Skip to main content

Advertisement

SpringerLink
Log in

Clinical Spectrum of Ras-Associated Autoimmune Leukoproliferative Disorder (RALD)

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Ras-associated autoimmune leukoproliferative disorder (RALD) is a clinical entity initially identified in patients evaluated for an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. It remains a matter of debate whether RALD is a chronic and benign lymphoproliferative disorder or a pre-malignant condition. We report the case of a 7-year-old girl diagnosed with RALD due to somatic KRAS mutation who progressed to a juvenile myelomonocytic leukemia phenotype and finally evolved into acute myeloid leukemia. The case report prompted a literature review by a search for all RALD cases published in PubMed and Embase. We identified 27 patients with RALD. The male-to-female ratio was 1:1 and median age at disease onset was 2 years (range 3 months–36 years). Sixteen patients (59%) harbored somatic mutations in KRAS and 11 patients (41%) somatic mutations in NRAS. The most common features were splenomegaly (26/27 patients), autoimmune cytopenia (15/16 patients), monocytosis (18/24 patients), pericarditis (6 patients), and skin involvement (4 patients). Two patients went on to develop a hematopoietic malignancy. In summary, the current case documents an additional warning about the long-term risk of malignancy in RALD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wang J, Zheng L, Lobito A, Ka-Ming Chan F, Dale J, Snelleret M, et al. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell. 1999;98:47–58.

    Article  CAS  Google Scholar 

  2. Magerus-Chatinet A, Stolzenberg M-C, Lanzarotti N, Neven B, Daussy C, Picard C, et al. Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation. J Allergy Clin Immunol. 2013;131:486–90.

    Article  CAS  Google Scholar 

  3. Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L, et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118(18):4798–807.

    Article  CAS  Google Scholar 

  4. Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 2007;104(21):8953–8.

    Article  CAS  Google Scholar 

  5. Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K, et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood. 2011;117(10):2887–90.

    Article  CAS  Google Scholar 

  6. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459–65.

    Article  CAS  Google Scholar 

  7. Loh ML. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol. 2011;152:677–87.

    Article  CAS  Google Scholar 

  8. NOPHO-DBH AML (2012) Protocol: research study for treatment of children and adolescents with acute myeloid leukaemia 0-18 years. EudraCT Number 2012-002934-35 http://www.clinicaltrialsregister.eu/ctr-search/search?query=nopho+dbh+aml.

  9. Calvo KR, Price S, Braylan RC, Oliveira JB, Lenardo M, Fleisher TA, et al. JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities. Blood. 2015;125(18):2753–8.

    Article  CAS  Google Scholar 

  10. Niemela JE, Lu L, Fleisher TA, Davis J, Caminha L, Natter M, et al. Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood. 2011;117(10):2883–6.

    Article  Google Scholar 

  11. Tran TA, Grow W, Chang CC. Superficial and deep cutaneous involvement by RAS-associated autoimmunne leukoproliferative disease (RALD cutis): a histologic mimicker of histiocytoid sweet syndrome. Am J Dermatopathol. 2019;41(8):606–10.

    Article  Google Scholar 

  12. Lanzarotti N, Bruneau J, Trinquand A, Stolzenberg MC, Neven B, Fregeac J, et al. RAS-associated lymphoproliferative disease evolves into severe juvenile myelo-monocytic leukemia. Blood. 2014;123(12):1960–3.

    Article  CAS  Google Scholar 

  13. Shiota M, Yang X, Kubokawa M, Morishima T, Tanaka K, Mikami 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. 2015;35:454–8.

    Article  CAS  Google Scholar 

  14. Moritake H, Takagi M, Kinoshita M, Ohara O, Yamamoto S, Moriguchi S, et al. Autoimmunity including intestinal Behçet disease bearing the mutation in lymphocytes: a case report. Pediatrics. 2016;137(3):e20152891.

    Article  Google Scholar 

  15. Kubara K, Yamazaki K, Ishihara Y, Naturo T, Lin HT, Nishimura K, et al. Status of KRAS in iPSCs impacts upon self-renewal and differentiation propensity. Stem Cell Reports. 2018;11:1–15.

    Article  Google Scholar 

  16. Ragotte RJ, Dhanrajani A, Pleydell-Pearce J, Del Bel KL, Tarailo-Graovac M, van Karnebeek C, et al. The importance of considering monogenic causes of autoimmunity: a somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus. Clin Immunol. 2017;175:143–6.

    Article  CAS  Google Scholar 

  17. Levy-Mendelovich S, Lev A, Rechavi E, Barel O, Golan H, Bielorai B, et al. T and B cell clonal expansion in Ras-associated lymphoproliferative disease (RALD) as revealed by next-generation sequencing. Clin Exp Immunol. 2017;189:310–7.

    Article  CAS  Google Scholar 

  18. Toyoda H, Deguchi T, Iwamoto S, Kihira K, Hori H, Komada Y, et al. Weekly rituximab followed by monthly rituximab treatment for autoimmune disease associated with RAS-associated autoimmune leukoproliferative disease. J Pediatr Hematol Oncol. 2018;40:516–8.

    Article  Google Scholar 

  19. Giacaman A, Bauzá Alonso A, Salinas Sanz JA, Dapena Diaz JL, Ramos Asensio R, Ferrés Ramis L, et al. Cutaneous involvement in an 8-year-old boy with Ras-associated autoimmune leucoproliferative disorder (RALD). Clin Exp Dermatol. 2018;43:913–6.

    Article  CAS  Google Scholar 

  20. Wang W, Zhou Y, Zhong L, Wang L, Tang X, Ma M, et al. RAS-associated autoimmune leukoproliferative disease (RALD) manifested with early-onset SLE-like syndrome: a case series of RALD in Chinese children. Pediatr Rheumatol. 2019;17:55.

