Pediatric Myeloid neoplasms associated with Germline Predisposition
2023-06-27 Sheng Xiao, MD , Chunxiao Yang Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2. Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)
Classification
Definition
Certain germline gene mutations lead to an increased risk of myeloid neoplasms, in addition to congenital abnormalities affecting various organs and systems. The age of presentation for myeloid neoplasms varies among different genes and can exhibit heterogeneity even within the same family. While certain neoplasms, such as JMML in RASopathies, often occur in infants and toddlers, the median age of onset for AML in individuals with Fanconi Anemia is typically around 7-8 years.1 On the other hand, most other myeloid neoplasms associated with germline predisposition manifest between the ages of 20 and 40.2 The penetrance rates for myeloid neoplasms associated with germline predisposition also vary depending on the genes involved. The following are the estimated penetrance rates for hematopoietic malignancies:
CEBPA mutations: almost 100% 3
GATA2 mutations: 70-75% 4
RUNX1 mutations: 35-40% 5
Severe Congenital Neutropenia (SCN): 10-20% 6, 7
Shwachman-Diamond syndrome (SDS): 10-30% 8
Fanconi anemia (FA): 10-30% 9, 10
DKC1 mutations (Dyskeratosis Congenita): 3-33% 11
SAMD9L mutations: 70% 12
ANKRD26 mutations: 8% 5
The table below lists germline mutations that lead to dominantly inherited myeloid neoplasms. Please note that it does not include other germline mutations associated with solid tumors and hematopoietic malignancies such as Li-Fraumeni syndrome.
| Pediatric Myeloid neoplasms associated with germline predisposition | Genetic marker(s) | Table |
|---|---|---|
| CEBPA-associated familial AML | The dominant driver gene of CEBPA-associated familial AML is the CEBPA mutation. The inherited mutation in CEBPA is often located in the N-terminal region, while the somatic mutation is typically found in the C-terminal region, specifically within the b-ZIP domain of CEBPA. Karyotype is typically normal.13 | |
| Familial platelet disorder with associated myeloid malignancy | The dominant driver gene is the RUNX1 mutation. Additional frequently mutated genes include FLT3, BCOR, GATA2.14 Additional chromosome aberrations include monosomy 7. | |
| GATA2-deficiency | The dominant driver gene is the GATA2 mutation. Additional frequently mutated genes include RUNX1, SETBP1, IKZF1, CRLF2.15 Additional chromosome aberrations include monosomy 7 or trisomy 8. | |
| Severe congenital neutropenia | Mutations of the ELANE, HAX1, SRP54 are common drivers in pediatric severe congenital neutropenia.16-18 Common chromosomal aberrations include monosomy 7. | |
| Shwachman-Diamond syndrome | Mutations of the SBDS, EFL1, DNAJC21, SRP54 are common drivers in pediatric Shwachman-Diamond syndrome.19 | |
| Fanconi anemia | Mutations of the FANCA, FANCC, FANCG (>22 genes) are common drivers in pediatric Fanconi anemia. Mitomycin C-induced chromosomal breakage is a characteristic finding in this disease.20 | |
| Dyskeratosis congenita and other telomere biology disorders | Mutations of the DKC1, TINF2, TERC, TERT, NHP2, NOP10, NAF1, PARN, WRAP53, ACD, STN1, CTC1, RTEL1, TINF2, POT1 are common drivers in pediatric Dyskeratosis congenita and other telomere biology disorders. 21 | |
| Rasopathies | Mutations of the NF1, CBL, KRAS, NRAS are common drivers in pediatric Rasopathies.22 | |
| MIRAGE syndrome | The dominant driver gene is the SAMD9 mutation. Additional chromosome aberrations include del(7q).23 | |
| SAMD9L-related ATXPC syndrome | The dominant driver gene is the SAMD9L mutation. Additional chromosome aberrations include del(7q).24 | |
| ANKRD26-related thrombocytopenia | The dominant driver gene is the ANKRD26 mutation.25 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 25455269 | 2014 | Fanconi anemia and the development of leukemia. | Alter BP et al |
| 2 | 31309983 | 2019 | Germline Predisposition to Hematolymphoid Neoplasia. | Weinberg OK et al |
| 3 | 33225257 | 2020 | Genetic predisposition in pediatric oncology. | Pruteanu DP et al |
| 4 | 35054439 | 2021 | Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition. | Gao J et al |
| 5 | 34658019 | 2022 | Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges. | Tawana K et al |
| 6 | 12555210 | 2003 | Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. | Dale DC et al |
| 7 | 18544696 | 2008 | Lessons from congenital neutropenia: 50 years of progress in understanding myelopoiesis. | Berliner N et al |
| 8 | 36542827 | 2023 | Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances. | Reilly CR et al |
| 9 | 12393424 | 2003 | Cancer incidence in persons with Fanconi anemia. | Rosenberg PS et al |
| 10 | 18322251 | 2008 | Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. | Rosenberg PS et al |
| 11 | 19282459 | 2009 | Cancer in dyskeratosis congenita. | Alter BP et al |
| 12 | 33038986 | 2020 | Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. | Sahoo SS et al |
| 13 | 35178345 | 2022 | Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions. | Su L et al |
| 14 | 32208489 | 2020 | RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. | Brown AL et al |
| 15 | 36799265 | 2023 | Gene mutation analysis using next-generation sequencing and its clinical significance in patients with myeloid neoplasm: A multi-center study from China. | Li J et al |
| 16 | 36815775 | 2023 | Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance. | Fan EM et al |
| 17 | 30775052 | 2019 | Description of an ELANE Mutation in a Girl with Severe Congenital Neutropenia: A Paradigm of Targeted Genetic Screening Based on Clinical Findings. | Gogou M et al |
| 18 | 30598852 | 2018 | Novel HAX1 Gene Mutation in a Vietnamese Boy with Severe Congenital Neutropenia. | Tran TT et al |
| 19 | 33046118 | 2020 | Somatic development in children with Shwachman-Diamond syndrome. | Bogusz-Wójcik A et al |
| 20 | 30792206 | 2019 | Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. | Mori M et al |
| 21 | 20301779 | 1993 | Dyskeratosis Congenita and Related Telomere Biology Disorders. | Savage SA et al |
| 22 | 25877329 | 2015 | A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. | Ratner N et al |
| 23 | 27182967 | 2016 | SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. | Narumi S et al |
| 24 | 28570036 | 1993 | SAMD9L Ataxia-Pancytopenia Syndrome. | Raskind WH et al |
| 25 | 29927566 | 1993 | ANKRD26-Related Thrombocytopenia. | Perez Botero J et al |
Citation
Sheng Xiao, MD ; Chunxiao Yang
Pediatric Myeloid neoplasms associated with Germline Predisposition
Atlas Genet Cytogenet Oncol Haematol. 2023-06-27
Online version: http://atlasgeneticsoncology.org/solid-tumor/209176/pediatric-myeloid-neoplasms-associated-with-germline-predisposition
