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.

Keywords: Autologous stem cell transplantation; Bone marrow failure; Fanconi anemia; Gene therapy; Mosaicism.

Fig. 1

Several mechanisms by which additional chromosomal rearrangements or mutations may facilitate correction of an inherited recessive genetic disorder. The yellow and blue bars indicate an individual gene, with black hashes indicating a disease-causing mutation. Reversion mutations may arise either during or subsequent to DNA replication and may involve transfer of genetic material between paired chromosomes (gene conversion or intragenic crossover) or mutations within a single chromosome (and gene). Gene conversion, intragenic crossover, and back mutations result in genetic correction in one allele within a daughter cell (indicated by the green border and background). Second-site mutations (white hash) result in a gene capable of generating a functional protein (indicated by the green dashed border and green background) in one allele, although the gene itself may differ from wildtype. Adapted from Pasmooij et al. [17]

Fig. 2

In the cohort of FA mosaic patients (n = 37) with normalized blood counts and information regarding clinical outcomes, individuals were included from the following cohorts: Spain (n = 13), Germany (n = 10), France (n = 8), the USA (n = 5), and Japan (n = 1). Complementation groups of patients identified in this cohort included: Group A (n = 24), Group B (n = 1), Group C (n = 1), Group E (n = 1), and Group T (n = 1); in n = 7 patients, complementation group was unknown

Fig. 3

Swimmer plot depicting clinical course for 37 FA mosaic patients with normalized blood counts, including age at diagnosis (when available), last follow-up, and occurrences of BMF, AML/MDS, allogeneic HSCT, and solid organ cancers. The majority of patients (34 of 37) were alive without BMF, malignancy, or transplant at last follow-up. Criteria for normalization are provided in the text and are in general more stringent (exclusive) than those applied by investigators in Table 1