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Cytogenetic Profile in 1,921 Cases of Trisomy 21 Syndrome
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ORIGINAL ARTICLE
Cytogenetic Profile in 1,921 Cases of Trisomy 21 Syndrome in Mexican Patients Q3
Francisco Flores-Ramırez,a Claudia Palacios-Guerrero,a,b Constanza Garcıa-Delgado,a Ariadna Berenice Morales-Jimenez,a Christian Martın Arias-Villegas,a Alicia Cervantes,b and Ver onica Fabiola Moran-Barrosoa a
Departamento de Genetica, Hospital Infantil de Mexico Federico Gomez, Mexico, D.F., Mexico Servicio de Genetica, Hospital General de Mexico Dr. Eduardo Liceaga, Facultad de Medicina, UNAM, Mexico, D.F., Mexico
b
Received for publication March 4, 2015; accepted August 17, 2015 (ARCMED-D-15-00147).
Background and Aims. Trisomy 21 is the most frequent genetic cause of intellectual disability. It is caused by different cytogenetic aberrations: free trisomy, Robertsonian translocations, mosaicism, duplication of the critical region and other structural rearrangements of chromosome 21. The aim of the study was to identify in Mexican trisomy 21 patients who attended Hospital Infantil de Mexico Federico Gomez from 1992e2011 the type and frequency of the cytogenetic aberration and to evaluate the effect of maternal age. Methods. A retrospective analysis of epidemiological data and karyotype reports were carried out; type and frequency of the cytogenetic variants were determined. Results. We identified 2,018 cases referred with a clinical diagnosis of trisomy 21. In 1,921 analyses (95.2%) a cytogenetic variant of trisomy 21 was identified: free trisomy 21 in 1,787 cases (93.02%), four cases (0.21%) had an additional non-contributory aberration; Robertsonian translocations in 92 cases (4.79%); mosaicism in 31 cases (1.61%) and seven cases (0.36%) had other chromosomal abnormalities, five (0.26%) had other contributory structural rearrangements and two corresponded to double aneuploidies (0.10%). Gender distribution was 1,048 (54.56%) males and 873 (45.44%) females. A maternal age effect was observed in patients with free trisomy 21 with mothers O36 years of age. Conclusion. The present work reports the experience of a Mexican referral center regarding the karyotype diagnosis of patients with trisomy 21 and is one of the most extensive studies published so far. Percentages of the cytogenetic abnormalities present in our population reflect the ones previously reported for these cytogenetic alterations worldwide. Ó 2015 IMSS. Published by Elsevier Inc. Key Words: Trisomy 21, Down syndrome, Robertsonian translocation, Mosaicism, Chromosome 21.
Introduction Down syndrome (DS) was described by John Langdon Down in 1866 (1) and, because it is caused by an extra copy of chromosome 21 (2), is also called trisomy 21 syndrome. DS is the most frequent cause of intellectual disability of genetic origin with a general presentation from 1:850e1 in 1,000 newborns (3,4). In Mexico its frequency is 1:650 newborns (5). Address reprint requests to: Veronica Fabiola Moran-Barroso, Dr. Marquez 162, Col. Doctores, Mexico, D.F. 06720, Mexico; Phone: (þ52) (55) 5228-9917 ext. 2037; FAX: (þ52) (55) 5228-9917, ext. 2344; E-mail: [email protected]
The cytogenetic variants that cause DS are free trisomy 21, Robertsonian translocations, mosaicism, duplication of the DS critical region and other structural rearrangements involving chromosome 21 (6e8). In 90e95% of DS patients the presence of the extra chromosome 21 was originated from a meiotic nondisjunction event. In 80% of these cases it occurred during maternal meiosis and was associated with a maternal age effect O35 years (6,9,10). In 4% of DS cases, chromosome 21 may be translocated to another acrocentric chromosome. These so-called Robertsonian translocations usually involve chromosome 14 or another chromosome 21 even if the latter are mostly isochromosomes 21q or rea(21;21). In 25% of the
0188-4409/$ - see front matter. Copyright Ó 2015 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2015.08.001 ARCMED2041_proof ■ 22-8-2015 0-41-42
