Transient Myeloproliferative Disorder (TMD), Acute Lymphoblastic Leukemia (ALL), and Juvenile Myelomonocytic Leukemia (JMML) in a Child with Noonan Syndrome: Sequential Occurrence, Single Center Experience, and Review of the Literature
Abstract
:1. Introduction
2. Materials and Methods
3. Biological Mechanisms Shared between NS and Hematological Malignancies
4. Results (Cases from Center of Pediatric Hematology Oncology in Catania—Italy)
4.1. Case 1
4.2. Case 2 (UPN 1021127)
4.3. Case 3 (UPN 1052079)
5. Discussion
5.1. Noonan Syndrome and Transient Myeloproliferative Disorder (TMD)
5.2. Noonan Syndrome (NS) and Juvenile Myelomonocytic Leukemia (JMML)
5.3. Noonan Syndrome (NS) and Acute Lymphoblastic Leukemia (ALL)
5.4. Noonan Syndrome (NS) and Other Malignancies
References | Cases (Age—Gender) | Type of Tumor | Genetic Aberration |
---|---|---|---|
Jongmans et al. [49] | 4-year-old male | Embryonal RMS | c.2183 A>T (p.Lys728Ile) in SOS1 |
Cianci et al. [39] | 7-year-old male | Burkitt lymphoma | c.776 C>T (p.Ser259Phe) in RAF1 |
Nair et al. [46] | 14-year-old male | Astrocytoma | c.417G>C in exon 4 of PTPN11 |
McWilliams et al. [44] | 8-year-old male | DNET | p.Glu139Asp in PTPN11 |
Prasad et al. [41] | 14-year-old female | Colorectal cancer | c.1310 T>C (p. Ile437Thr) in SOS1 |
Boonyawat et al. [47] | 11-year-old female | Subependymoma | c.922 A>G(p.Asn308Asp) in PTPN11 |
Lodi et al. [45] | 13-year-old female | Glioma | c.922 A>G, p.Asn308Asp in PTPN11 |
Avery et al. [40] | 25-year-old female | T-cell lymphoma | c.4 A>G p.S2G in SHOC2 |
6. Recommendations and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Roberts, A.E.; Allanson, J.E.; Tartaglia, M.; Gelb, B.D. Noonan syndrome. Lancet 2013, 381, 333–342. [Google Scholar] [CrossRef] [PubMed]
- Jongmans, M.C.; van der Burgt, I.; Hoogerbrugge, P.M.; Noordam, K.; Yntema, H.G.; Nillesen, W.M.; Kuiper, R.P.; Ligtenberg, M.J.; van Kessel, A.G.; van Krieken, J.H.; et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur. J. Hum. Genet. 2011, 19, 870–874. [Google Scholar] [CrossRef] [PubMed]
- Hasle, H. Malignant diseases in Noonan syndrome and related disorders. Horm. Res. 2009, 72, 8–14. [Google Scholar] [CrossRef] [PubMed]
- Kratz, C.P.; Franke, L.; Peters, H.; Kohlschmidt, N.; Kazmierczak, B.; Finckh, U.; Bier, A.; Eichhorn, B.; Blank, C.; Kraus, C.; et al. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br. J. Cancer 2015, 112, 1392–1397. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, G.L.; Aguena, M.; Gos, M.; Hung, C.; Pilch, J.; Fahiminiya, S.; Abramowicz, A.; Cristian, I.; Buscarilli, M.; Naslavsky, M.S.; et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015, 52, 413–421. [Google Scholar] [CrossRef]
- Tartaglia, M.; Kalidas, K.; Shaw, A.; Song, X.; Musat, D.L.; van der Burgt, I.; Brunner, H.G.; Bertola, D.R.; Crosby, A.; Ion, A.; et al. PTPN11 mutations in Noonan syndrome: Molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am. J. Hum. Genet. 2002, 70, 1555–1563. [Google Scholar] [CrossRef]
