Constitutional Trisomy 8 Mosaicism with Persistent Macrocytosis

Abstract

Constitutional trisomy 8 mosaicism (CT8M) is a rare chromosomal abnormality. The phenotype varies from normal features to severe malformations. CT8M increases the risk of developing leukemia and myelodysplastic syndrome. As CT8M is very rare, its diagnosis can easily be overlooked, especially in cases with mild phenotypes. Here, we report the diagnostic process of a 40-year-old female patient with CT8M and discuss the importance of follow-up in monitoring for hematological malignancies.

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

“…Around 80% of germline GATA2 carriers develop a myeloid malignancy before the age of 40 years ( 40 ), and it is shown that the progression to malignancy can occur through multi-step secondary events targeting various hematopoietic pathways. These include (but are not limited to) acquired biallelic mutations in CEBPA ( 41 , 42 ) which lead to differentiation blocks in some AML subtypes ( 38 ), NRAS, ASXL1, SETBP1, NPM1, and WT1 secondary mutations ( 43 ), chromosomal abnormalities (monosomy 7 or trisomy 8) ( 44 )), disrupting the regeneration abilities of enhancers ( 45 ), HSC exhaustion following repeated infections, and changes in DNA binding affinities that result in disruptions to interaction partners/target genes. ( Figure 1 ) For example, the GATA2 p.T354M missense variant may contribute to the leukemogenic process in two ways, by partial loss of GATA2 transactivation activity and simultaneous increased affinity to PU.1 ( 46 ), thereby potentially interfering with differentiation and driving cells towards granulocytic disease ( 7 ).…”