Lymphoproliferative syndrome X-linked, type 2D81.4

Lymphoproliferative syndrome, X-linked, also known as XLP2 for short, is an X-linked primary immunodeficiency and is associated with dysregulation of the immune system. The disease is associated with mutations in the XIAP gene.

In the first years of life, later occurrence is possible.

Clinical symptoms include hemophagocytic lymphohistiocytosis (HLH), often associated with chronic EBV infection, as well as splenomegaly, fever, colitis or inflammatory bowel disease (IBD), and recurrent infections.

Laboratory abnormalities vary but may include hypogammaglobulinemia, cytopenias, and low levels of NKT- cells,. Functional studies show increased T cell sensitivity to apoptosis (activation-induced cell death, AICD), impaired cytokine production, including TNF-alpha (TNFA - 191160), and general immune system dysregulation, such as increased IL18 levels (600953). However, circulating levels of lymphocytes and NK cells are usually normal.

Many patients with this immunodeficiency die from fulminant hemophagocytic lymphohistiocytosis. The only curative treatment option is hematopoietic stem cell transplantation, although this procedure is associated with a poor prognosis. Female mutation carriers are usually asymptomatic. (see Yang et al. 2015).

Dziadzio et al (2015) reported a large Caucasian family with lymphoproliferative syndrome, X-linked (XLP2), including 6 affected males. There was wide phenotypic variability. Four men suffered from colitis with onset ranging from infancy to 12 years of age, 5 had pyodermic skin involvement, including boils and erythema nodosum , and 3 had recurrent respiratory infections. Only 2 patients had features consistent with hemophagocytic lymphohistiocytosis, and 3 were positive for EBV. Three boys died at 2, 12, and 16 years of age, 1 patient after bone marrow transplantation. The least severely affected patient was 30 years old. He suffered from an episode of unusual febrile illness at age 15 years, as well as recurrent respiratory infections, and severe acne. Six of seven female carriers were affected to varying degrees by erythema nodosum and/or variable bowel symptoms, including irritable bowel syndrome.

Yang et al (2015) reported on a Japanese family in which 3 siblings, 2 boys and one girl, had manifestations of XLP2. The boys were more severely affected, but all 3 had pancytopenia, fever, and signs of EBV infection. The boys had splenomegaly. The boys developed hemophagocytic lymphohistiocytosis (HHL) in infancy and at 5 years of age, respectively, whereas the girl presented with pancytopenia at 7 years of age but did not fully meet the criteria for hemophagocytic lymphohistiocytosis and was classified as "incomplete HLH." None of the boys had hypogammaglobulinemia. Genetic testing revealed that the boys were hemizygous for a truncating mutation in the XIAP gene, and the mother and daughter were heterozygous for the mutation. The cells of all three affected siblings showed decreased expression of the XIAP protein, impaired NOD2 (605956) signaling with decreased production of TNF-alpha (TNFA; 191160), and increased peripheral blood mononuclear cell (PBMC) AICD. Patients also had a marked increase in serum IL18 (600953).

Nishida et al (2015) reported three unrelated Japanese boys with dysgammaglobulinemia associated with a specific mutation in the XIAP gene (glu349del; 300079.0005). These patients had recurrent infections and hypogammaglobulinemia without additional symptoms, notably no HLH or colitis, although one developed aplastic anemia and required hematopoietic stem cell transplantation. Patient cells had normal XIAP expression, but 2 patients had reduced numbers of CD19+ switched B cells. Microarray analysis showed that gene expression patterns were different in patients with the E349del mutation compared with patients with other mutations in the XIAP gene. Patients with E349del had 10-fold lower expression of a number of genes, including those involved in B-cell development and Ig levels.

1. Dziadzio M et al. (2015) Symptomatic male and female carriers in a large Caucasian kindred with XIAP deficiency. J Clin Immun 35: 439-444.
2. Gerasimenko JV et al (2002) Menadione-induced apoptosis: roles of cytosolic Ca(2+) elevations and the mitochondrial permeability transition pore. J Cell Sci. 2002 Feb 1;115(Pt 3):485-97.
3. Latour S et al (2015) XIAP deficiency syndrome in humans. Semin. Cell Dev Biol 39: 115-123.
4. Nishida N et al (2015) Dysgammaglobulinemia associated with glu349del, a hypomorphic XIAP mutation. J Invest Allergol Clin Immun 25: 205-213.
5. Pachlopnik Schmid J et al (2011) Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 117: 1522-1529.
6. Rigaud S et al. (2006) XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444: 110-114.
7. Worthey EA et al (2011) Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13: 255-262.
8. Yang X et al. (2015) A female patient with incomplete hemophagocytic lymphohistiocytosis caused by a heterozygous XIAP mutation associated with non-random X-chromosome inactivation skewed toward the wild-type XIAP allele. J Clin Immun 35: 244-248.