Genetic disorder linked to the long arm of the
X-chromosome affecting males and characterized by an extreme sensitivity to
Epstein-Barr virus (EBV) infection.
Duncan Disease (named after the last name of a common
ancestor of the first described boys by Purtilo); Purtilo Syndrome; Epstein
Barr Virus Susceptibility Syndrome.
About 350 cases have been described.
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).
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 Tand 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
(seroand 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.
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). 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.
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. As mentioned earlier, 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 and
ultimately often results in death. The ileocecal area and the central
nervous system are the most common primary sites of these lymphomas. About
30% present with dysgammaglobulinemia (variants ranging from
agammaglobulinemia over hypogammaglobulinemia [hypo-IgG1 and IgG3]
to polyclonal hypergammaglobulinemia [hyper-IgA, hyper-IgM] ...