RAS相关自身免疫淋巴细胞增殖性疾病诊疗进展

任佳宁; 万扬; 竺晓凡

doi:10.7499/j.issn.1008-8830.2502103

PDF(792 KB)

HTML

中国当代儿科杂志 ›› 2025, Vol. 27 ›› Issue (9) : 1149-1155. DOI: 10.7499/j.issn.1008-8830.2502103

综述

RAS相关自身免疫淋巴细胞增殖性疾病诊疗进展

任佳宁 ¹ (综述) ,
万扬 ² ,
竺晓凡 ¹^,² (审校)

作者信息 +

Progress in diagnosis and treatment of RAS-related autoimmune lymphoproliferative disorder

Author information +

文章历史 +

摘要

RAS相关自身免疫淋巴细胞增殖性疾病（RAS-associated autoimmune lymphoproliferative disorder, RALD）是由NRAS或KRAS体细胞突变引发的罕见先天性免疫缺陷病，其主要病理特征为免疫失调性血细胞破坏，表现为自身免疫性疾病样症状。该病临床异质性显著，可出现自身免疫性疾病表现、肝脾大、淋巴结肿大、单核细胞增多及感染等。RALD因罕见且性质未明，目前缺乏标准化治疗方案。该文就RALD的发病机制、临床表现、鉴别诊断及最新治疗进展进行综述，以期为认知和治疗该病提供新视角和参考。

Abstract

RAS-associated autoimmune lymphoproliferative disorder (RALD) is a rare congenital immunodeficiency disorder caused by somatic mutations in NRAS or KRAS. Its main pathological feature is immune dysregulation-induced hematologic destruction, presenting with symptoms resembling autoimmune diseases. RALD exhibits significant clinical heterogeneity, with manifestations including autoimmune phenomena, hepatosplenomegaly, lymphadenopathy, monocytosis, and increased susceptibility to infections. Owing to its rarity and its unclear nature, a standardized therapeutic regimen for RALD is currently lacking. This review summarizes the latest advances in the pathogenesis, clinical manifestations, differential diagnosis, and treatment of RALD, aiming to provide new insights and reference for the understanding and management of this disorder.

导出引用

任佳宁, 万扬, 竺晓凡. RAS相关自身免疫淋巴细胞增殖性疾病诊疗进展[J]. 中国当代儿科杂志. 2025, 27(9): 1149-1155 https://doi.org/10.7499/j.issn.1008-8830.2502103

Jia-Ning REN, Yang WAN, Xiao-Fan ZHU. Progress in diagnosis and treatment of RAS-related autoimmune lymphoproliferative disorder[J]. Chinese Journal of Contemporary Pediatrics. 2025, 27(9): 1149-1155 https://doi.org/10.7499/j.issn.1008-8830.2502103

参考文献

列表( 原文顺序 | 文献年度倒序 | 文中引用次数倒序 ) 可视化分析

[1]	Neven Q, Boulanger C, Bruwier A, et al. Clinical spectrum of Ras-associated autoimmune leukoproliferative disorder (RALD)[J]. J Clin Immunol, 2021, 41(1): 51-58. DOI: 10.1007/s10875-020-00883-7 . https://www.ncbi.nlm.nih.gov/pubmed/33011939 本文引用 [3]

[2]

Calvo

, Price

, Braylan

, et al. JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities[J]. Blood, 2015, 125(18): 2753-2758. PMCID: PMC4424627. DOI: 10.1182/blood-2014-11-567917 .

https://www.ncbi.nlm.nih.gov/pubmed/25691160

本文引用 [5]

[3]	Papa R, Rusmini M, Schena F, et al. Type I interferon activation in RAS-associated autoimmune leukoproliferative disease (RALD)[J]. Clin Immunol, 2021, 231: 108837. DOI: 10.1016/j.clim.2021.108837 . https://www.ncbi.nlm.nih.gov/pubmed/34455097 本文引用 [2]

[4]	Yu JE. New primary immunodeficiencies 2023 update[J]. Curr Opin Pediatr, 2024, 36(1): 112-123. DOI: 10.1097/MOP.0000000000001315 . https://www.ncbi.nlm.nih.gov/pubmed/38001560 本文引用 [1]

[5]	Lanzarotti N, Bruneau J, Trinquand A, et al. RAS-associated lymphoproliferative disease evolves into severe juvenile myelo-monocytic leukemia[J]. Blood, 2014, 123(12): 1960-1963. DOI: 10.1182/blood-2014-01-548958 . https://www.ncbi.nlm.nih.gov/pubmed/24652966 本文引用 [4]