- Roberts, A.E.; Araki, T.; Swanson, K.D.; Montgomery, K.T.; Schiripo, T.A.; Joshi, V.A.; Li, L.; Yassin, Y.; Tamburino, A.M.; Neel, B.G.; et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat. Genet. 2007, 39, 70–74. [Google Scholar] [CrossRef]
- Aoki, Y.; Niihori, T.; Inoue, S.; Matsubara, Y. Recent advances in RASopathies. J. Hum. Genet. 2016, 61, 33–39. [Google Scholar] [CrossRef]
- Brasil, A.S.; Pereira, A.C.; Wanderley, L.T.; Kim, C.A.; Malaquias, A.C.; Jorge, A.A.; Krieger, J.E.; Bertola, D.R. PTPN11 and KRAS gene analysis in patients with Noonan and Noonan-like syndromes. Genet. Test Mol. Biomark. 2010, 14, 425–432. [Google Scholar] [CrossRef]
- Lissewski, C.; Chune, V.; Pantaleoni, F.; De Luca, A.; Capri, Y.; Brinkmann, J.; Lepri, F.; Daniele, P.; Leenders, E.; Mazzanti, L.; et al. Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications. Eur. J. Hum. Genet. 2021, 29, 51–60. [Google Scholar] [CrossRef]
- Sarkozy, A.; Carta, C.; Moretti, S.; Zampino, G.; Digilio, M.C.; Pantaleoni, F.; Scioletti, A.P.; Esposito, G.; Cordeddu, V.; Lepri, F.; et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum. Hum. Mutat. 2009, 30, 695–702. [Google Scholar] [CrossRef]
- Pires, L.V.L.; Bordim, R.A.; Maciel, M.B.R.; Tanaka, A.C.S.; Yamamoto, G.L.; Honjo, R.S.; Kim, C.A.; Bertola, D.R. Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant. Am. J. Med. Genet. A 2021, 185, 3099–3103. [Google Scholar] [CrossRef] [PubMed]
- Zenker, M.; Edouard, T.; Blair, J.C.; Cappa, M. Noonan syndrome: Improving recognition and diagnosis. Arch. Dis. Child. 2022, 107, 1073–1078. [Google Scholar] [CrossRef] [PubMed]
- Tartaglia, M.; Mehler, E.L.; Goldberg, R.; Zampino, G.; Brunner, H.G.; Kremer, H.; van der Burgt, I.; Crosby, A.H.; Ion, A.; Jeffery, S.; et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, causing Noonan syndrome. Nat. Genet. 2001, 29, 465–468. [Google Scholar] [CrossRef] [PubMed]
- Tartaglia, M.; Niemeyer, C.M.; Fragale, A.; Song, X.; Buechner, J.; Jung, A.; Hählen, K.; Hasle, H.; Licht, J.D.; Gelb, B.D.; et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat. Genet. 2003, 34, 148–150. [Google Scholar] [CrossRef]
- Tartaglia, M.; Aoki, Y.; Gelb, B.D. The molecular genetics of RASopathies: An update on novel disease genes and new disorders. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 425–439. [Google Scholar] [CrossRef]
- Tartaglia, M.; Martinelli, S.; Cazzaniga, G.; Cordeddu, V.; Iavarone, I.; Spinelli, M.; Palmi, C.; Carta, C.; Pession, A.; Aricò, M.; et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 2004, 104, 307–313. [Google Scholar] [CrossRef]
- Conter, V.; Valsecchi, M.G.; Cario, G.; Zimmermann, M.; Attarbaschi, A.; Stary, J.; Niggli, F.; Dalla Pozza, L.; Elitzur, S.; Silvestri, D.; et al. Four additional doses of PEG-L-Asparaginse during the Consolidation Phase in the AIEOP-BFM ALL 2009 protocol do not improve outcome and increase toxicity in High-Risk ALL: Results of a randomized trial. J. Clin. Oncol. 2024, 42, 915–926. [Google Scholar] [CrossRef]
