We report the occurrence of X-linked lymphoproliferative disease (XLP) in two brothers in a Malaysian family. In this disorder, a primary Epstein-Barr virus (EBV) infection is followed by an abnormal proliferation of transformed B-cells that cannot be controlled by suppressor T-cells, leading to the development of deranged immune function. This results in fatal infectious mononucleosis, acquired hypogammaglobulinaemia, virus-infected haemophagocytic syndrome and non-Hodgkin's lymphoma. The diagnosis should be considered when there is a family history of any male having a fulminant course of infectious mononucleosis, an otherwise benign disease. Early diagnosis is important as bone marrow transplantation is the only curative option in this disorder.
Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.