[6]	Chen K, Zhang Y, Qian L, et al. Emerging strategies to target RAS signaling in human cancer therapy[J]. J Hematol Oncol, 2021, 14(1): 116. PMCID: PMC8299671. DOI: 10.1186/s13045-021-01127-w . https://www.ncbi.nlm.nih.gov/pubmed/34301278 本文引用 [1]

[7]	Gysin S, Salt M, Young A, et al. Therapeutic strategies for targeting ras proteins[J]. Genes Cancer, 2011, 2(3): 359-372. PMCID: PMC3128641. DOI: 10.1177/1947601911412376 . https://www.ncbi.nlm.nih.gov/pubmed/21779505

[8]

Levy-Mendelovich

, Lev

, Rechavi

, et al. T and B cell clonal expansion in Ras-associated lymphoproliferative disease (RALD) as revealed by next-generation sequencing[J]. Clin Exp Immunol, 2017, 189(3): 310-317. PMCID: PMC5543497. DOI: 10.1111/cei.12986 .

https://www.ncbi.nlm.nih.gov/pubmed/28500641

本文引用 [2]

[9]	Cicenas J, Tamosaitis L, Kvederaviciute K, et al. KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma[J]. Med Oncol, 2017, 34(2): 26. DOI: 10.1007/s12032-016-0879-9 . https://www.ncbi.nlm.nih.gov/pubmed/28074351 本文引用 [1]

[10]	Gámez-Díaz L, Grimbacher B. Immune checkpoint deficiencies and autoimmune lymphoproliferative syndromes[J]. Biomed J, 2021, 44(4): 400-411. PMCID: PMC8514790. DOI: 10.1016/j.bj.2021.04.005 . https://www.ncbi.nlm.nih.gov/pubmed/34384744 本文引用 [1]

[11]	Yin C, Zhu B, Zhang T, et al. Pharmacological targeting of STK19 inhibits oncogenic NRAS-driven melanomagenesis[J]. Cell, 2019, 176(5): 1113-1127.e16. DOI: 10.1016/j.cell.2019.01.002 . https://www.ncbi.nlm.nih.gov/pubmed/30712867 本文引用 [1]

[12]	Linglart L, Gelb BD. Congenital heart defects in Noonan syndrome: diagnosis, management, and treatment[J]. Am J Med Genet C Semin Med Genet, 2020, 184(1): 73-80. PMCID: PMC7682536. DOI: 10.1002/ajmg.c.31765 . https://www.ncbi.nlm.nih.gov/pubmed/32022400 本文引用 [1]

[13]	Astiazaran-Symonds E, Ney GM, Higgs C, et al. Cancer in Costello syndrome: a systematic review and meta-analysis[J]. Br J Cancer, 2023, 128(11): 2089-2096. PMCID: PMC10205753. DOI: 10.1038/s41416-023-02229-7 . https://www.ncbi.nlm.nih.gov/pubmed/36966234

[14]

Perrino

, Das

, Scollon

, et al. Update on pediatric cancer surveillance recommendations for patients with neurofibromatosis type 1, Noonan syndrome, CBL syndrome, Costello syndrome, and related RASopathies[J]. Clin Cancer Res, 2024, 30(21): 4834-4843. PMCID: PMC11530332. DOI: 10.1158/1078-0432.CCR-24-1611 .

https://www.ncbi.nlm.nih.gov/pubmed/39196581

[15]	Niemeyer CM. RASdiseases in children[J]. Haematologica, 2014, 99(11): 1653-1662. PMCID: PMC4222471. DOI: 10.3324/haematol.2014.114595 . https://www.ncbi.nlm.nih.gov/pubmed/25420281 本文引用 [1]

[16]

Teodorovic

, Babolin

, Rowland

, et al. Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies[J]. Proc Natl Acad Sci U S A, 2014, 111(27): E2797-E2806. PMCID: PMC4103347. DOI: 10.1073/pnas.1402159111 .

https://www.ncbi.nlm.nih.gov/pubmed/24958853

本文引用 [1]

[17]	Meynier S, Rieux-Laucat F. FAS and RAS related apoptosis defects: from autoimmunity to leukemia[J]. Immunol Rev, 2019, 287(1): 50-61. DOI: 10.1111/imr.12720 . https://www.ncbi.nlm.nih.gov/pubmed/30565243 本文引用 [3]

