title: Somatic mosaicism for a NRAS mutation associates with disparate clinical features in RAS-associated leukoproliferative disease: a report of two cases.
abstract: RAS-associated leukoproliferative disease (RALD) is a newly classified disease; thus its clinical features and management are not fully understood. The cases of two patients with characteristic features of RALD are described herein. Patient 1 was a 5-month-old female with clinical features typical of autoimmune lymphoproliferative syndrome (ALPS) and markedly elevated TCRαβ(+)CD4(-)CD8(-) T cell numbers. Genetic analyses failed to detect an ALPS-related gene mutation; however, whole exome sequencing and other genetic analyses revealed somatic mosaicism for the G13D NRAS mutation. These data were indivative of NRAS-associated RALD with highly elevated αβ-double-negative T cells. Patient 2 was a 12-month-old girl with recurrent fever who clearly met the diagnostic criteria for juvenile myelomonocytic leukemia (JMML). Genetic analyses revealed somatic mosaicism, again for the G13D NRAS mutation, suggesting RALD associated with somatic NRAS mosaicism. Notably, unlike most JMML cases, Patient 2 did not require steroids or hematopoietic stem cell transplantation. Genetic analysis of RAS should be performed in patients fulfilling the diagnostic criteria for ALPS in the absence of ALPS-related gene mutations if the patients have elevated αβ-double-negative-T cells and in JMML patients if autoimmunity is detected. These clinical and experimental data increase our understanding of RALD, ALPS, and JMML.
authors.affiliation: Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan, mi-shiota@kitano-hp.or.jp.
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Shiota
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Mei
authors.initials: M
authors.lastname: Kubokawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morishima
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tanaka
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Mikami
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Masako
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Kazushi
authors.initials: K
authors.lastname: Izawa
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nishikomori
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Sakaguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hata
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
mesh_terms: D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics / Q000276:immunology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D011905:Genes, ras / Q000276:immunology*; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics*; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human