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translocation cases, one of the parents is a carrier (7,11). Mosaic cases account for 3e5% of DS and are caused by a nondisjunction postzgotic event (12). Other structural rearrangements are less frequent causes of DS and the diagnosis requires molecular cytogenetic techniques such as FISH (7). SD associated with chromosomal alterations other than trisomy 21 has also been reported (13e15). DS is one of the main causes for consultation at the Genetic Department of the Hospital Infantil de Mexico Federico G omez (HIMFG) in Mexico City, Mexico for diagnosis and follow-up of patients. In this study we analyzed the cytogenetic results of the large population of DS patients who have attended our institution during a 20-year period in order to determine the type and frequency of cytogenetic alteration and to evaluate the effect of maternal age. Patients and Methods All karyotype GTG banding technique reports from the Cytogenetics Laboratory, Department of Genetics, HIMFG from 1992e2011 associated with a clinical and/or cytogenetic diagnosis of DS were included. Cases identified with a confirmatory trisomy 21 chromosomal aberration were reviewed to register the age of the patients and the age of the parents. The frequency of each type of cytogenetic variant associated with DS was determined. Cases with a cytogenetic diagnosis of trisomy 21 and another chromosomal alteration were also included. When the cytogenetic report corresponded to a clinical diagnosis different from DS, the clinical chart was reviewed. The research board of our institution approved the study.
Results During the study period a total of 9,862 GTG banding analyses were reported; a clinical diagnosis of DS was the indication for the chromosomal analysis in 2,018 (20.46%) of these cases. In 1,921 of the cases, a confirmatory cytogenetic diagnosis of trisomy 21 was established corresponding to 1,048 (54.56%) reports in males and 873 (45.44%) in female patients. Age data were established in 1,782 patients. Age range was from 1 daye25 years old. Most patients (1,359 cases/76.26%) were !1 year of age, with the most frequent age group from 1 to 12 months with 857 cases. The second most frequent age group was from 1 to 30 days and included 502 patients. When age data were not available, the cases were not considered in this analysis but were taken into consideration for the type of karyotype variant result analysis. With one exception, all patients were from the Mexican mestizo ethnic group. A normal chromosome complement was reported in 96 cases (4.75%); one patient (0.05%) had a 48,XXXX karyotype. The remainder of the reports corresponding to 1,921
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180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 Table 1. Chromosomal abnormalities in children with Down syndrome Q2 206 207 Number 208 Karyotype of cases % 209 210 Free trisomy 21 47,XX,þ21 812 42.27 211 47,XY,þ21 975 50.75 212 Other non-contributory aberrations 213 47,XY,inv (3) (p12q24),þ21 1 0.052 214 47,XX,inv (9) (p22q13) pat,þ21 1 0.052 215 1 0.052 47,XX, t(1;15) (q32;q22) pat,þ2a 46,XY, t(13;14), þ21 1 0.052 216 Robertsonian translocations 217 rob(13;21), þ21 4 0.21 218 rob(14;21), þ21 59 3.07 219 rob(15;21), þ21 1 0.05 220 rea(21;21), þ21 28 1.46 Mosaicism 221 mos 47,XX,þ21/46,XX 14 0.73 222 mos 47,XY,þ21/46,XY 16 0.84 223 46,XX,rea(21;21) (q10;q10), þ21/46,XX 1 0.05 224 Other contributory structural rearrangements 225 46,XX,der (5) t(5;21) (p11;p11), þ21 1 0.052 47,XY,der (9) (pter-Oq22::?), þ21 1 0.052 226 47,XY,þder (21) t(21;?) (q22;?) pat 1 0.052 227 46,XX,þ21,idic r (21,21) 1 0.052 228 (::q22.3-Op11.2?::p11.2?-O22.3::) 229 mos 46,XX,þ21,idic (21) (q22.3)/46,XX 1 0.052 230 Double aneuploidies 48,XXY,þ21 1 0.05 231 mos 48,XYY,þ21/47,XY,þ21 1 0.05 232 Total 1921 233 a 234 Case reported by Garcıa-Delgado et al. (16). analyses (95.2%) had one cytogenetic variant causing DS. A free trisomy 21 was identified in 1,787 cases (93.02%); in four patients (0.21%) another non-contributory chromosomal abnormality in addition to the free trisomy 21 was identified. Robertsonian translocation or a rea(21;21) was present in 92 cases (4.79%), mosaicism in 31 cases (1.61%), five (0.26%) patients had other contributory structural rearrangements and in two patients double aneuploidy was detected (0.10%) (Table 1 and Figure 1). Regarding the 92 cases with a Robertsonian translocation, rob(14;21) was the most frequent type with 59 patients (64.13%) followed by rea(21;21) in 28 cases (30.43%), four (4.34%) cases had a rob(13;21) and only one (1.1%) had a rob(15;21). Mosaics were the least frequently reported cytogenetic variant in this study with 31 cases identified that corresponded to !2% of the total. All patients had two cellular lines; 30 had a normal one and another line with a free trisomy 21. The one remaining case (0.05%) had a trisomy 21 due to a de novo rea(21;21) and a normal cell line (Table 1). The average number of analyzed cells was 52; the trisomic line range was 6e75%. At present, the number of analyzed metaphases in our laboratory is 25/case; however, the number of analyzed metaphases during the period of study varied from eight up to 100.
