Ras-Associated Autoimmune Leukoproliferative Disease

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

NRAS, KRAS, FAS, FASLG, CASP10, MME

Drugs

Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, haematopoietic stem cells and blood progenitors umbilical cord-derived expanded with (1R, 4R)-N1-(2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl)cyclohexane-1,4-diamine dihydrobromide dihydrate

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RAS-associated autoimmune leukoproliferative disease (RALD) is a rare genetic disorder characterized by monocytosis, autoimmune cytopenias, lymphoproliferation, hepatosplenomegaly, and hypergammaglobulinemia.

Epidemiology

Prevalence of this disorder is not known. It is extremely rare with fewer than 20 patients reported to date.

Clinical description

Age of onset of the clinical signs is invariably in infancy or early childhood. Most patients have atypical features such as elevated counts for cells of myeloid origin (monocytosis and granulocytosis) making their clinical presentation indistinguishable from juvenile myelomonocytic leukemia (JMML; see this term). Many patients undergo repeated bone marrow assessments showing normal cytogenetics despite dysplastic marrow morphology. Lymphoma in adulthood in one patient and only one case of unexplained sudden death in adolescence have been reported. Hypergammaglobulinemia, autoantibodies and expansion of B lymphocytes in peripheral blood have also been noted.

Etiology

RALD is caused by somatic mutations in the NRAS (1p13.2) and KRAS (12p12.1) genes encoding RAS proteins involved in regulating cell proliferation causing impairment of the intrinsic apoptosis pathway.

Diagnostic methods

Double-negative T-cells (DNTs) may be mildly elevated in patients with RALD but are usually normal. Apoptosis assay can identify these patients due to their distinct cellular phenotype showing impaired cell death following serum or IL2 withdrawal.

Genetic counseling

The pattern of inheritance for RALD is not known. RAS mutations are considered somatic and limited to the circulating peripheral blood mononuclear cells.