In white blood cells derived from 2 unrelated children with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G-to-A transition in the NRAS gene, resulting in a gly13-to-asp (G13D) substitution.
Oliveira et al. (2007) identified a heterozygous G-to-A transition in the NRAS gene, resulting in a gly13-to-asp (G13D) substitution, in a 49-year-old patient with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470). The patient 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 alpha/beta CD4-/CD8- 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 cells indicated a decrease of the proapoptotic protein BIM (BCL2L11; 603827), which is critical for withdrawal-induced mitochondrial apoptosis. 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. The patient had no developmental abnormalities or features of Noonan syndrome. Oliveira et al. (2007) noted that the same mutation had been identified somatically in myeloid and lymphoid malignancies (Bos et al., 1985; Lubbert et al., 1990). Niemela et al. (2010) stated that the NRAS mutation found by Oliveira et al. (2007) was a somatic mutation.
De Filippi et al. (2009) identified a de novo germline heterozygous G13D substitution in the NRAS gene in a male infant who presented at age 2 months with juvenile myelomonocytic leukemia (JMML; 607785) and was later noted to have dysmorphic features suggestive of, but not diagnostic of, Noonan syndrome (NS6; 613224). Features included short stature, relative macrocephaly, high forehead, epicanthal folds, long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and low scores on performance tasks. Cardiac studies were normal. There were no hematologic abnormalities related to RALD in this patient.