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235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289
Figure 1. Frequency of the cytogenetic types in patients with Down syndrome (DS).
In five cases (0.26%) a chromosomal abnormality including chromosome 21 was identified; three had a derivative from a translocation between chromosome 21 and another autosome. The mentioned cases corresponded to: a) a derivative chromosome 5 from a t(5;21) where the patient had both monosomy 5p and trisomy 21; b) a derivative chromosome 9 with trisomy 21 and probably monosomy 9q; c) a case with a der(21) t(21;?) (q22;?); d) a chromosome 21 double ring that showed dynamic mosaicism; the last case of this group e) was a mosaic with an isodicentric chromosome, 46,XX,þ21,idic (21) (q22.3)/46,XX (Table 1). In two cases a double aneuploidy was identified, one corresponded to a patient with a trisomy 21 and Klinefelter syndrome and the second one was a mosaic 48,XYY,þ21/47,XY,þ21 (Table 1). It was possible to carry out a karyotype analysis in 35 couples of parents of DS patients with a Robertsonian translocation. In another six cases there was the possibility to analyze the sample of only one of the parents corresponding to five mothers and one father. We identified seven carrier mothers. Six had a rob(14;21) and one had a rea(21;21). All belonged to the group of the studied couples; therefore, hereditary cases due to a Robertsonian translocation corresponded to 20%. A maternal grandmother was also identified as a carrier of a rob(14;21). Regarding the group of patients with free trisomy 21 and another non-contributory chromosomal aberration, two cases were identified: one was a carrier father of an inversion of chromosome 9 and the other was a carrier father of a t(1;15) (q32;q22) (16). Among the contributory chromosomal rearrangements, there was a patient with a 47,XY,þder(21) t(21;?) (q22;?). The father of this patient was a carrier of an apparently balanced rearrangement 46,XY,t(21;?) (q22;?). This patient had two brothers. One brother was diagnosed with a mosaic corresponding to a cell line with the balanced rearrangement and another with an additional chromosome 21; the second brother had a normal karyotype.
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Maternal age range varied widely in this study (Figure 2A). The most frequent age group for both parents was 21 to 25 years old in all cytogenetic variants. Regarding free trisomy 21 patients, age of the mother was older than for the other variants; average maternal age was 29 years old with 19 years of age being the most frequent maternal age with a median of 29 years. There were two peaks for the maternal age (Figure 2A), one corresponding to the most frequent reproductive age period and the other one between 36 and 40 years. We consider that these peaks reflect the maternal age effect in DS that has been previously reported. Maternal age in the Robertsonian translocation group was different from the other cytogenetic variants, the average age being 24 years old with a median of 23 years and the most frequent maternal age was 20 years (Figure 2A). In the case of the fathers, the average age in free trisomy 21 cases was 31 years old. In the mosaics it was 32 years old and for the Robertsonian translocations was 27 years old (Figure 2B).
