An update on Fanconi anemia: Clinical, cytogenetic and molecular approaches (Review)

Abstract

Fanconi anemia is a genetic syndrome clinically characterized by congenital malformations that affect several human systems, leads to progressive bone marrow failure and predisposes an individual to cancer, particularly in the urogenital area as well as the head and neck. It is commonly caused by the biallelic compromise of one of 22 genes involved in the FA/BRCA repair pathway in most cases. The diagnosis is based on clinical suspicion and confirmation using genetic analysis, where the chromosomal breakage test is considered the gold standard. Other diagnostic methods used include western blotting, multiplex ligation-dependent probe amplification and next-generation sequencing. This genetic condition has variable expressiveness, which makes early diagnosis difficult in certain cases. Although early diagnosis does not currently allow for improved cure rates for this condition, it does enable healthcare professionals to perform a specific systematic follow-up and, if indicated, a bone marrow transplantation that improves the mobility and mortality of affected individuals. The present review article is a theoretical revision of the pathophysiology, clinical manifestations and diagnosis methods intended for different specialists and general practitioners to improve the diagnosis of this condition.

Hematopoietic Cells from Pluripotent Stem Cells: Hope and Promise for the Treatment of Inherited Blood Disorders

“…FA patients have progressive loss of HSCs in their BM [32], which clinically manifests as reduced mature cells. Mutations in at least 22 genes, all involved in DNA repair and genome stability, termed complementation groups FANCA-FANCW, have been associated to this disease [33]. All the genes are inherited in an autosomal recessive manner, except for FANCB that is localized on the X chromosome and causes X-linked FA.…”

Case Report: Refractory Cytopenia With a Switch From a Transient Monosomy 7 to a Disease-Ameliorating del(20q) in a NHEJ1-Deficient Long-term Survivor

“…The responsible genetic defects often produce recognizable syndromes, whose main features are microcephaly, growth retardation as well as inconsistent other physical malformations and organ abnormalities. Such germline alterations comprise pathogenic variants in genes that encode for transcription factors such as GATA2, RUNX1 and ETV6, products that are involved in telomere maintenance (dyskeratosis congenita), ribosomal biogenesis (Blackfan-Diamond anemia) and maturation (Shwachman-Diamond syndrome; SDS), DNA maintenance and repair (Fanconi anemia), protein folding and trafficking (severe congenital neutropenia) as well as in the regulation of cell proliferation and apoptosis (SAMD9/9L) (3)(4)(5)(6)(7)(8)(9). In many instances characteristic clinical, laboratory and hematologic parameters alone will already suffice to identify the respective syndrome.…”

Correction of Fanconi Anemia Mutations Using Digital Genome Engineering

“…The FA pathway/complex is comprised of 23 known genes, including FANCA , FANCC , FANCD1 (BRCA2), FANCD2 , FANCG , FANCN (PALB2), FANCO (RAD51C), FANCQ (ERCC4/XPF), FANCR (RAD51), FANCS (BRCA1), and FANCV (REV7) [ 5 , 6 , 7 ]. Mutations in any of these genes can lead to different disease states with a wide range of clinical presentations; however, ~70% of FA cases are caused by mutations on FANCA [ 8 ]. The accumulation of unrepaired ICLs from endogenous and exogenous sources such as aldehydes, reactive oxygen species (ROS), or alkylating agents such as Mitomycin C (MMC), are the driving forces of disease progression and phenotypic presentation [ 5 ].…”