- Sun, Y.Q.; Chang, Y.J.; Huang, X.J. Update on current research into haploidentical hematopoietic stem cell transplantation. Expert Rev. Hematol. 2018, 11, 273–284. [Google Scholar] [CrossRef]
- Athota, J.P.; Bhat, M.; Nampoothiri, S.; Gowrishankar, K.; Narayanachar, S.G.; Puttamallesh, V.; Farooque, M.O.; Shetty, S. Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC Med. Genet. 2020, 21, 50. [Google Scholar] [CrossRef]
- Niemeyer, C.M. RAS diseases in children. Haematologica 2014, 99, 1653–1662. [Google Scholar] [CrossRef] [PubMed]
- Ferraris, F.; Lanza, C.; Barisone, E.; Bertorello, N.; Farinasso, D.; Miniero, R. Transient abnormal myelopoiesis in Noonan syndrome. J. Pediatr. Hematol. Oncol. 2002, 24, 763–764. [Google Scholar] [CrossRef]
- Nemcikova, M.; Vejvalkova, S.; Fenci, F.; Sukova, M.; Krepelova, A. A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation-a review of the literature. Eur. J. Pediatr. 2016, 175, 587–592. [Google Scholar] [CrossRef] [PubMed]
- Bastida, P.; García-Miñaúr, S.; Ezquieta, B.; Dapena, J.L.; Sanchez de Toledo, J. Myeloproliferative disorder in Noonan syndrome. J. Pediatr. Hematol. Oncol. 2011, 33, 43–45. [Google Scholar] [CrossRef]
- O’Halloran, K.; Ritchey, A.K.; Djokic, M.; Friehling, E. Transient juvenile myelomonocytic leukemia in the setting of PTPN11 mutation and Noonan syndrome with secondary development of monosomy 7. Pediatr. Blood Cancer 2017, 64, e26408. [Google Scholar] [CrossRef]
- Strullu, M.; Caye, A.; Lachenaud, J.; Cassinat, B.; Gazal, S.; Fenneteau, O.; Pouvreau, N.; Pereira, S.; Baumann, C.; Contet, A.; et al. Juvenile myelomonocytic leukaemia and Noonan syndrome. J. Med. Genet. 2014, 51, 689–697. [Google Scholar] [CrossRef]
- Mason-Suares, H.; Toledo, D.; Gekas, J.; Lafferty, K.A.; Meeks, N.; Pacheco, M.C.; Sharpe, D.; Mullen, T.E.; Lebo, M.S. Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome. Eur. J. Hum. Genet. 2017, 25, 509–511. [Google Scholar] [CrossRef]
- Choong, K.; Freedman, M.H.; Chitayat, D.; Kelly, E.N.; Taylor, G.; Zipursky, A. Juvenile myelomonocytic leukemia and Noonan syndrome. J. Pediatr. Hematol. Oncol. 1999, 21, 523–527. [Google Scholar] [CrossRef]
- Cheong, J.L.; Moorkamp, M.H. Respiratory failure, juvenile myelomonocytic leukemia, and neonatal Noonan syndrome. J. Pediatr. Hematol. Oncol. 2007, 29, 262–264. [Google Scholar] [CrossRef]
- Ortiz, M.V.; Skoda-Smith, S.; Rauen, K.A.; Allan, R.W.; Slayton, W.B. Juvenile myelomonocytic leukemia in a 16-year-old with Noonan syndrome: Case report. J. Pediatr. Hematol. Oncol. 2012, 34, 569–572. [Google Scholar] [CrossRef]
- Rehman, A.U.; Rahman, M.U.; Khan, M.T.; Saud, S.; Liu, H.; Song, D.; Sultana, P.; Wadood, A.; Chen, H.F. The Landscape of Protein Tyrosine Phosphatase (Shp2) and Cancer. Curr. Pharm. Des. 2018, 24, 3767–3777. [Google Scholar] [CrossRef] [PubMed]