Discussion From a total of 9,862 karyotype results carried out in our laboratory during a 20-year period, a fifth of them were related to a DS patient medical consultation. The large number of studies may reflect the fact that our hospital is a specialized center for childhood diseases including trisomy 21 syndrome. It is interesting that in 4.75% of the patients who were referred due to a clinical diagnosis of DS, a normal karyotype was reported. This is not an unusual situation as has been previously described in the literature with percentages ranging from 5.4e12.22% (15,17) of the samples studied. It may be related to different factors. Among these factors may be a first clinical evaluation identifying facial features that suggested a DS diagnosis as occurred in the X polysomy case reported here. However, in a few patients with a normal karyotype, the clinical diagnosis of DS was confirmed by the clinician despite the laboratory report. Several explanations may also be taken into consideration for this situation as, for example, it is possible that a mosaic case may not have been identified due to the number of metaphases analyzed in that particular case. Another possibility is the presence of the DS critical region duplication, a diagnosis that requires molecular cytogenetic techniques such as FISH, which was not available in our laboratory at the time of this study. Recently, an epidemiological study regarding the incidence of DS in Mexican newborns was reported by Sierra et al. (18). During a period from 2008e2011 a total of 8,250,375 births were registered in Mexico. Among them, 3,076 cases of DS were identified, indicating that in Mexico 0.04% of births show a possible DS diagnosis. However, almost 90% of these cases did not have a cytogenetic
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Figure 2. Age of the parents of DS patients. The age according to the type of cytogenetic trisomy 21 abnormality is shown. (A) Age of the mothers. (B) Age of the fathers.
confirmatory study and therefore this report was excluded from our general analysis. In our study we identified that the number of male patients was higher than the number of female patients. Differences between genders in DS have been previously reported (14,19e27). Seth et al. (21) reported a 2.3:1 ratio, but slight variations may occur as in the case reported by Astete et al. (17) with a male:female ratio of 1:1.3. In the
present study, age of the parents for the different cytogenetic types of trisomy 21 varied according to the estimates previously reported in the literature (6,9,10). In 95.2% of the cytogenetic analyses, a trisomy 21 result was confirmed. When taking into consideration the number of karyotype results, this is the most extensive report in Mexico and is also one of the most extensive studies worldwide (Table 2). It is important to note that some of the
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Table 2. Cytogenetic analyses of patients with Down syndrome
Reference Country Years of study Patients confirmed Free T21 num (%) Non-contributory aberration num (%) rob þ rea(21;21) num (%) Mosaicism num (%) Other alterations Other contributory structural rearrangements num (%) Double or triple aneuploidies num (%)
Jyothy et al. Metneki et al. Chandra et al. Aboussair et al. 2010 (30) 2012 (31) 2002 (28) 2005 (29)a India ND 1021 892 (87.37)
Hungary 30 3390 3083 (90.94)
India 28 1020 855 (83.82) 1 (0.1)
Morocco 17 1095 1039 (94.88)
41 (4.01) 88 (8.62)
155 (4.58) 147 (4.33)
52 (5.1) 110 (10.78)
39 (3.56) 15 (1.37)
1 (0.03) 4 (0.12)
2 (0.2)
2 (0.18)
Morris et al. 2012 (10)a
Present study 2015
Total
England and Wales 20 29,255 27,943 (95.51) 64 (0.22)
Mexico 20 1921 1787 (93.02) 4 (0.21)
37,702 35,599 (94.42) 69 (0.18)
779 (2.66) 347 (1.19)
92 (4.79) 31 (1.61)
1158 (3.07) 738 (1.96)
38 (0.13)
5 (0.26)
44 (0.12)
84 (0.29)
2 (0.1)
94 (0.25)
ND, not determined. a Studies including prenatal diagnosis.
