Delayed diagnosis and complications of Fanconi anaemia at advanced age – a paradigm

Abstract

SummaryFanconi anaemia (FA) is a rare recessive DNA repair disorder clinically characterised by congenital malformations, progressive bone marrow failure and a high propensity for developing malignancies at an early age, predominantly acute myeloid leukaemia (AML) and squamous cell carcinoma. It is conceivable that a number of patients with hypomorphic mutations are not diagnosed as FA until severe complications in the treatment of a malignancy occur. Here, we report on a patient with FA-A, diagnosed only at the age of 49 years due to persistent pancytopenia and myelodysplastic syndrome/AML induced by a first cycle of chemotherapy for bilateral metachronic breast cancer. This exceptional case clearly demonstrates that, in instances of long-lasting mild pancytopenia or development of malignancies, especially at an unusually young age, FA should be ruled out, irrespective of the patient's age and features, especially before inflicting severe genotoxic stress. . In the IFAR (Kutler et al, 2003), 10% of patients were diagnosed with one or more solid tumours, predominantly squamous cell carcinomas in the oro-pharyngeoesophageal and anogenital regions. Only three patients, however, were reported to have breast cancer. The risk of developing haematological and non-haematological malignancies amounted over time to a cumulative incidence of 33% and 28%, respectively, by 40 years of age. During the 20-year observation period, 38% of patients died at a median age of 24 years (Kutler et al, 2003). On a cellular level, FA is characterised by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents, such as mitomycin C (MMC), diepoxybutane (DEB) and cisplatin (D'Andrea & Grompe, 2003;Venkitaraman, 2003;Thompson et al, 2005). Complementation studies based on the correction of this hypersensitivity by somatic cell fusion have defined at least 12 complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M) (Levitus et al, 2003). Eleven genes in which germline defects in patients result in the clinical phenotype of FA have been identified (FANCA, B, C, D1, D2, E, F, G, J, L, M) (Joenje & Arwert, 2001;Howlett et al, 2002;Levitus et al, 2005;Levran et al, 2005a;Meetei et al, 2005). Functional assays suggest that a core FA complex composed of the proteins FANCA, B, C, E, F, G, L and M as well as the FAassociated proteins FAAP100 (Meetei et al, 2003;Fei et al, 2005) activates FANCD2 by monoubiquitination (GarciaHiguera et al, 2001;Timmers et al, 2001). Monoubiquitinated FANCD2 protein, also referred to as FANCD2-L, then interacts with BRCA2/FANCD1 in chromatin (Hussain et al, 2004;Wang et al, 2004). FANCJ as the BRCA1-interacting helicase BRIP1 has recently been identified by us and others (Levitus et al, 2005;Levran et al, 2005a) and might be involved in the stabilising role that has been described for BRCA1 in the ubiquitination of FANCD2 (Vandenberg et al, 2003). Defects within the FA pathway result in prolonged G2/M transition in the cell cycle (Dutrillaux et al, 1982;Seyschab et al, 1995) and defectiv...

Diagnosis of Fanconi anemia in patients with bone marrow failure

“…It is possible that delayed FA diagnosis to adulthood was related to somatic mosaicism and/or to hypomorphic FANC mutations. 36 Importantly, this diagnostic strategy ruled out an FA diagnosis in all of the other patients who had skin samples available, including those who had some evidence of an inherited condition associated to the BMF. Twenty-one patients retained a final diagnosis of an 'uncategorized inherited syndrome' based on the multiplicity of physical exam findings associated to BMF, and/or the positive family history, and also on failing to formally fulfill clinical diagnostic criteria for a known phenotype (Table 2 and Online Supplementary Table S1).…”

Fanconi anaemia

“…Our case provides further evidence for varied clinical manifestations of FA, highlighted and discussed in the report by Huck et al (2006).…”

“…I read with interest the article by Huck et al (2006) on Fanconi anaemia (FA) presenting at an advanced age.…”

“…This can delay the diagnosis of FA indefinitely or until certain genotoxic stress occurs (Alter et al, 2005). The patient described by us (Huck et al, 2006) had biallelic germline mutations in FANCA, one of which was a missense substitution in a conserved gene region. This hypomorphic mutation allele enabled the patient to lead a normal life and to give birth to a normal child who only later developed a brain tumour.…”

Retrospective NGS Study in High-risk Hereditary Cancer Patients at Masaryk Memorial Cancer Institute

“…Relativní riziko u heterozygotních nosičů mutace v ně kte rém z FANC genů je značně variabilní [10]. Mutace v genu FANCI jsou celosvětově velmi vzácné, riziko solidních nádorů u heterozygotních alelická mutace v německé populaci u ženy s relativně pozdními projevy FA (AML po 40. roce věku) a s nádorem prsu ve 37 letech [9]. U pa cientky s nádorem slinivky (roč-ník 1992) s rodinnou anamnézou karcinomu prsu a karcinomu slinivky byla zachycena nonsense mutace v genu…”