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.
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Acknowledgments
This study was supported as Research on Measures for Intractable Disease Project, and by grants from the Ministry of Health, Labour, and Welfare of Japan. We thank Mr. Katsuyuki Ohmori for his expertise in flow cytometric analysis. We also thank Drs. Kazuyuki Matsuda, Dr. Yuichi Shiraishi, Dr. Kenichi Chiba, and Dr. Hiroko Tanaka, Ms. Chikako Sakai and Mr. Hitoshi Moriuchi for technical assistance. Clinical advice from Dr. Itaru Kato, Dr. Katsutsugu Umeda, Dr. Hidefumi Hiramatsu, Dr. Takahiro Yasumi, and Dr. Ken-ichiro Watanabe is gratefully acknowledged. Helpful discussion offered by Dr. Sumpei Yokota, Dr. Kenichi Koike, Dr. Yuichi Abe, Dr. Toshio Heike and Dr. Toshio Miyawaki is deeply appreciated.
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Mitsutaka Shiota, Xi Yang and Mei Kubokawa contributed equally to this work.
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Comparison of patients in this study with RALD patients reported in the literature. (PPTX 43.9 kb)
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Shiota, M., Yang, X., Kubokawa, M. et al. Somatic Mosaicism for a NRAS Mutation Associates with Disparate Clinical Features in RAS-associated Leukoproliferative Disease: a Report of Two Cases. J Clin Immunol 35, 454–458 (2015). https://doi.org/10.1007/s10875-015-0163-3
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DOI: https://doi.org/10.1007/s10875-015-0163-3