Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists
Abstract
:1. Introduction
2. Telomeropathies
2.1. Primary Telomeropathies
2.2. Secondary Telomeropathies
3. GATA2 Related Disorders
4. Shwachman-Diamond Syndrome
5. SAMD9/SAMD9L Related Syndromes
6. Diamond-Blackfan Anemia
7. RUNX1, ANKRD26 and ETV6 Related Familial Thrombocytopenia
8. Severe Congenital Neutropenia
9. Cytogenetic Features of IBMFS
Monosomy 7 in IBMFS
10. HSCT in MDS Arising in IBMFS
11. Pitfalls in Detecting IBMFS in Adult Patients: A Case Report
11.1. What Should We Rule Out?
11.2. Should the Diagnostic Process Stop Here?
11.3. Which Tests Should Be Run to Exclude IBMFS?
11.4. How Is the Detection of a Telomeropathy Going to Change the Approach to the Patient?
12. Discussion and Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Syndromes | Gene | Inheritance | Cellular Function | Associated Phenotype | Evolution to MDS/AML |
---|---|---|---|---|---|
DC/Telomeropathy | DKC1 [18] | X-linked | Telomere maintenance | Mucocutaneous features (nail dystrophy, skin pigmentation abnormalities, oral leukoplakia) Idiopathic pulmonary fibrosis Liver diseases Immunodeficiency/immune dysregulation Endocrinopathies Osteoporosis, dental abno malities, short stature CNS abnormalities/cerebellar hypoplasia Secondary cancer (oral and gastrointestinal squamous cell carcinoma) [19,20,21,22] | Cumulative incidence of evolution to MDS i creases with age, with a prevalence of 13% in non-transplanted patients [22] |
TERT, TERC, TINF2, RTEL1 ACD/TPP1, PARN, NAF1 STN1 | AD | ||||
TERT, WRAP53 NOLA3, NOLA2 TCB1, RTEL1 CTC1, CD/TPP1 PARN, NHP2 NOP10 [23] | AR | ||||
FA | FANC (A, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, W) | AR | DNA Repair pathway | Short stature, café au lait, spots and hyper/hypopigmentation, abnormal thumbs, absent radii, microcephaly, micro- ophthalmia, structural renal/urogenital, cardiac malformations abnormalities/malformations, endocrinopathies, hypogonadism, squamous cell carcinoma: oral, gastrointestinal, genitourinary. FANCD1/BRCA2 Subtype: solid tumors and ALL [24,25] | Cumulative incidence of evolution to MDS/AML of 33% by 40 years old [25,26,27] |
FANCB [28] | X-linked | ||||
Emberger syndrome MonoMAC syndrome DCML | GATA2 [29,30] | AD | Transcription factor | Emberger syndrome: lymphedema, sensorineural hearing loss and monosomy 7 MonoMAC syndrome: monocytopenia and Mycobacterium avium complex infection DCML: susceptibility to mycobacterial, fungal, viral infections; warts; molluscum; pulmonary alveolar proteinosis [31,32] | Cumulative risk of evolution to MDS/AML: 6% at the age of 10 years, 39% at the age of 20 years, and 81% at the age of 40 years [33,34,35] |
SDS | SBDS [36,37] | AR | Biogenesis of ribosomes and mitotic spindle stabilization | Short stature, exocrine pancreatic dysfunction, pancreatic lipomatosis/atresia, skeletal dysplasia, osteopenia, eczema, transient transaminitis/hepatomegaly in early childhood, dental anomalies, immunodeficiencies, endocrinopathies, neurocognitive and other variable congenital anomalies [38] | Cumulative risk of evolution to MDS/AML: 18.8% at 20 years and 36.1% at 30 years of age [39] |
MIRAGE syndrome ATXPC/MLSM7 | SAMD9 SAMD9L [40,41,42] | AD | Proliferation control | MIRAGE syndrome: cytopenias, immunologic abnormalities, short stature, a renal hypoplasia, invasive bacterial infections, gastrointestinal (chronic diarrhea, genitourinary abnormalities, delay of developmental milestones, intrauterine growth restriction ATXPC: ataxia, cerebellar hypoplasia, invasive bacterial infections, alveolar proteinosis, cytopenia [43,44] | No data on cumulative risk of evolution to MDS/AML |
