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Juvenile myelomonocytic leukemia(JMML)

MedGen UID:
138109
Concept ID:
C0349639
Neoplastic Process
Synonyms: JMML; LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
SNOMED CT: Juvenile chronic myelomonocytic leukemia (128832006); Juvenile myelomonocytic leukemia (128832006); Juvenile myelomonocytic leukemia (445227008); JCML - Juvenile chronic myeloid leukemia (277587001); Juvenile chronic myeloid leukemia (277587001)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Somatic mutation
MedGen UID:
107465
Concept ID:
C0544886
Cell or Molecular Dysfunction
Sources: HPO, OMIM
A mode of inheritance in which a trait or disorder results from a de novo mutation occurring after conception, rather than being inherited from a preceding generation.
Somatic mutation (HPO, OMIM)
 
Genes (locations): ARHGAP26 (5q31.3); CBL (11q23.3); NF1 (17q11.2); PTPN11 (12q24.13)
 
HPO: HP:0012209
OMIM®: 607785
Orphanet: ORPHA86834

Definition

Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML. [from OMIM]

Clinical features

From HPO
Juvenile myelomonocytic leukemia
MedGen UID:
138109
Concept ID:
C0349639
Neoplastic Process
Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML.
Juvenile myelomonocytic leukemia
MedGen UID:
138109
Concept ID:
C0349639
Neoplastic Process
Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML.
Juvenile myelomonocytic leukemia
MedGen UID:
138109
Concept ID:
C0349639
Neoplastic Process
Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML.

Conditions with this feature

Juvenile myelomonocytic leukemia
MedGen UID:
138109
Concept ID:
C0349639
Neoplastic Process
Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML.
Noonan syndrome 3
MedGen UID:
349931
Concept ID:
C1860991
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Noonan syndrome 6
MedGen UID:
413028
Concept ID:
C2750732
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia
MedGen UID:
462153
Concept ID:
C3150803
Disease or Syndrome
Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; 163950) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by Martinelli et al., 2010). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as also seen in patients with Noonan syndrome (summary by Niemeyer et al., 2010).

Professional guidelines

PubMed

Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS; American Society of Clinical Oncology.
J Clin Oncol 2014 Mar 10;32(8):833-40. Epub 2014 Feb 3 doi: 10.1200/JCO.2013.50.9257. PMID: 24493721Free PMC Article

Recent clinical studies

Etiology

Gadgeel M, Bagla S, Buck S, Shamoun M, Ravindranath Y
Pediatr Blood Cancer 2020 Sep;67(9):e28555. Epub 2020 Jul 10 doi: 10.1002/pbc.28555. PMID: 32648963
Wajid M A, Gupta AK, Das G, Sahoo D, Meena JP, Seth R
Pediatr Hematol Oncol 2020 Oct;37(7):573-581. Epub 2020 May 27 doi: 10.1080/08880018.2020.1767244. PMID: 32459546
Miao Y, Li B, Ding L, Zhu H, Luo C, Wang J, Luo C, Chen J
Eur J Pediatr 2020 Mar;179(3):463-472. Epub 2019 Dec 5 doi: 10.1007/s00431-019-03468-8. PMID: 31807902Free PMC Article
Yoshida N, Sakaguchi H, Yabe M, Hasegawa D, Hama A, Hasegawa D, Kato M, Noguchi M, Terui K, Takahashi Y, Cho Y, Sato M, Koh K, Kakuda H, Shimada H, Hashii Y, Sato A, Kato K, Atsuta Y, Watanabe K; Pediatric Myelodysplastic Syndrome Working Group of the Japan Society for Hematopoietic Cell Transplantation.
Biol Blood Marrow Transplant 2020 May;26(5):902-910. Epub 2019 Nov 29 doi: 10.1016/j.bbmt.2019.11.029. PMID: 31790827
Flotho C, Sommer S, Lübbert M
Semin Cancer Biol 2018 Aug;51:68-79. Epub 2017 Nov 9 doi: 10.1016/j.semcancer.2017.10.011. PMID: 29129488

Diagnosis

Satoh T, Kayano H, Watanabe A, Ohta A, Endoh T, Shimizu Y, Fukushima T, Tanaka R, Yasuda M
Int J Hematol 2021 Oct;114(4):517-523. Epub 2021 Jul 16 doi: 10.1007/s12185-021-03189-5. PMID: 34272652
Lambert WA, DiGiuseppe JA, Lara-Ospina T, Bookland MJ, Martin JE, Hersh DS
Childs Nerv Syst 2021 Jun;37(6):2075-2079. Epub 2021 Jan 6 doi: 10.1007/s00381-020-05013-7. PMID: 33404720
Gadgeel M, Bagla S, Buck S, Shamoun M, Ravindranath Y
Pediatr Blood Cancer 2020 Sep;67(9):e28555. Epub 2020 Jul 10 doi: 10.1002/pbc.28555. PMID: 32648963
Wajid M A, Gupta AK, Das G, Sahoo D, Meena JP, Seth R
Pediatr Hematol Oncol 2020 Oct;37(7):573-581. Epub 2020 May 27 doi: 10.1080/08880018.2020.1767244. PMID: 32459546
Edison MN, O'Dell MC, Letter HP, Scherer K, Williams JL
Pediatr Radiol 2017 Jan;47(1):104-107. Epub 2016 Oct 7 doi: 10.1007/s00247-016-3710-z. PMID: 27717995