- Piombo, M.; Rosanda, C.; Pasino, M.; Marasini, M.; Cerruti, P.; Comelli, A. Acute lymphoblastic leukemia in Noonan syndrome: Report of two cases. Med. Pediatr. Oncol. 1993, 21, 454–455. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, T.; Isomura, M.; Xu, Y.; Liang, J.; Yagasaki, H.; Kamachi, Y.; Kudo, K.; Kiyoi, H.; Naoe, T.; Kojma, S. PTPN11, RAS and FLT3 mutations in childhood acute lymphoblastic leukemia. Leuk. Res. 2006, 30, 1085–1089. [Google Scholar] [CrossRef]
- Sakamoto, K.; Imamura, T.; Asai, D.; Goto-Kawashima, S.; Yoshida, H.; Fujiki, A.; Furutani, A.; Ishida, H.; Aoki, Y.; Hosoi, H. Acute lymphoblastic leukemia developing in a patient with Noonan syndrome harboring a PTPN11 germline mutation. J. Pediatr. Hematol. Oncol. 2014, 36, 136–139. [Google Scholar] [CrossRef]
- Pauli, S.; Steinemann, D.; Dittmann, K.; Wienands, J.; Shoukier, M.; Möschner, M.; Burfeind, P.; Manukjan, G.; Göhring, G.; Escherich, G. Occurrence of acute lymphoblastic leukemia and juvenile myelomonocytic leukemia in a patient with Noonan syndrome carrying the germline PTPN11 mutation p.E139D. Am. J. Med. Genet. A 2012, 158, 652–658. [Google Scholar] [CrossRef]
- Kaya, Z.; Keser, E.; Atalay, E.; Kayhan, G.; Karamercan, S.; Topuz, B.; Kirkiz, S.; Koçak, Ü. Two distinct syndromic children with T-acute lymphoblastic leukemia: Noonan syndrome and Sotos syndrome. Leuk. Res. 2022, 123, 106981. [Google Scholar] [CrossRef]
- Laux, D.; Kratz, C.; Sauerbrey, A. Common acute lymphoblastic leukemia in a girl with genetically confirmed LEOPARD syndrome. J. Pediatr. Hematol. Oncol. 2008, 30, 602–604. [Google Scholar] [CrossRef]
- Chinton, J.; Huckstadt, V.; Mucciolo, M.; Lepri, F.; Novelli, A.; Gravina, L.P.; Obregon, M.G. Providing more evidence on LZTR1 variants in Noonan syndrome patients. Am. J. Med. Genet. A 2020, 182, 409–414. [Google Scholar] [CrossRef]
- Cianci, P.; Tono, V.; Sala, A.; Locatelli, L.; Carta, C.; Rizzari, C.; Biondi, A.; Selicorni, A. A boy with Burkitt lymphoma associated with Noonan syndrome due to a mutation in RAF1. Am. J. Med. Genet. A 2013, 161A, 1401–1404. [Google Scholar] [CrossRef]
- Avery, A.; Metcalf, J.S.; Maize, J.C.; Swanson, L.A. Cutaneous T-cell lymphoma in SHOC2 mutation-associated Noonan-like syndrome with loose anagen hair. JAAD Case Rep. 2022, 24, 52–55. [Google Scholar] [CrossRef]
- Prasad, R.M.; Mody, R.J.; Myers, G.; Mullins, M.; Naji, Z.; Geiger, J.D. A genome-wide analysis of colorectal cancer in a child with Noonan syndrome. Pediatr. Blood Cancer 2018, 65, 27362. [Google Scholar] [CrossRef] [PubMed]
- Thom, M.; Toma, A.; An, S.; Martinian, L.; Hadjivassiliou, G.; Ratilal, B.; Dean, A.; McEvoy, A.; Sisodiya, S.M.; Brandner, S. One hundred and one dysembryoplastic neuroepithelial tumors: An adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J. Neuropathol. Exp. Neurol. 2011, 70, 859–878. [Google Scholar] [CrossRef] [PubMed]