considered studies also included prenatal karyotyping diagnosis. The number of studied cases varies among the centers reporting the information in Mexico (15,32). An explanation for these differences may be that the health services offered in the mentioned centers are different among them. For example, our institution is a pediatric center and the other two institutions are a general care hospital and a university referral center for karyotype analysis. The most frequent cytogenetic abnormality in DS patients in the present study was a free trisomy 21, present in 93.02% of the cases and is within the range reported from other studies (95.51e83.82%) (Table 2). The discrepancy regarding the different percentages may be related to the number of metaphases analyzed. Other cytogenetic structural or numerical non-contributory aberrations have been previously reported in a range from 0 to 2.2%. In our study it was 0.21% (Table 2). In this work the frequency of Robertsonian translocations was within the previously reported range (2.66e5.1%) (Table 2). Our results are in accordance with reports that identified rob(14;21) and rea(21;21) as the most frequent translocations associated with trisomy 21 (10,14,21,22,24,27,30). It is interesting that up to 20% of the Robertsonian translocations identified in this study corresponded to inherited rearrangements. This situation underlines the importance of carrying out cytogenetic studies in the parents in order to offer adequate genetic assessment. The frequency of mosaic cases reported in our study is within the ample percentage variation observed in different studies and range from 1.19e10.78% (Table 2). An explanation for the differences found may be related once again to the number of analyzed cells per study. When carrying out the chromosomal formula review, we realized that among the results reported for this group of patients, there was a particularly interesting case where a postzygotic de
novo rea(21;21) was identified. To our knowledge this karyotype is very infrequently reported in DS patients and possibly implies a different mechanism of origin than the one responsible for its formation during maternal meiosis (33,34). Five cases were identified with other contributory structural rearrangements, corresponding to different abnormalities, all associated with a trisomy 21 syndrome phenotype that was the original indication for the cytogenetic study. This percentage is slightly higher than previously reported particularly when considering studies with O1000 individuals (Table 2). In our study in all hereditary patients with a Robertsonian translocation, the mother was the carrier. Most were associated with a rob(14;21). Interestingly, there were three carrier fathers, two of them corresponded to a noncontributory aberration, one had an inv (9) and another was a carrier of a t(1;15). This case has been reported (16). The last father of this group had an apparently balanced contributory rearrangement, 46,XY,t(21;?) (q22;?), that could not be appropriately characterized. We compared our data with several published series of karyotype studies belonging to different populations of DS patients (Table 2) and concluded that the most frequent karyotype alteration reported in DS is the free trisomy 21 with 94.42%, followed by Robertsonian translocations with 3.07% and in third place were the mosaics with 1.96%. Other contributory structural rearrangements corresponded to 0.12%, the cases with double or triple aneuploidies corresponded to 0.25%. In general terms, percentages of the different cytogenetic abnormalities reported here are in accordance with the reports in the literature. In conclusion, the present work reports the experience of a Mexican referral center regarding the karyotype diagnosis of patients with DS. The number of studies reported corresponds to the most extensive study regarding Mexican DS
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patients and is one of the most extensive studies reported so far. The free 21 trisomy karyotype was the most frequent result identified corresponding to 93.02%, followed by Robertsonian translocations with 4.79% and mosaics were in third place with 1.61%. These last two results are slightly different when compared with the analyzed accumulated data; however, in general terms a similar tendency was observed among the different reports. This study also reflects the important percentage that for our laboratory represents the karyotype analysis of DS patients and offers us an insight about the requirements that this population of patients may need including genetic assessment.
15.
16.
17. 18.
Acknowledgments
19.
CPG received a PROBEI scholarship from C.C.I.N.S.H.A.E, Health Secretariat, Mexico for participating in the protocol HIMFG 2012/073.
20. 21. 22.
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ORIGINAL ARTICLE
Cytogenetic Profile in 1,921 Cases of Trisomy 21 Syndrome in Mexican Patients Q3
Francisco Flores-Ramırez,a Claudia Palacios-Guerrero,a,b Constanza Garcıa-Delgado,a Ariadna Berenice Morales-Jimenez,a Christian Martın Arias-Villegas,a Alicia Cervantes,b and Ver onica Fabiola Moran-Barrosoa a
Departamento de Genetica, Hospital Infantil de Mexico Federico Gomez, Mexico, D.F., Mexico Servicio de Genetica, Hospital General de Mexico Dr. Eduardo Liceaga, Facultad de Medicina, UNAM, Mexico, D.F., Mexico
b
Received for publication March 4, 2015; accepted August 17, 2015 (ARCMED-D-15-00147).