    Article  Google Scholar 

  21. Anastas V, Wang W, Price S, Zhao Z, Koneti Rao V, Calvo KR. Indolent phenotype of RAS-associated autoimmune leukoproliferative disorder (RALD) is characterized by single somatic mutations in RAS genes with absence of cooperating mutations. (abstract). Blood. 2016;128:4268.

    Article  Google Scholar 

  22. Bouillet P, Metcalf D, Huang D, Tarlinton DM, Kay TW, Köntgen R, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science. 1999;286:1735–8.

    Article  CAS  Google Scholar 

  23. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91:479–89.

    Article  CAS  Google Scholar 

  24. Meynier S, Rieux-Laucat F. FAS and RAS related apoptosis defects: from autoimmunity to leukemia Immunol. Rev. 2019;287:50–61.

    CAS  Google Scholar 

  25. Bader-Meunier B, Cavé H, Jeremiah N, Magerus A, Lanzarotti N, Rieux-Laucat F, et al. Are RASopathies new monogenic predisposing conditions to the development of systemic lupus erythematosus? Case report and systematic review of the literature. Semin Arthritis Rheum. 2013;43(2):217–9.

    Article  Google Scholar 

  26. Aringer M, Costenbader K, David Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71(9):1400–12.

    Article  Google Scholar 

  27. Quaio CR, Carvalho JF, da Silva CA, Buena C, Brasil AS, Pereira AC, et al. Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies. Am J Med Genet A. 2012;158A(5):1077–82.

    Article  Google Scholar 

  28. Niemeyer CM, Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood. 1997;89(10):3534–43.

    CAS  PubMed  Google Scholar 

  29. Matsuda K, Shimada A, Yoshida N, Ogawa A, Watanabe A, Yajima S, et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood. 2007;109(12):5477–80.

    Article  CAS  Google Scholar 

  30. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  Google Scholar 

  31. Chan RJ, Cooper T, Kratz CP, Weiss B, Loh ML. Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res. 2009;33:355–62.

    Article  Google Scholar 

  32. de Vries AC, Zwaan CM, van den Heuvel-Eibrink MM. Molecular basis of juvenile myelomonocytic leukemia. Haematologica. 2010;95(2):179–82.

    Article  Google Scholar 

  33. Meynier S. Apoptosis defects discriminate the Ras-associated lymphoproliferative disease (RALD) and juvenile myelomonocytic leukaemia (JMML) conditions [abstract]. Focused meeting of the European Society for Immunodefiencies 2019.

  34. Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet. 2011;157:83–9.

    Article  Google Scholar 

  35. Niemeyer CM. RAS diseases in children. Haematologica. 2014;99:1653–62.

    Article  CAS  Google Scholar 

  36. Takagi M, Piao J, Lin L, Kawaguchi H, Imai C, Ogawa A, et al. Autoimmunity and persistent RAS-mutated clones long after the spontaneous regression of JMML. Leukemia. 2013;27:1926–8.

    Article  CAS  Google Scholar 

  37. Murakami N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, et al. Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood. 2018;131:1576–86.

    Article  CAS  Google Scholar 

  38. Stieglitz E, Troup CB, Gelston LC, Haliburton J, Chow ED, Yu KB, et al. Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia. Blood. 2015;125(3):516–24.

    Article  CAS  Google Scholar 

  39. Stieglitz E, Mazor T, Olshen AB, Geng H, Gelston LC, Akutagawa J, et al. Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun. 2017;8(1):2127.

    Article  Google Scholar 

  40. Caye A, Strullu M, Guidez F, Cassinat B, Gazal S, Fenneteau O, et al. Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet. 2015;47(11):1334–40.

    Article  CAS  Google Scholar 

  41. Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi TM, et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet. 2013;45(8):937–41.

    Article  CAS  Google Scholar 

  42. Osumi T, Kato M, Ouchi-Uchiyama M, Tomizawa D, Kataoka K, Fuhii Y, et al. Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic KRAS. Pediatr Blood Cancer. 2017;64(9):e26496.

    Article  Google Scholar 

  43. Meynier S, Rieux-Laucat F. After 95 years, it’s time to eRASe JMML. Blood Rev. 2020;43:100652.

Download references

Funding

I.M. and L.M. are funded by FWO G0C8517N and by the VIB Grand Challenges Program and by the Jeffrey Modell Foundation.

Author information

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium

    Quentin Neven, Cécile Boulanger, Maëlle de Ville de Goyet, An Van Damme & Bénédicte Brichard

  2. Department of Pediatrics, Grand Hôpital de Charleroi, Charleroi, Belgium

    Annelyse Bruwier

  3. Laboratory for Inborn Errors of Immunity, Department of Immunology, Microbiology and Transplantation, University Hospitals Leuven, Leuven, Belgium

    Isabelle Meyts & Leen Moens

  4. Department of Pediatrics, ERN-RITA Core Center, University Hospitals Leuven, Leuven, Belgium

    Isabelle Meyts

Authors
  1. Quentin Neven
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cécile Boulanger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annelyse Bruwier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maëlle de Ville de Goyet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabelle Meyts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leen Moens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. An Van Damme
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bénédicte Brichard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Quentin Neven.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethics Statement

Written informed consent was obtained from the patient’s parents in accordance with the 1975 Declaration of Helsinki. Approval was granted by the Ethics Committee of the University Hospitals Leuven (S58466).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neven, Q., Boulanger, C., Bruwier, A. et al. Clinical Spectrum of Ras-Associated Autoimmune Leukoproliferative Disorder (RALD). J Clin Immunol 41, 51–58 (2021). https://doi.org/10.1007/s10875-020-00883-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-020-00883-7

Keywords

Search

Navigation