X-Linked Lymphoproliferative (XLP) Syndrome

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] have been described). Other manifestations may include aplastic anemia, vasculitis, and pulmonary lymphomatoid granulomatosis leading to arterial wall destruction and aneurysm formation. Seventy percent of the boys where a follow-up exists (87% of patients) died before the age of 10 years, and only two lived to 40 years. The clinical management includes regular treatment with immunoglobulins containing antibodies against EBV. In patients with hypogammaglobulinemia, immunoglobulins are indicated to prevent recurrent infections. Allogenic bone marrow transplant is a newer and successful treatment option; however, it remains to be seen whether the long-term outcome changes for these patients.

Evaluate for cardiac dysfunction, review baseline chest radiographs and ECG. Blood work should include a complete blood cell count, electrolytes, and liver function (e.g., transaminases, coagulation tests, serum proteins). Transfuse as necessary. If major surgery is planned, make sure that irradiated blood products are available. If the patient has had a bone marrow transplant and is on immunosuppressant and cortisone, it is important to evaluate renal function and plan for stress doses of steroids.

Depending on the manifestations of the disease, these patients may be at a very high risk or at only a slightly increased risk for anesthesia. In the period of acute infectious mononucleosis with liver failure, anesthesia should be restricted to real emergency procedures only. Because the primary site of non-Hodgkin lymphoma is most often extranodal, compression of the airway or major vessels is most likely not present. However, it can result in increased intracranial pressure or ileus, requiring an appropriate anesthesia technique according to the standards. Use a strictly aseptic technique for insertion of any catheters. Avoid regional anesthesia in uncorrected thrombocytopenia.

Parenchymal liver disease alters the metabolism of drugs with high hepatic extraction ratio. Keep in mind that serum protein concentrations may be skewed and the free fraction of highly protein-bound drugs, and their efficacy, can be changed significantly.

For a summary, see Primary Immunodeficiencies

Chronic Granulomatous Disease: An inherited immune deficiency with abnormality of phagocytic cells that is caused by dysfunctional oxidative metabolism leading to recurrent life-threatening bacterial and fungal infections. Few patients survive into the fourth decade.

Omenn Syndrome: An autosomal recessive inherited severe combined immunodeficiency (SCID) secondary to defective T-lymphocytes and a lack of B-lymphocytes.