- Siegfried, A.; Cances, C.; Denuelle, M.; Loukh, N.; Tauber, M.; Cavé, H.; Delisle, M.B. Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature. Am. J. Med. Genet A 2017, 173, 1061–1065. [Google Scholar] [CrossRef] [PubMed]
- McWilliams, G.D.; SantaCruz, K.; Hart, B.; Clericuzio, C. Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy. Am. J. Med. Genet. A 2016, 170, 195–201. [Google Scholar] [CrossRef] [PubMed]
- Lodi, M.; Boccuto, L.; Carai, A.; Cacchione, A.; Miele, E.; Colafati, G.S.; Diomedi Camassei, F.; De Palma, L.; De Benedictis, A.; Ferretti, E.; et al. Low-Grade Gliomas in Patients with Noonan Syndrome: Case-Based Review of the Literature. Diagnostics 2020, 10, 582. [Google Scholar] [CrossRef]
- Nair, S.; Fort, J.A.; Yachnis, A.T.; Williams, C.A. Optic nerve pilomyxoid astrocytoma in a patient with Noonan syndrome. Pediatr. Blood Cancer 2015, 62, 1084–1086. [Google Scholar] [CrossRef]
- Boonyawat, B.; Charoenpitakchai, M.; Suwanpakdee, P. A First Case Report of Subependymoma in PTPN11 Mutation-Associated Noonan Syndrome. Case Rep. Neurol. Med. 2019, 209, 6091059. [Google Scholar] [CrossRef]
- Chen, Y.; Takita, J.; Hiwatari, M.; Igarashi, T.; Hanada, R.; Kikuchi, A.; Hongo, T.; Taki, T.; Ogasawara, M.; Shimada, A.; et al. Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies. Genes Chromosomes Cancer 2006, 45, 583–591. [Google Scholar] [CrossRef]
- Jongmans, M.C.; Hoogerbrugge, P.M.; Hilkens, L.; Flucke, U.; van der Burgt, I.; Noordam, K.; Ruiterkamp-Versteeg, M.; Yntema, H.G.; Nillesen, W.M.; Ligtenberg, M.; et al. Noonan syndrome, the SOS1 gene and embryonal rhabdomyosarcoma. Genes Chromosomes Cancer 2010, 49, 635–641. [Google Scholar] [CrossRef]
- Romano, A.A.; Allanson, J.E.; Dahlgren, J.; Gelb, B.D.; Hall, B.; Pierpont, M.E.; Roberts, A.E.; Robinson, W.; Takemoto, C.M.; Noonan, J.A. Noonan Syndrome: Clinical features, diagnosis, and management guidelines. Pediatrics 2010, 126, 746–759. [Google Scholar] [CrossRef]
Age | Type of Alteration | Management |
---|---|---|
At birth | Neoformation diagnosed, with juvenile xantogranuloma-like Langherans histiocytosis | No treatment |
First week | Respiratory distress and sepsis caused by Pseudomonas aeruginosa | Ventilatory support and intravenous antibiotic therapy |
First Month | Leukocytosis and splenomegaly diagnosed as transient myeloproliferative disorder (TMD) | Spontaneous recovery |
Second Year | B-cell precursor acute lymphoblastic leukemia (BCP-ALL) | AIEOP-BFM ALL 2009 protocol |
Seventh Year | Genetic characterization of Noonan syndrome by identification of germline PTPN11 mutation | No treatment |
Tenth Year | Juvenile myelomonocytic leukemia (JMML) | 6-mercaptopurine (final dose 50 mg/die) |
Eleventh Year | Treatment failure characterized by hyperleukocytosis associated with thrombocytopenia and splenomegaly | Haploidentical stem cell transplantation (father as donor) |