Therapy

Satoh T, Kayano H, Watanabe A, Ohta A, Endoh T, Shimizu Y, Fukushima T, Tanaka R, Yasuda M
Int J Hematol 2021 Oct;114(4):517-523. Epub 2021 Jul 16 doi: 10.1007/s12185-021-03189-5. PMID: 34272652
Wajid M A, Gupta AK, Das G, Sahoo D, Meena JP, Seth R
Pediatr Hematol Oncol 2020 Oct;37(7):573-581. Epub 2020 May 27 doi: 10.1080/08880018.2020.1767244. PMID: 32459546
Yoshida N, Sakaguchi H, Yabe M, Hasegawa D, Hama A, Hasegawa D, Kato M, Noguchi M, Terui K, Takahashi Y, Cho Y, Sato M, Koh K, Kakuda H, Shimada H, Hashii Y, Sato A, Kato K, Atsuta Y, Watanabe K; Pediatric Myelodysplastic Syndrome Working Group of the Japan Society for Hematopoietic Cell Transplantation.
Biol Blood Marrow Transplant 2020 May;26(5):902-910. Epub 2019 Nov 29 doi: 10.1016/j.bbmt.2019.11.029. PMID: 31790827
Flotho C
Epigenetics 2019 Mar;14(3):236-244. Epub 2019 Mar 8 doi: 10.1080/15592294.2019.1583039. PMID: 30773984Free PMC Article
Krombholz CF, Aumann K, Kollek M, Bertele D, Fluhr S, Kunze M, Niemeyer CM, Flotho C, Erlacher M
Haematologica 2016 May;101(5):597-606. Epub 2016 Feb 17 doi: 10.3324/haematol.2015.138545. PMID: 26888021Free PMC Article

Prognosis

Satoh T, Kayano H, Watanabe A, Ohta A, Endoh T, Shimizu Y, Fukushima T, Tanaka R, Yasuda M
Int J Hematol 2021 Oct;114(4):517-523. Epub 2021 Jul 16 doi: 10.1007/s12185-021-03189-5. PMID: 34272652
Lambert WA, DiGiuseppe JA, Lara-Ospina T, Bookland MJ, Martin JE, Hersh DS
Childs Nerv Syst 2021 Jun;37(6):2075-2079. Epub 2021 Jan 6 doi: 10.1007/s00381-020-05013-7. PMID: 33404720
Gadgeel M, Bagla S, Buck S, Shamoun M, Ravindranath Y
Pediatr Blood Cancer 2020 Sep;67(9):e28555. Epub 2020 Jul 10 doi: 10.1002/pbc.28555. PMID: 32648963
Miao Y, Li B, Ding L, Zhu H, Luo C, Wang J, Luo C, Chen J
Eur J Pediatr 2020 Mar;179(3):463-472. Epub 2019 Dec 5 doi: 10.1007/s00431-019-03468-8. PMID: 31807902Free PMC Article
Liao XY, Qiu KY, Fang JP, Wu RH, Guo SY, Huang K, Zhou DH
Hematology 2019 Dec;24(1):577-582. doi: 10.1080/16078454.2019.1651548. PMID: 31389303

Clinical prediction guides

Niemeyer CM, Flotho C, Lipka DB, Starý J, Rössig C, Baruchel A, Klingebiel T, Micalizzi C, Michel G, Nysom K, Rives S, Schmugge Liner M, Zecca M, Schönung M, Baumann I, Nöllke P, Benettaib B, Biserna N, Poon J, Simcock M, Patturajan M, Menezes D, Gaudy A, van den Heuvel-Eibrink MM, Locatelli F
Blood Adv 2021 Jul 27;5(14):2901-2908. doi: 10.1182/bloodadvances.2020004144. PMID: 34297046Free PMC Article
Wang WH, Lu MY, Tsai CH, Wang SC, Chou SW, Jou ST
J Formos Med Assoc 2021 Apr;120(4):1148-1152. Epub 2020 Sep 12 doi: 10.1016/j.jfma.2020.08.034. PMID: 32933826
Yoshida N, Sakaguchi H, Yabe M, Hasegawa D, Hama A, Hasegawa D, Kato M, Noguchi M, Terui K, Takahashi Y, Cho Y, Sato M, Koh K, Kakuda H, Shimada H, Hashii Y, Sato A, Kato K, Atsuta Y, Watanabe K; Pediatric Myelodysplastic Syndrome Working Group of the Japan Society for Hematopoietic Cell Transplantation.
Biol Blood Marrow Transplant 2020 May;26(5):902-910. Epub 2019 Nov 29 doi: 10.1016/j.bbmt.2019.11.029. PMID: 31790827
Pearson S, Guo B, Pierce A, Azadbakht N, Brazzatti JA, Patassini S, Mulero-Navarro S, Meyer S, Flotho C, Gelb BD, Whetton AD
J Proteome Res 2020 Jan 3;19(1):194-203. Epub 2019 Nov 12 doi: 10.1021/acs.jproteome.9b00495. PMID: 31657576Free PMC Article
Kurata T, Matsuda K, Hirabayashi K, Shigemura T, Sakashita K, Nakahata T, Koike K
Pediatr Blood Cancer 2018 Nov;65(11):e27261. Epub 2018 Jul 16 doi: 10.1002/pbc.27261. PMID: 30014555

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