Malignant hematological diseases in the presence of Fanconi anemia (FA)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory*
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative

* For AML and FA: obligatory, for MDS and FA: facultative

Based on the current guidelines and the current state of research, there are different diagnostic recommendations for patients with malignant hematologic disorders in the presence of Fanconi anemia. We have summarized the most important information on classification and diagnostic methods at MLL. In addition, we provide further links on prognosis and staging in FA, so that you can inform yourself in more detail.

Fanconi anemia: Background

Pathogenesis and clinical appearance of Fanconi anemia

Fanconi anemia (FA) is a consequence of germline mutations in FA/BRCA DNA repair genes and is the most common genetic cause of bone marrow insufficiency. FA patients typically develop pancytopenia in the first decade of life, which usually begins with thrombocytopenia and leukopenia. The fact that all hematopoietic lineages are affected suggests hematopoietic stem cell (HSC) dysfunction. This theory is supported by the low percentage of CD34-positive cells in the bone marrow of young FA patients, a cell fraction enriched in HSCs. Therefore, a prenatal defect of HSCs in FA patients is assumed (Garaycoechea & Patel 2014). To date, pathogenic variants have been identified in 23 genes that play a role in the development of FA (FANCA-FANCW) (Moreno et al. 2021, Bhandari et al. 2022).

Due to chromosomal instability, the risk of cancer is generally increased in FA patients. The cumulative incidence of bone marrow failure is approximately 50-90% by the age of 40. Most commonly, FA patients develop myelodysplastic syndromes (MDS) or acute myeloid leukemias (AML); often in early childhood with cumulative risk of disease later in life (30% for MDS and 10% for AML at age 40) (Feurstein et al. 2016, Bhandari et al. 2022). Therefore, close monitoring of hematopoiesis is necessary. For this purpose, a bone marrow analysis is recommended at FA diagnosis and in the further course. This should include a bone marrow aspiration (biopsy) and a cytogenetic examination (Peffault de Latour & Soulier 2016, Frohnmayer et al. 2020).


Diagnosis of Fanconi anemia

In Germany, analyses to confirm the diagnosis of Fanconi anemia are performed at the Institute of Human Genetics at the University of Würzburg and at the University of Düsseldorf, among others.

The diagnosis of FA is classically made by chromosome breakage testing. FA cells show an increased number of chromosome breaks compared to wild-type cells. Another diagnostic test is cell cycle analysis after mitomycin C (MMC) treatment by flow cytometry (FACS), where FA cells show accumulation in G2 arrest compared to wild-type cells (Auerbach 2009). FA diagnosis is nowadays substantially supported by sequence analyses of the genes that constitute the 23 known genetic subtypes of FA (Longerich et al. 2014, Dong et al. 2015, Bluteau et al. 2016, Dufour 2017, Knies et al. 2017, Moreno et al. 2021). The particular FA genotype is clinically relevant because, for example, the genetic subtypes FANCD1 (BRCA2 mutation) and FANCN (PALB2 mutation) are associated with severe phenotypic expression of FA and are associated with early development of leukemias (median 2.2 years) and pediatric cancers (Gille et al. 2012).

A distinctive feature that may occur in FA patients is somatic reversion in part of the blood and bone marrow cells (mosaic), correcting the FA gene defect, which gives this cell population an enormous growth advantage. In these cases, a chromosome break test in fibroblasts of the skin is necessary to confirm the diagnosis (Auerbach 2009, Frohnmayer et al. 2020).

Malignant hematologic diseases in the presence of Fanconi anemia: Diagnostics

Fanconi anemia: Prognosis and staging

Chromosomal aberrations in patients with Fanconi anemia, particularly +3q, -7/7q, and RUNX1 aberrations, are usually associated with MDS/AML and indicate an unfavorable prognosis. Complex karyotypes are also associated with an unfavorable prognosis. +1q, on the other hand, represents an early event and is found in all stages of Fanconi anemia and therefore cannot be associated with malignant transformation. Other aberrations such as 5q-, 11q-, or 20q- are found as well as in non-FA-associated MDS cases, but less frequently, and are not considered to indicate an unfavorable prognosis. If such non-prognosis relevant chromosomal aberrations are found without or with mild cytopenia, close follow-up of the blood count and bone marrow (morphology and cytogenetics) is recommended.

As soon as a high-risk constellation is present in bone marrow staging, HSCT is indicated. Due to the high toxicity of DNA-damaging agents for FA patients, intensity-reduced conditioning (RIC) is applied by default prior to stem cell transplantation.

Due to the high risk of secondary malignancies as well as chronic graft-versus-host disease (GvHD), long-term monitoring with regular examinations in FA patients is strongly recommended (Peffault de Latour & Soulier 2016).

Fanconi anemia: Further literature

Deutsche Fanconi-Anämie-Hilfe e.V. Fanconi anemia: Ein Handbuch für Eltern, Patienten und ihre Ärzte; auf dem Original von Lynn und Dave Frohnmayer basierende und ergänzte deutsche Überarbeitung. 2005. ISBN 3-00-015621-6.
Download unter: https://fanconi.de/informationen-zur-fa/

Frohnmayer D et al. Fanconi Anemia Clinical Care Guidelines. Fifth Edition.  Fanconi Anemia Research Fund, Inc 2020.
Download at: https://www.fanconi.org/explore/clinical-care-guidelines

Fanconi anemia mutation database: https://www2.rockefeller.edu/fanconi/

Status: December 2023

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