Background and Aims. Trisomy 21 is the most frequent genetic cause of intellectual disability. It is caused by different cytogenetic aberrations: free trisomy, Robertsonian translocations, mosaicism, duplication of the critical region and other structural rearrangements of chromosome 21. The aim of the study was to identify in Mexican trisomy 21 patients who attended Hospital Infantil de Mexico Federico Gomez from 1992e2011 the type and frequency of the cytogenetic aberration and to evaluate the effect of maternal age. Methods. A retrospective analysis of epidemiological data and karyotype reports were carried out; type and frequency of the cytogenetic variants were determined. Results. We identified 2,018 cases referred with a clinical diagnosis of trisomy 21. In 1,921 analyses (95.2%) a cytogenetic variant of trisomy 21 was identified: free trisomy 21 in 1,787 cases (93.02%), four cases (0.21%) had an additional non-contributory aberration; Robertsonian translocations in 92 cases (4.79%); mosaicism in 31 cases (1.61%) and seven cases (0.36%) had other chromosomal abnormalities, five (0.26%) had other contributory structural rearrangements and two corresponded to double aneuploidies (0.10%). Gender distribution was 1,048 (54.56%) males and 873 (45.44%) females. A maternal age effect was observed in patients with free trisomy 21 with mothers O36 years of age. Conclusion. The present work reports the experience of a Mexican referral center regarding the karyotype diagnosis of patients with trisomy 21 and is one of the most extensive studies published so far. Percentages of the cytogenetic abnormalities present in our population reflect the ones previously reported for these cytogenetic alterations worldwide. Ó 2015 IMSS. Published by Elsevier Inc. Key Words: Trisomy 21, Down syndrome, Robertsonian translocation, Mosaicism, Chromosome 21.
Introduction Down syndrome (DS) was described by John Langdon Down in 1866 (1) and, because it is caused by an extra copy of chromosome 21 (2), is also called trisomy 21 syndrome. DS is the most frequent cause of intellectual disability of genetic origin with a general presentation from 1:850e1 in 1,000 newborns (3,4). In Mexico its frequency is 1:650 newborns (5). Address reprint requests to: Veronica Fabiola Moran-Barroso, Dr. Marquez 162, Col. Doctores, Mexico, D.F. 06720, Mexico; Phone: (þ52) (55) 5228-9917 ext. 2037; FAX: (þ52) (55) 5228-9917, ext. 2344; E-mail: [email protected]
The cytogenetic variants that cause DS are free trisomy 21, Robertsonian translocations, mosaicism, duplication of the DS critical region and other structural rearrangements involving chromosome 21 (6e8). In 90e95% of DS patients the presence of the extra chromosome 21 was originated from a meiotic nondisjunction event. In 80% of these cases it occurred during maternal meiosis and was associated with a maternal age effect O35 years (6,9,10). In 4% of DS cases, chromosome 21 may be translocated to another acrocentric chromosome. These so-called Robertsonian translocations usually involve chromosome 14 or another chromosome 21 even if the latter are mostly isochromosomes 21q or rea(21;21). In 25% of the
0188-4409/$ - see front matter. Copyright Ó 2015 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2015.08.001 ARCMED2041_proof ■ 22-8-2015 0-41-42
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translocation cases, one of the parents is a carrier (7,11). Mosaic cases account for 3e5% of DS and are caused by a nondisjunction postzgotic event (12). Other structural rearrangements are less frequent causes of DS and the diagnosis requires molecular cytogenetic techniques such as FISH (7). SD associated with chromosomal alterations other than trisomy 21 has also been reported (13e15). DS is one of the main causes for consultation at the Genetic Department of the Hospital Infantil de Mexico Federico G omez (HIMFG) in Mexico City, Mexico for diagnosis and follow-up of patients. In this study we analyzed the cytogenetic results of the large population of DS patients who have attended our institution during a 20-year period in order to determine the type and frequency of cytogenetic alteration and to evaluate the effect of maternal age. Patients and Methods All karyotype GTG banding technique reports from the Cytogenetics Laboratory, Department of Genetics, HIMFG from 1992e2011 associated with a clinical and/or cytogenetic diagnosis of DS were included. Cases identified with a confirmatory trisomy 21 chromosomal aberration were reviewed to register the age of the patients and the age of the parents. The frequency of each type of cytogenetic variant associated with DS was determined. Cases with a cytogenetic diagnosis of trisomy 21 and another chromosomal alteration were also included. When the cytogenetic report corresponded to a clinical diagnosis different from DS, the clinical chart was reviewed. The research board of our institution approved the study.
