The average age at the time of diagnosis is 3 to 5 years. Common presenting symptoms are initially nonspecific, such as fever, nausea, vomiting, and abdominal pain. The three main phenotypes can be distinguished. About half of patients experience a fulminant mononucleosis resulting in liver failure and death. About a quarter of all patients develop a malignant non-Hodgkin lymphoma (often B-cell lymphoma of the Burkitt type) later in life, which may well respond to the initial treatment but seems to have a high relapse rate ...

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