[18]	Takagi M, Shinoda K, Piao J, et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation[J]. Blood, 2011, 117(10): 2887-2890. DOI: 10.1182/blood-2010-08-301515 . https://www.ncbi.nlm.nih.gov/pubmed/21063026 本文引用 [2]

[19]	Riller Q, Rieux-Laucat F. RASopathies: from germline mutations to somatic and multigenic diseases[J]. Biomed J, 2021, 44(4): 422-432. PMCID: PMC8514848. DOI: 10.1016/j.bj.2021.06.004 . https://www.ncbi.nlm.nih.gov/pubmed/34175492 本文引用 [1]

[20]	Sullivan KE, Lambert M. Ras-associated autoimmune lymphoproliferative disorder[J]. Br J Haematol, 2024, 205(3): 819-822. DOI: 10.1111/bjh.19564 . https://www.ncbi.nlm.nih.gov/pubmed/38797558 本文引用 [6]

[21]	唐文静, 张宇, 张志勇, 等. RAS基因相关自身免疫淋巴增殖性疾病1例并文献复习[J]. 中国实用儿科杂志, 2022, 37(7): 537-540. DOI: 10.19538/j.ek2022070614 . 本文引用 [5]

[22]	Giacaman A, Bauzá Alonso A, Salinas Sanz JA, et al. Cutaneous involvement in an 8-year-old boy with Ras-associated autoimmune leucoproliferative disorder (RALD)[J]. Clin Exp Dermatol, 2018, 43(8): 913-916. DOI: 10.1111/ced.13668 . https://www.ncbi.nlm.nih.gov/pubmed/29908030 本文引用 [1]

[23]

TAN

Tran

, Grow

, Chang

. Superficial and deep cutaneous involvement by RAS-associated autoimmunne leukoproliferative disease (RALD cutis): a histologic mimicker of histiocytoid sweet syndrome[J]. Am J Dermatopathol, 2019, 41(8): 606-610. DOI: 10.1097/DAD.0000000000001332 .

https://www.ncbi.nlm.nih.gov/pubmed/31335417

本文引用 [1]

[24]

Ragotte

, Dhanrajani

, Pleydell-Pearce

, et al. The importance of considering monogenic causes of autoimmunity: a somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus[J]. Clin Immunol, 2017, 175: 143-146. DOI: 10.1016/j.clim.2016.12.006 .

https://www.ncbi.nlm.nih.gov/pubmed/28043923

本文引用 [1]

[25]

Tang

, Wang

, Zhao

, et al. RAS-associated Autoimmune Leukoproliferative disease (RALD-KRAS) consistent with the clinical diagnosis of Rosai-Dorfman disease: a 15-year follow-up[J]. J Clin Immunol, 2024, 44(5): 123. DOI: 10.1007/s10875-024-01728-3 .

https://www.ncbi.nlm.nih.gov/pubmed/38758494

本文引用 [2]

[26]	Lambert MP. Presentation and diagnosis of autoimmune lymphoproliferative syndrome (ALPS)[J]. Expert Rev Clin Immunol, 2021, 17(11): 1163-1173. DOI: 10.1080/1744666X.2021.1978842 . https://www.ncbi.nlm.nih.gov/pubmed/34503378 本文引用 [1]

[27]

Rudelius

, Weinberg

, Niemeyer

, et al. The international consensus classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia[J]. Virchows Arch, 2023, 482(1): 113-130. DOI: 10.1007/s00428-022-03447-9 .

https://www.ncbi.nlm.nih.gov/pubmed/36445482

[28]

Khoury

, Solary

, Abla

, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms[J]. Leukemia, 2022, 36(7): 1703-1719. PMCID: PMC9252913. DOI: 10.1038/s41375-022-01613-1 .

https://www.ncbi.nlm.nih.gov/pubmed/35732831

[29]

Blanchard-Rohner

, Ragotte

, Junker

, et al. Idiopathic splenomegaly in childhood and the spectrum of RAS-associated lymphoproliferative disease: a case report[J]. BMC Pediatr, 2021, 21(1): 45. PMCID: PMC7819237. DOI: 10.1186/s12887-021-02508-3 .

https://www.ncbi.nlm.nih.gov/pubmed/33472608

本文引用 [2]

[30]

Shiota

, Yang

, Kubokawa

, et al. Somatic mosaicism for a NRAS mutation associates with disparate clinical features in RAS-associated leukoproliferative disease: a report of two cases[J]. J Clin Immunol, 2015, 35(5): 454-458. DOI: 10.1007/s10875-015-0163-3 .