Results During the study period a total of 9,862 GTG banding analyses were reported; a clinical diagnosis of DS was the indication for the chromosomal analysis in 2,018 (20.46%) of these cases. In 1,921 of the cases, a confirmatory cytogenetic diagnosis of trisomy 21 was established corresponding to 1,048 (54.56%) reports in males and 873 (45.44%) in female patients. Age data were established in 1,782 patients. Age range was from 1 daye25 years old. Most patients (1,359 cases/76.26%) were !1 year of age, with the most frequent age group from 1 to 12 months with 857 cases. The second most frequent age group was from 1 to 30 days and included 502 patients. When age data were not available, the cases were not considered in this analysis but were taken into consideration for the type of karyotype variant result analysis. With one exception, all patients were from the Mexican mestizo ethnic group. A normal chromosome complement was reported in 96 cases (4.75%); one patient (0.05%) had a 48,XXXX karyotype. The remainder of the reports corresponding to 1,921
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180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 Table 1. Chromosomal abnormalities in children with Down syndrome Q2 206 207 Number 208 Karyotype of cases % 209 210 Free trisomy 21 47,XX,þ21 812 42.27 211 47,XY,þ21 975 50.75 212 Other non-contributory aberrations 213 47,XY,inv (3) (p12q24),þ21 1 0.052 214 47,XX,inv (9) (p22q13) pat,þ21 1 0.052 215 1 0.052 47,XX, t(1;15) (q32;q22) pat,þ2a 46,XY, t(13;14), þ21 1 0.052 216 Robertsonian translocations 217 rob(13;21), þ21 4 0.21 218 rob(14;21), þ21 59 3.07 219 rob(15;21), þ21 1 0.05 220 rea(21;21), þ21 28 1.46 Mosaicism 221 mos 47,XX,þ21/46,XX 14 0.73 222 mos 47,XY,þ21/46,XY 16 0.84 223 46,XX,rea(21;21) (q10;q10), þ21/46,XX 1 0.05 224 Other contributory structural rearrangements 225 46,XX,der (5) t(5;21) (p11;p11), þ21 1 0.052 47,XY,der (9) (pter-Oq22::?), þ21 1 0.052 226 47,XY,þder (21) t(21;?) (q22;?) pat 1 0.052 227 46,XX,þ21,idic r (21,21) 1 0.052 228 (::q22.3-Op11.2?::p11.2?-O22.3::) 229 mos 46,XX,þ21,idic (21) (q22.3)/46,XX 1 0.052 230 Double aneuploidies 48,XXY,þ21 1 0.05 231 mos 48,XYY,þ21/47,XY,þ21 1 0.05 232 Total 1921 233 a 234 Case reported by Garcıa-Delgado et al. (16). analyses (95.2%) had one cytogenetic variant causing DS. A free trisomy 21 was identified in 1,787 cases (93.02%); in four patients (0.21%) another non-contributory chromosomal abnormality in addition to the free trisomy 21 was identified. Robertsonian translocation or a rea(21;21) was present in 92 cases (4.79%), mosaicism in 31 cases (1.61%), five (0.26%) patients had other contributory structural rearrangements and in two patients double aneuploidy was detected (0.10%) (Table 1 and Figure 1). Regarding the 92 cases with a Robertsonian translocation, rob(14;21) was the most frequent type with 59 patients (64.13%) followed by rea(21;21) in 28 cases (30.43%), four (4.34%) cases had a rob(13;21) and only one (1.1%) had a rob(15;21). Mosaics were the least frequently reported cytogenetic variant in this study with 31 cases identified that corresponded to !2% of the total. All patients had two cellular lines; 30 had a normal one and another line with a free trisomy 21. The one remaining case (0.05%) had a trisomy 21 due to a de novo rea(21;21) and a normal cell line (Table 1). The average number of analyzed cells was 52; the trisomic line range was 6e75%. At present, the number of analyzed metaphases in our laboratory is 25/case; however, the number of analyzed metaphases during the period of study varied from eight up to 100.
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235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289
Figure 1. Frequency of the cytogenetic types in patients with Down syndrome (DS).
