DIAGNOSIS OF FANCONI’S ANEMIA BY DIEPOXYBUTANE ANALYSIS IN CHILDREN FROM SERBIA
Cirkovic S1,*, Guc-Scekic M1,2, Vujic D3,5, Ilic N1, Micic D4, Skoric D6, Jovanovic A4
*Corresponding Author: Sanja Cirkovic, Department of Medical Genetics, Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic”, Radoja Dakica 6-8 st., 11070 Belgrade, Serbia; Tel.: +381-11-3108-273; Mobile tel.: +381-62-860-1180; E-mail: genetikaimd@beotel.rs, sanja.s.cirkovic@gmail.com
page: 65

DISCUSSION

Fanconi’s anemia is rare autosomal recessive disorder, characterized by a high clinical and genetic heterogeneity [14,16-21]. Diagnosis of FA on the basis of clinical features is often difficult and unreliable, due to the possible overlap of the FA phenotype with that of a variety of genetic and non genetic BFM syndromes [2,22]. Nowadays, chromosome fragility induced by ICL-inducing agents, such as DEB or MMC is the most widely used test for the diagnosis of FA. We report here the results of the DEB-induced chromosome fragility test as screening for FA in Serbian children with clinical suspicion of FA. This study revealed 10 (15.2%) out of 66 examined patients to have a FA cellular phenotype with increased DEB-induced chromosome fragility. A lower incidence of FA in the cohort of 66 patients with pediatric AA when compared to published data (25-30%) [1], could not be the true frequency of FA in Serbian patients with pediatric AA, as there might be the chance of selection bias, assuming that not all of patients with AA underwent DEB testing. In our study, the spontaneous chromosome fragility (percentage of aberrant cells and breaks/cell) values in 10 FA patients were overlapping those in non FA patients. The International Fanconi’s Anemia Registry (IFAR) study showed that the range of spontaneous chromosome breaks in FA group of 104 patients (0.02- 1.90 breaks/cell with a mean of 0.27) was overlapping with the range found in a non FA group of 224 patients (0.00-0.12 breaks/cell with a mean of 0.02) [16]. In this study, the unreliability of base line of chromosome breakage in differential diagnosis of FA [16,22] was confirmed. Thus, baseline breakage frequency was proven not to be a useful method for discrimination of FA patients. According to the DEB sensitivity test, the percentage of DEB-induced aberrant cells in the examined groups was increased more than 26 times in FA patients when compared to non FA patients. The number of DEB-induced breaks/cells was more than 68 times higher in FA patients when compared to non FA patients. There was a clear discrimination between FA and non FA subgroups with no overlapping. The IFAR study, also significantly differed the FA group from the non FA group on the basis of DEB-induced chromosome fragility. The percentage of induced aberrant cells in their study was 85.15% in FA patients and 5.12% in the non FA group [16]. Similarly, the mean of DEBinduced breaks/cell in FA patients was 8.96, while in the non FA group it was 0.06 [16]. These two groups showed no overlapping. Our results are in the line with IFAR report [16] and other similar studies [22-24] because FA and non FA groups could be distinguished by the percentage of DEB-induced aberrant cells (FA 22.00-82.00% vs. non FA 0.00-12.00%) and breaks/cell (FA 0.26-4.39 vs. non FA 0.00-0.20). However, the level of variability in DEB-induced aberrant cells between the 10 patients with FA is very high with ranges from 22.00 to 82.00% (see Tables 1 and 2; Figure 2). Part of this high variability in the patients with FA is due to the existence of subgroup of patients who have lower values of chromosome fragility parameters (Table 2; borderline patients Nos. 3, 4 and 10). This subgroup corresponds to FA patients with T-cell mosaicism, who represent 15-25% of all FA patients [25-27]. Somatic mosaicism is produced when one of the pathogenic mutations is reverted in a hematopoietic precursor cell [27-29]. In previously published studies, FA patients with <40% of aberrant cells were considered mosaic, while those with a proportion between 40 and 60% were considered as possible mosaics; FA patients with proportion >60% of aberrant cells were considered as non mosaic patients with FA [30]. Similarly, in our study, all FA patients with <35 % of aberrant cells were considered mosaic (patients Nos. 1 and 3, –20%), while those with a proportion >60% of aberrant cells were considered non mosaic patients with FA, awaiting for additional evidence of mosaicism. However, the high level of variability of DEB-induced aberrant cells we found in the group of non FA patients, with range from 0.00 to 12.00%, due to the borderline DEB sensitivity of some patients. These patients might be considered mosaic FA or they represent non FA patients with higher sensitivity (up to 16%) to ICL agents due to an unknown genetic background [30]. Although high sensitivity to ICL-inducing agents is the hallmark of FA cells, an accurate diagnosis is compromised in some cases, especially in mosaic patients. Recently, Castella et al. [30] proposed a new chromosome fragility index that provides a clear cut-off diagnostic level unambiguously distinguishing patients with FA, including mosaic from non FA individuals, which should be improved in the near future. However, molecular investigation and identification of the FA complementary group for each DEB sensitive FA patient is the next step necessary in establishing the diagnosis of FA, its therapy management and genetic counseling of affected families.



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