Mosaicism in Fanconi anemia: concise review and evaluation of published cases with focus on clinical course of blood count normalization

Abstract

Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs.

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant

“…Moreover, the phenomenon of hematopoietic mosaicism is responsible for some of the varied clinical presentations observed in a small subset of FA patients and can be diagnostically challenging ( Rickman et al 2015 ; Asur et al 2018 ). Hematopoietic mosaicism can result in partial or full rescue of chromosomal breakage levels in the peripheral blood and protect against aplastic anemia through restoration of a functional allele ( Gregory et al 2001 ; Nicoletti et al 2020 ). In suspected cases, cultured fibroblasts are required for definitive diagnosis of FA.…”

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

“…Mosaicism appears due to the reversion of one of the original germline PV causing FA, it is calculated to be present in up to 20% of patients with FA and can have multiple origins, including gene conversion, back mutation, second-site mutation and others. There is no standard methodology for the diagnosis of mosaicism, however a patient is generally considered to have hematopoietic mosaicism when a sub-population of his/her lymphocytes displays DEB resistance, while their fibroblast show DEB sensitivity [49]. The presence of mosaicism has clinical implications, if the reversion occurs early in the primitive hematopoietic stem cells it might lead to increased blood cell counts, improved aplastic anemia, as well as a reduction in the incidence of bone marrow failure and hematologic neoplasia [49].…”

“…There is no standard methodology for the diagnosis of mosaicism, however a patient is generally considered to have hematopoietic mosaicism when a sub-population of his/her lymphocytes displays DEB resistance, while their fibroblast show DEB sensitivity [49]. The presence of mosaicism has clinical implications, if the reversion occurs early in the primitive hematopoietic stem cells it might lead to increased blood cell counts, improved aplastic anemia, as well as a reduction in the incidence of bone marrow failure and hematologic neoplasia [49]. figures, translocations, deletions and duplications were commonly observed in FA cells [50] Although the two challenge agents are effective, the use of DEB for diagnosis is preferred, because the results are less variable and the difference between non-FA vs FA cells is generally clearer.…”

Causes and Consequences of Chromosomal Instability in Fanconi Anemia. Alterations at the Cellular and Organism Level

“…Mosaicism appears due to the reversion of one of the original germline pathogenic variants causing FA, is calculated to be present in up to 20% of the patients with FA and can have multiple origins, including gene conversion, back mutation, second-site mutation and others. The presence of mosaicism has clinical implications, if the reversion occurs early in the primitive hematopoietic stem cells it might lead to increased blood cell counts and improved aplastic anemia as well as a reduction in the incidence of bone marrow failure and hematologic neoplasias [41]. It has also been shown that progression towards MDS and AML in FA is associated with the presence of clonal and non-clonal chromosomal alterations.…”

“…These gross changes in the karyotype are important, since each cell has a specific genome reorganization that generates a new genome system, susceptible to being selected and moving towards a macro-cellular evolution, a previous step to micro-cellular evolution that will present chromosomal clonal changes and alterations at the gene level [43]; both non clonal and clonal chromosomal abnormalities are valuable biomarkers for detecting progression to cancer. In fact, some specific SCA for FA such as the gain of 1q23-32 (minimal region) and 3q36-29 (minimal region), and other commonly found in FA and non-FA patients, like the monosomy 7 or loss of chromosome 7q31-qter (minimal region), are recurrent anomalies with clinical value for the diagnosis of FA and as factors associated with clonal evolution [40,41].…”