References | Case (Gender and Age) | Type of Clinical Aberration | Genetic Aberration |
---|---|---|---|
Ferraris et al. [22] | Male—2 months old | Transient Abnormal Myelopoiesis | Not identified |
Kratz et al. [4] | Male—10 months old | Leukopenia and TMD | c.69A>T (p. Lys23Asn) in RIT1 |
Bastida et al. [24] | Male—3 months old | TMD | (F285S) in exon 8 of the PTPN11 gene |
Bastida et al. [24] | Male—22 days old | TMD | (D61G) in exon 3 of the PTPN11 gene |
O’Halloran et al. [25] | At birth | Transient JMML and monosomy 7 | Ser502Leu in PTPN11 |
Reference | Case | Type of Hematological Malignancy | Genetic Aberration |
---|---|---|---|
Choong et al. [28] | At birth | JMML | Not specified |
Cheong, J.L. et al. [29] | At birth | JMML | PTPN11 mutation C-T substitution at 218 |
Ortiz et al. [30] | 16 years old | JMML | KRAS2 missense mutation at codon 13 (Gly-Cys) |
Strullu, M. et al. [26] | 20 cases | JMML | See reference [26] |
References | Cases | Type of Hematological Malignancy | Genetic Aberration |
---|---|---|---|
Piombo et al. [32] | 30-month-old | BCP-ALL | PTPN11 mutation not specified |
Yamamoto et al. [33] | 6 out of 95 children | BCP-ALL | 922A>G (N308D) in PTPN11 |
Laux et al. [37] | 8-year-old | BCP-ALL ^ | c.836 A>G, in exon 7 in PTPN11 |
Pauli et al. [35] | 4-year-old | BCP-ALL and JMML | c.417 G>C (p.E139D) in PTPN11 |
Sakamoto et al. [34] | 6-year-old | BCP-ALL | c.922 A>G; (p. N308D) in PTPN11 |
Chinton et al. [38] | 3-year-old | BCP-ALL | c.742 G>A (p. Gly248Arg) in LZTR1 |
Kaya et al. [36] | 9-year-old | T-ALL | 1502 G>A (p. Arg501Lys) in PTPN11 |
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Arrabito, M.; Li Volsi, N.; La Rosa, M.; Samperi, P.; Pulvirenti, G.; Cannata, E.; Russo, G.; Di Cataldo, A.; Lo Nigro, L. Transient Myeloproliferative Disorder (TMD), Acute Lymphoblastic Leukemia (ALL), and Juvenile Myelomonocytic Leukemia (JMML) in a Child with Noonan Syndrome: Sequential Occurrence, Single Center Experience, and Review of the Literature. Genes 2024, 15, 1191. https://doi.org/10.3390/genes15091191
Arrabito M, Li Volsi N, La Rosa M, Samperi P, Pulvirenti G, Cannata E, Russo G, Di Cataldo A, Lo Nigro L. Transient Myeloproliferative Disorder (TMD), Acute Lymphoblastic Leukemia (ALL), and Juvenile Myelomonocytic Leukemia (JMML) in a Child with Noonan Syndrome: Sequential Occurrence, Single Center Experience, and Review of the Literature. Genes. 2024; 15(9):1191. https://doi.org/10.3390/genes15091191
Chicago/Turabian StyleArrabito, Marta, Nicolò Li Volsi, Manuela La Rosa, Piera Samperi, Giulio Pulvirenti, Emanuela Cannata, Giovanna Russo, Andrea Di Cataldo, and Luca Lo Nigro. 2024. "Transient Myeloproliferative Disorder (TMD), Acute Lymphoblastic Leukemia (ALL), and Juvenile Myelomonocytic Leukemia (JMML) in a Child with Noonan Syndrome: Sequential Occurrence, Single Center Experience, and Review of the Literature" Genes 15, no. 9: 1191. https://doi.org/10.3390/genes15091191