Aetiology of MDS: With a Focus on Hereditary Predisposition
Abstract
:1. Introduction
2. Environmental Epidemiology
3. Inherited Quantitative Trait Loci
4. ‘Inflammation’ as an Indirect Etiological Factor
5. Clonal Haematopoiesis
6. Therapy-Related MDS
7. Familial Predisposition to Myeloid Malignancy
- Prior chemo/radiotherapy,
- Family history of myeloid malignancy, other cancers,
- Family history of attendance at haematology clinics (thrombocytopenia, macrocytosis, vitamin B12/folate supplementation),
- Pulmonary or hepatic disease (typically fibrosis), or other non-haematological features described below.
- Discussion of the limitations of current testing, including the possibility of unexpected or difficult-to-interpret results such as private variants of unknown significance unique to specific families. These may require functional testing to prove a pathogenic role, which may not be available at the time of the test.
- Possible implications for the patient and family members should be discussed, including the importance of sharing relevant results to guide further testing.
- The possibility that tests may not yield any significant findings should be raised, and the fact that this would not exclude a germline predisposition, given the ongoing discovery of novel variants as knowledge and technology progress over time.
8. Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cellular Function, Gene | Clinical Features | Frequency |
---|---|---|
Transcription factors | ||
Familial platelet disorder with predisposition to myeloid malignancy RUNX1 | Thrombocytopenia, platelet dysfunction, bleeding phenotype, eczema, T-ALL, hairy cell leukaemia | Rare |
GATA2-spectrum disorders GATA2 | Emberger syndrome, MonoMAC syndrome, immunodeficiency (DC, monocyte, B and NK-cell deficiency), lymphoedema, warts, atypical mycobacterial infection, hearing loss, CMML, JMML, monosomy 7 | Childhood MDS: 7%; Adult MDS: unknown but likely underdiagnosed |
Thrombocytopenia 5 ETV6 | Thrombocytopenia, platelet dysfunction, B-ALL, CMML, MM | Rare |
DNA repair and genome instability syndromes | ||
Fanconi anaemia FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1/BACH1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCU/XRCC2, FANCV/REV7, FANCW/RFWD3 | Bone marrow failure, short stature, skeletal and facial abnormalities, congenital cardiac, renal and ocular/auditory abnormalities, café-au-lait spots, squamous cell carcinoma (oral, gastrointestinal, genitourinary), breast cancer, positive chromosome breakage testing, elevated HbF | Childhood BM failure: most frequent cause [31] Adult MDS: very rare |
Mismatch repair disorders MLH1, MSH6, PMS2, MSH2, EPCAM | Colon/ovarian/uterine/CNS cancer, ALL, lymphoma | |
Bloom syndrome BLM | Short stature, photosensitive rash, pulmonary disease, diabetes, ALL, lymphoma | |
Ribosome disorders | ||
Diamond-Blackfan anaemia RPS19, RPL5, RPS26, RPL11, RPL35a, RPS10 | Bone marrow failure, short stature, congenital cardiac, renal, skeletal and facial abnormalities, elevated HbF, sarcoma | Extremely rare |
Schwachman-Diamond syndrome SBDS | Bone marrow failure, short stature, pancreatic insufficiency, preceding isolated neutropenia, skeletal abnormalities | Formerly thought to be very rare, phenotypically silent cases may represent 4% of young MDS [32] |
Telomeropathies | ||
Dyskeratosis congenita and telomere biology disorders DKC1, TERC, TERT, TINF2, RTEL1 | Nail dystrophy, abnormal skin and hair pigmentation, oral leukoplakia, pulmonary and hepatic fibrosis, oral and GI squamous cell carcinoma, telomere lengths < 1st percentile for age | Syndromically rare, however rare TERT variants associated with short telomeres have been recently identified in 3% of MDS transplant recipients [33] |
Signal transducers (Ras pathway) | ||
Noonan syndrome PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1 | Short stature, cardiac and facial abnormalities, coagulopathy, webbed neck, developmental delay, JMML | |
Noonan-like CBL | JMML | |
Tumour suppressors Li-Fraumeni syndrome TP53 | Early onset breast malignancy (age < 30), sarcoma, CNS, adrenocortical carcinoma, paediatric hypodiploid ALL, lymphoma, therapy-related leukaemias | Very rare |
Other DDX41 | Malignancies at older ages (>50), CML, lymphoma | Most frequent HMMS: 2–3% in adult MDS |
Thrombocytopenia 2 ANKRD26 | Thrombocytopenia, platelet dysfunction, CLL, CML, CMML | |
MIRAGE Syndrome SAMD9 | Myelodysplasia, infection, restriction of growth, adrenal insufficiency, genital phenotypes and enteropathy, monosomy 7 | Previously thought to be very rare, one study recently identified SAMD9/SAMD9L lesions in 17% of paediatric MDS [34] |
Ataxia-pancytopenia syndrome SAMD9L | Bone marrow failure, ataxia, monosomy 7 | |
Neurofibromatosis 1 NF1 | Café au-lait spots, neurofibromas, axillary freckles, Lisch nodules, CNS cancers | |
SRP72 | Bone marrow failure, sensorineural hearing loss | |
Severe congenital neutropenia ELANE, CSF3R, HAX1, G6PC3, WAS | Osteopenia (ELANE), neurodevelopmental (HAX1), cardiac (G6PC3), monocytopenia (WAS) |
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Khan, A.B.; Bowen, D. Aetiology of MDS: With a Focus on Hereditary Predisposition. Hemato 2022, 3, 17-37. https://doi.org/10.3390/hemato3010003
Khan AB, Bowen D. Aetiology of MDS: With a Focus on Hereditary Predisposition. Hemato. 2022; 3(1):17-37. https://doi.org/10.3390/hemato3010003
Chicago/Turabian StyleKhan, Anjum B., and David Bowen. 2022. "Aetiology of MDS: With a Focus on Hereditary Predisposition" Hemato 3, no. 1: 17-37. https://doi.org/10.3390/hemato3010003
APA StyleKhan, A. B., & Bowen, D. (2022). Aetiology of MDS: With a Focus on Hereditary Predisposition. Hemato, 3(1), 17-37. https://doi.org/10.3390/hemato3010003