Familiar MDS associated with thrombocytope-nia | RUNX1, ANKRD26, ETV6 [45] | AD | Transcription factor | Thrombocytopenia, platelet dysfunction [46] | Prevalence of MDS and AML is of about 40% in patients with RUNX1, of 8% in patients with ANKRD26 and of 23% in patients with ETV6 [47,48] |
DBA | GATA1, RPL5, 9, 11, 15, 18, 26, 27, 31, 35, 35a, RPS7, 10, 15a, 17, 19, 24, 26, 27, 28, 29 [49] | AD | Ribosomopathy | Short stature, severe macrocytic hyporigenerative anemia in infancy, facial dysmorphisms, radial ray anomalies, skeletal anomalies, genitourinary and heart malformations. Neutropenia and immunodeficiencies associated with RPL35a [50] | Cumulative risk of evolution to AML of 2% by 45 years [51] |
Severe congenital neutropenia | ELANE [52] | AD | ELANE encodes for neutrophil elastase | Osteopenia | Cumulative risk of evolution to MDS/AML of 22% after 15 years for ELANE [53] |
GFI1 | Lymphopenia | ||||
HAX1 | AR | Seizures, neurologic abno malities [54] | |||
G6PC3 | Structural heart disease, urogenital anomalies, prominent veins, deafness, skeletal anomalies, immune dysregulation, colitis, poor growth, thrombocytopenia [53] | ||||
JAGN1 [54] | Skeletal, dental anomalies |
Main Characteristics of the Patient and Diagnostic Findings | |
---|---|
Age (years) | 27 |
Sex | Male |
Congenital abnormalities | None |
Comorbidities | Left brachial plexus injury; Epilepsy |
Family history | Father†; Mother† (leukemia) |
Complete blood count | WBC 3.200/µL Neutrophils 850 × 10^6/µL Lymphocytes 1700 × 10^6/µL Monocytes 500 × 10^6/µL Eosinophils 150 × 10^6/µL Basophils 100 × 10^6/µL Hemoglobin 14.1 g/dL Platelets 196.000/µL Blasts < 2% |
ANA | Negative |
HBV, HCV, HIV | Negative |
Bone marrow aspirate | Trilinear dysplasia, blasts 3% |
Karyotype | 46, XY [20] |
NGS analysis on 52 genes commonly mutated in MDS | No mutation |
DEB and Cell cycle test | Negative |
Telomere length | <33° percentile |
Somatic and germline testing for DC associated mutations | c.835G > A p.Ala279Thr and c.833C > T p.Pro278Leu mutation in heterozygosity in TERT gene |
Hepatic elastometry | Absence of steatosis or fibrosis |
Pulmonary CT scan | No signs of fibrosis |
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Crisà, E.; Boggione, P.; Nicolosi, M.; Mahmoud, A.M.; Al Essa, W.; Awikeh, B.; Aspesi, A.; Andorno, A.; Boldorini, R.; Dianzani, I.; et al. Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists. Int. J. Mol. Sci. 2021, 22, 2525. https://doi.org/10.3390/ijms22052525
Crisà E, Boggione P, Nicolosi M, Mahmoud AM, Al Essa W, Awikeh B, Aspesi A, Andorno A, Boldorini R, Dianzani I, et al. Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists. International Journal of Molecular Sciences. 2021; 22(5):2525. https://doi.org/10.3390/ijms22052525
Chicago/Turabian StyleCrisà, Elena, Paola Boggione, Maura Nicolosi, Abdurraouf Mokhtar Mahmoud, Wael Al Essa, Bassel Awikeh, Anna Aspesi, Annalisa Andorno, Renzo Boldorini, Irma Dianzani, and et al. 2021. "Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists" International Journal of Molecular Sciences 22, no. 5: 2525. https://doi.org/10.3390/ijms22052525
APA StyleCrisà, E., Boggione, P., Nicolosi, M., Mahmoud, A. M., Al Essa, W., Awikeh, B., Aspesi, A., Andorno, A., Boldorini, R., Dianzani, I., Gaidano, G., & Patriarca, A. (2021). Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists. International Journal of Molecular Sciences, 22(5), 2525. https://doi.org/10.3390/ijms22052525