Fanconi anaemia: genetics, molecular biology, and cancer – implications for clinical management in children and adults

Abstract

Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities, cross-linker hypersensitivity and extreme cancer predisposition. With better understanding of the genetic and molecular basis of the disease, and improved clinical management, FA has been transformed from a life-limiting paediatric disease to an uncommon chronic condition that needs lifelong multidisciplinary management, and a paradigm condition for the understanding of the gene-environment interaction in the aetiology of congenital anomalies, haematopoiesis and cancer development. Here we review genetic, molecular and clinical aspects of FA, and discuss current controversies and future prospects.

Somatic, hematologic phenotype, long‐term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology–Oncology)

“…Of the 70 patients with non severe cytopenia (44 mild and 26 moderate), 9 (12.9%) improved, 18 (25.7%) maintained the initial cytopenia degree, and 43 (61.4%) dropped to a more severe degree. Of the 24 patients with initial severe cytopenia 22 remained so, and two ameliorated to moderate [1] and mild [1] degree. Of the 11 patients who improved blood counts (9 from the mild/moderate groups and 2 from the severe ones), 8 did not receive any medical treatment, 1 had received 3 years of androgens and steroids which were stopped for inefficacy 6 years prior to improvement, 1 had received steroids and G-CSF for some months early after cytopenia diagnosis and stopped several years before improvement.…”

“…Details are in Supporting Information Tables I and II. The grade of cytopenia was defined according to an adjusted classification based on that of the FA Guidelines for Diagnosis and Management, 3rd edition 2008 [6], published by Fanconi anemia Research Fund. The adjustment was made following local and national guidelines to define cytopenia, specifically [1] mild cytopenia was defined as at least one of the following: Hb >10 g/dL but lower than the inferior limit according to age, polymorphonuclear cells (PMN) 1.0 < 1.5 3 10 9 /L, platelets 50 < 150 3 10 9 /L; [2] moderate cytopenia was defined as at least one of the following: Hb 8 < 10 g/dL, PMN 0.5 < 1.0 3 10 9 /L, platelets 20 < 50 3 10 9 /L, and [3] severe cytopenia was defined as at least one of the following: Hb < 8 g/dL, PMN < 0.5 3 10 9 /L, platelets <20 3 10 9 /L. The lowest value of the three cell lineages defined the level, meaning for example that a patient with Hb 9 g/dL, PMN 0.7 3 10 9 /L, and platelets 10 3 10 9 /L was regarded as having severe cytopenia.…”

“…Fanconi anemia (FA) is a rare genetic disease due to a recessive or X-linked defect in one of 17 genes (FANCA, B, C, D1 (BRCA2), D2, E, F, G, I, J, L, M, N, RAD51C, P, Q, UBE2T) [1,2]. The cellular defect common to all patients is DNA crosslink sensitivity with formation of double strand breaks after exposure to mitomycin C (MMC) or diepoxybutane (DEB) representing the basis of the diagnostic test for FA.…”

Genetic Diagnosis of Fanconi Anemia

“…FA cases caused by biallelic FANCD1/BRCA2 mutations are rare but are associated with an increased risk of medulloblastoma or Wilm's tumor and other embryonal tumors that may precede development of aplastic anemia or an earlier onset of leukemia [33][34][35][36][37][38]. Children with biallelic PALB2/FANCN mutations tend to have more serious cancer-related phenotypes, with early-onset of Wilm's tumor, AML and medulloblastomas [33][34][35]39,40].…”

“…Children with biallelic PALB2/FANCN mutations tend to have more serious cancer-related phenotypes, with early-onset of Wilm's tumor, AML and medulloblastomas [33][34][35]39,40]. Children with molecular defects in the FANCJ gene do not appear to have the severe phenotype associated with FANCD1/BRCA2 and FANCN/PALB2 [33][34][35]41].…”