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
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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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