Ras-Associated Autoimmune Leukoproliferative Disorder

A number sign (#) is used with this entry because of evidence that RAS-associated autoimmune leukoproliferative disorder (RALD) is caused by somatic mutation in the NRAS gene (164790) or the KRAS gene (190070) on chromosome 12p12. One patient with somatic mutation in the NRAS gene has been reported.

Description

RAS-associated leukoproliferative disorder is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by Oliveira, 2013 and Niemela et al., 2010).

The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; 601859) and was originally designated ALPS IV.

Clinical Features

Oliveira et al. (2007) reported a 49-year-old patient with autoimmune lymphoproliferative syndrome who had a lifelong overexpansion of lymphocytes and a history of childhood leukemia and early adulthood lymphoma, both successfully treated. There were no developmental defects. Laboratory studies showed increased serum CD4-/CD8- (double-negative) alpha/beta T cells and lymph node follicular hyperplasia. There was no evidence of CD95 (134637)-mediated apoptosis, but the patient's lymphocytes resisted death by IL2 (147680) withdrawal, indicating a specific defect in lymphocyte apoptosis. Further studies of the patient's lymphocytes showed a decrease of the proapoptotic protein BIM (BCL2L11; 603827), which is critical for cytokine withdrawal-induced mitochondrial apoptosis.

Niemela et al. (2010) reported 2 unrelated Caucasian girls with RALD presenting in childhood. One had lymphadenopathy, splenomegaly, and recurrent upper respiratory infections. She developed several autoimmune conditions, including hemolytic anemia and thrombocytopenia. Laboratory studies showed hypergammaglobulinemia, B-cell lymphocytosis, monocytosis, and autoantibodies. Alpha/beta CD4-/CD8- T cells were not increased. She continued to have recurrent inflammatory episodes affecting the respiratory tract, but without documentation of an infectious agent. She died at age 13 years after a fever and cardiac arrest. The second patient presented at age 5 years with acute viral infections and was found to have splenomegaly, neutropenia, monocytosis, thrombocytopenia, and a facial rash. Throughout childhood, she had recurrent vasculitis of the lower limbs and developed pancytopenia and lymphadenopathy. Laboratory studies showed autoantibodies and hypergammaglobulinemia. Her psychomotor development was normal. Patient T cells showed resistance to apoptosis after IL2 withdrawal, and BIM levels were reduced.

Takagi et al. (2011) reported 2 unrelated children who presented with RALD at ages 9 and 5 months, respectively. Both had significant lymphadenopathy and hepatosplenomegaly, hemolytic anemia, autoimmune thrombocytopenia, hypergammaglobulinemia, and autoantibodies. Neither had a significant increase of CD4-/CD8- alpha/beta T cells, but T cells from both patients showed apoptotic resistance to IL2 withdrawal. Western blot analysis showed decreased expression of BIM in activated T cells and B cells.

Molecular Genetics

In a patient with ALPS type IV, Oliveira et al. (2007) identified a heterozygous mutation in the NRAS gene (G13D; 164790.0003). The mutation was found in the patient's lymphoblasts, peripheral blood mononuclear cells, monocytes, EBV-transformed B cells, and buccal epithelial cells. It was not present in the patient's unaffected relatives, suggesting de novo occurrence. In vitro functional expression studies showed that the G13D mutation caused increased activation of NRAS and augmented downstream signaling, resulting in downregulation of the proapoptotic factor BIM. Niemela et al. (2010) stated that the NRAS mutation found by Oliveira et al. (2007) was a somatic mutation.

In 2 unrelated girls with RALD, Niemela et al. (2010) identified 2 different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, 190070.0005 and G13C, 190070.0023). In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapoptotic protein BIM, and facilitated lymphocyte proliferation through downregulation of CDKN1B (600778).

In 2 unrelated children with RALD, Takagi et al. (2011) identified a somatic heterozygous mutation in the KRAS gene (G13D; 190070.0003). The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes.