Pediatric Germline Predisposition to Myeloid Neoplasms

Thompson, Christineil; Ariagno, Sydney; Kohorst, Mira A.

doi:10.1007/s11899-022-00681-5

Cited by 2 publications

(5 citation statements)

References 70 publications

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“…Genes that have been implicated with germline associations with hematological malignancies include RUNX1 ( 8 ), DDX41 ( 9 ), CEPBA ( 10 ), TERT ( 11 ), GATA2 ( 12 ), ETV6 ( 13 ), DNMT3A ( 14 ) ANKRD26 ( 15 ), and RAS-MAPK pathway genes ( 16 ). Specific inherited bone marrow failure syndromes such as Schwachman Diamond syndrome, Diamond Blackfan anemia, Fanconi syndrome, and short telomere syndrome may have associated characteristic physical findings or systemic features prompting suspicion ( 17 , 18 ). Germline tests may be more frequently ordered for individuals with a strong family history of cancer, multiple primary malignancies, early onset of cancer, cancers affecting both paired organs, and association with congenital anomalies ( 17 , 19 ).…”

Section: Differences Between Somatic and Germline Testsmentioning

confidence: 99%

“…Her parents and siblings are well with no known medical conditions. Her full blood count showed an increase in total white cell count with monocytosis—white blood cells, 18.3 × 10 9 /L ( 6 – 18 ); hemoglobin, 9.9 g/dL (11.1–14.1); platelets, 107 × 10 9 /L (140–440); neutrophils, 6.41 × 10 9 /L (1.00–6.00); monocytes, 3.66 × 10 9 /L (0.2–1.2); blasts, 2%; promyelocytes, 1%; myelocytes, 2%; and metamyelocytes, 1%. Examination of the blood film showed a leukoerythroblastic blood film with monocytosis and blasts seen, suggestive of a myeloproliferative neoplasm.…”

Section: Casementioning

confidence: 99%

“…Specific inherited bone marrow failure syndromes such as Schwachman Diamond syndrome, Diamond Blackfan anemia, Fanconi syndrome, and short telomere syndrome may have associated characteristic physical findings or systemic features prompting suspicion (17,18). Germline tests may be more frequently ordered for individuals with a strong family history of cancer, multiple primary malignancies, early onset of cancer, cancers affecting both paired organs, and association with congenital anomalies (17,19). The identification of germline variants in higher risk individuals such as those with multiple affected family members can be as high as 57% (20).…”

Section: Differences Between Somatic and Germline Testsmentioning

confidence: 99%

“…The absence of a family history of hematological issues or malignancies does not exclude a germline cause (17). This is because genetic variants can arise de novo or be a recessive disorder inherited from asymptomatic carrier parents.…”

Section: Somatic Tests Can Identify Germline Variantsmentioning

confidence: 99%

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Challenges associated with the identification of germline variants on myeloid malignancy genomic profiling—a Singaporean experience

Chin,

Lam,

Christopher

et al. 2023

Front. Oncol.

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Genomic profiling to identify myeloid-malignancy-related gene mutations is routinely performed for patients with suspected or definite myeloid malignancies. The most common specimen types in our experience are peripheral blood and bone marrow aspirates. Although primarily intended to identify somatic mutations, not infrequently, potentially clinically significant germline variants are also identified. Confirmation of the germline status of these variants is typically performed by hair follicle or skin fibroblast testing. If the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene known to be associated with a disease relevant to the patient’s phenotype (for example, the identification of a DDX41 pathogenic variant in an individual with acute myeloid leukemia), the management algorithm is typically quite straightforward. Challenging situations may occur such as when the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene not known to be associated with the patient’s phenotype/presenting complaint. We have encountered several such challenging cases in which potentially clinically significant germline variants were identified on the initial genomic profiling of peripheral blood or bone marrow aspirate. In this article, we present these cases and discuss the genetic counseling and management approaches.

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Section: Differences Between Somatic and Germline Testsmentioning

confidence: 99%

Section: Casementioning

confidence: 99%

Section: Differences Between Somatic and Germline Testsmentioning

confidence: 99%

Section: Somatic Tests Can Identify Germline Variantsmentioning

confidence: 99%

See 2 more Smart Citations

Challenges associated with the identification of germline variants on myeloid malignancy genomic profiling—a Singaporean experience

Chin,

Lam,

Christopher

et al. 2023

Front. Oncol.

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“…Up until now, three different mechanisms of genetic reversion have been identified [192]. First, loss of heterozygosity of chromosome 7q with uniparental disomy (UPD) could result in the loss of the mutant allele [192,193]. Second, in cis LOF mutations could counteract the GOF mutations and cause a recovery of the cytopenia.…”

Section: Other Germline Predisposition For Mds/amlmentioning

confidence: 99%

Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management

Vissers,

van der Burg,

Lankester

et al. 2023

JCM

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Irreversible severe bone marrow failure (BMF) is a life-threatening condition in pediatric patients. Most important causes are inherited bone marrow failure syndromes (IBMFSs) and (pre)malignant diseases, such as myelodysplastic syndrome (MDS) and (idiopathic) aplastic anemia (AA). Timely treatment is essential to prevent infections and bleeding complications and increase overall survival (OS). Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for most types of BMF but cannot restore non-hematological defects. When using a matched sibling donor (MSD) or a matched unrelated donor (MUD), the OS after HSCT ranges between 60 and 90%. Due to the introduction of post-transplantation cyclophosphamide (PT-Cy) to prevent graft versus host disease (GVHD), alternative donor HSCT can reach similar survival rates. Although HSCT can restore ineffective hematopoiesis, it is not always used as a first-line therapy due to the severe risks associated with HSCT. Therefore, depending on the underlying cause, other treatment options might be preferred. Finally, for IBMFSs with an identified genetic etiology, gene therapy might provide a novel treatment strategy as it could bypass certain limitations of HSCT. However, gene therapy for most IBMFSs is still in its infancy. This review summarizes current clinical practices for pediatric BMF, including HSCT as well as other disease-specific treatment options.

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Pediatric Germline Predisposition to Myeloid Neoplasms

Cited by 2 publications

References 70 publications

Challenges associated with the identification of germline variants on myeloid malignancy genomic profiling—a Singaporean experience

Challenges associated with the identification of germline variants on myeloid malignancy genomic profiling—a Singaporean experience

Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management

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