https://www.ncbi.nlm.nih.gov/pubmed/25896945

本文引用 [2]

[31]

Wang

, Zhou

, Zhong

, et al. RAS-associated Autoimmune Leukoproliferative disease (RALD) manifested with early-onset SLE-like syndrome: a case series of RALD in Chinese children[J]. Pediatr Rheumatol Online J, 2019, 17(1): 55. PMCID: PMC6694547. DOI: 10.1186/s12969-019-0346-1 .

https://www.ncbi.nlm.nih.gov/pubmed/31412876

本文引用 [1]

[32]

Toyoda

, Deguchi

, Iwamoto

, et al. Weekly rituximab followed by monthly rituximab treatment for autoimmune disease associated with RAS-associated autoimmune leukoproliferative disease[J]. J Pediatr Hematol Oncol, 2018, 40(8): e516-e518. DOI: 10.1097/MPH.0000000000001276 .

https://www.ncbi.nlm.nih.gov/pubmed/30080751

本文引用 [1]

[33]	姜健, 步晓洁, 张秋业, 等. RAS基因相关性自身免疫淋巴增殖性疾病1例并文献复习[J]. 精准医学杂志, 2024, 39(5): 452-454, 458. DOI: 10.13362/j.jpmed.202405018 . 本文引用 [1]

[34]	张婧, 朱华, 罗成娟, 等. 异基因造血干细胞移植治疗Ras基因相关性自身免疫淋巴增殖性疾病1例并文献复习[J]. 内科理论与实践, 2020, 15(5): 347-351. DOI: 10.16138/j.1673-6087.2020.05.013 . 本文引用 [1]

[35]	Kurita D, Shiba N, Ohya T, et al. Severe RAS-associated lymphoproliferative disease case with increasing αβ double-negative T cells with atypical features[J]. J Clin Immunol, 2023, 43(8): 1992-1996. DOI: 10.1007/s10875-023-01566-9 . https://www.ncbi.nlm.nih.gov/pubmed/37644277 本文引用 [2]

[36]	Keeton AB, Salter EA, Piazza GA. The RAS-effector interaction as a drug target[J]. Cancer Res, 2017, 77(2): 221-226. PMCID: PMC5243175. DOI: 10.1158/0008-5472.CAN-16-0938 . https://www.ncbi.nlm.nih.gov/pubmed/28062402 本文引用 [1]

[37]	Sheridan C. Grail of RAS cancer drugs within reach[J]. Nat Biotechnol, 2020, 38(1): 6-8. DOI: 10.1038/s41587-019-0382-x . https://www.ncbi.nlm.nih.gov/pubmed/31919443 本文引用 [1]

[38]	Bouffet E, Hansford J, Garré ML, et al. Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600-mutant pediatric low-grade glioma (pLGG)[J]. J Clin Oncol, 2022, 40(17S): LBA2002. DOI: 10.1200/JCO.2022.40.17_suppl.LBA2002 . 本文引用 [1]

[39]

Stieglitz

, Lee

, Angus

, et al. Efficacy of the allosteric MEK inhibitor trametinib in relapsed and refractory juvenile myelomonocytic leukemia: a report from the children's oncology group[J]. Cancer Discov, 2024, 14(9): 1590-1598. PMCID: PMC11374478. DOI: 10.1158/2159-8290.CD-23-1376 .

https://www.ncbi.nlm.nih.gov/pubmed/38867349

本文引用 [1]

[40]	Oliveira JB, Bidère N, Niemela JE, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome[J]. Proc Natl Acad Sci U S A, 2007, 104(21): 8953-8958. PMCID: PMC1885609. DOI: 10.1073/pnas.0702975104 . https://www.ncbi.nlm.nih.gov/pubmed/17517660 本文引用 [1]

[41]

Lin

, Takagi

, Kubara

, et al. Monoallelic KRAS (G13C) mutation triggers dysregulated expansion in induced pluripotent stem cell-derived hematopoietic progenitor cells[J]. Stem Cell Res Ther, 2024, 15(1): 106. PMCID: PMC11021011. DOI: 10.1186/s13287-024-03723-2 .

https://www.ncbi.nlm.nih.gov/pubmed/38627844

本文引用 [3]

[42]	吴正宙, 黄科, 方建培, 等. RAS基因相关自身免疫性白细胞增殖性疾病进展为幼年型粒单核细胞白血病1例报告[J]. 临床儿科杂志, 2019, 37(4): 256-259. DOI: 10.3969/j.issn.1000-3606.2019.04.004 . 本文引用 [1]