In five cases (0.26%) a chromosomal abnormality including chromosome 21 was identified; three had a derivative from a translocation between chromosome 21 and another autosome. The mentioned cases corresponded to: a) a derivative chromosome 5 from a t(5;21) where the patient had both monosomy 5p and trisomy 21; b) a derivative chromosome 9 with trisomy 21 and probably monosomy 9q; c) a case with a der(21) t(21;?) (q22;?); d) a chromosome 21 double ring that showed dynamic mosaicism; the last case of this group e) was a mosaic with an isodicentric chromosome, 46,XX,þ21,idic (21) (q22.3)/46,XX (Table 1). In two cases a double aneuploidy was identified, one corresponded to a patient with a trisomy 21 and Klinefelter syndrome and the second one was a mosaic 48,XYY,þ21/47,XY,þ21 (Table 1). It was possible to carry out a karyotype analysis in 35 couples of parents of DS patients with a Robertsonian translocation. In another six cases there was the possibility to analyze the sample of only one of the parents corresponding to five mothers and one father. We identified seven carrier mothers. Six had a rob(14;21) and one had a rea(21;21). All belonged to the group of the studied couples; therefore, hereditary cases due to a Robertsonian translocation corresponded to 20%. A maternal grandmother was also identified as a carrier of a rob(14;21). Regarding the group of patients with free trisomy 21 and another non-contributory chromosomal aberration, two cases were identified: one was a carrier father of an inversion of chromosome 9 and the other was a carrier father of a t(1;15) (q32;q22) (16). Among the contributory chromosomal rearrangements, there was a patient with a 47,XY,þder(21) t(21;?) (q22;?). The father of this patient was a carrier of an apparently balanced rearrangement 46,XY,t(21;?) (q22;?). This patient had two brothers. One brother was diagnosed with a mosaic corresponding to a cell line with the balanced rearrangement and another with an additional chromosome 21; the second brother had a normal karyotype.
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Maternal age range varied widely in this study (Figure 2A). The most frequent age group for both parents was 21 to 25 years old in all cytogenetic variants. Regarding free trisomy 21 patients, age of the mother was older than for the other variants; average maternal age was 29 years old with 19 years of age being the most frequent maternal age with a median of 29 years. There were two peaks for the maternal age (Figure 2A), one corresponding to the most frequent reproductive age period and the other one between 36 and 40 years. We consider that these peaks reflect the maternal age effect in DS that has been previously reported. Maternal age in the Robertsonian translocation group was different from the other cytogenetic variants, the average age being 24 years old with a median of 23 years and the most frequent maternal age was 20 years (Figure 2A). In the case of the fathers, the average age in free trisomy 21 cases was 31 years old. In the mosaics it was 32 years old and for the Robertsonian translocations was 27 years old (Figure 2B).
Discussion From a total of 9,862 karyotype results carried out in our laboratory during a 20-year period, a fifth of them were related to a DS patient medical consultation. The large number of studies may reflect the fact that our hospital is a specialized center for childhood diseases including trisomy 21 syndrome. It is interesting that in 4.75% of the patients who were referred due to a clinical diagnosis of DS, a normal karyotype was reported. This is not an unusual situation as has been previously described in the literature with percentages ranging from 5.4e12.22% (15,17) of the samples studied. It may be related to different factors. Among these factors may be a first clinical evaluation identifying facial features that suggested a DS diagnosis as occurred in the X polysomy case reported here. However, in a few patients with a normal karyotype, the clinical diagnosis of DS was confirmed by the clinician despite the laboratory report. Several explanations may also be taken into consideration for this situation as, for example, it is possible that a mosaic case may not have been identified due to the number of metaphases analyzed in that particular case. Another possibility is the presence of the DS critical region duplication, a diagnosis that requires molecular cytogenetic techniques such as FISH, which was not available in our laboratory at the time of this study. Recently, an epidemiological study regarding the incidence of DS in Mexican newborns was reported by Sierra et al. (18). During a period from 2008e2011 a total of 8,250,375 births were registered in Mexico. Among them, 3,076 cases of DS were identified, indicating that in Mexico 0.04% of births show a possible DS diagnosis. However, almost 90% of these cases did not have a cytogenetic
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Figure 2. Age of the parents of DS patients. The age according to the type of cytogenetic trisomy 21 abnormality is shown. (A) Age of the mothers. (B) Age of the fathers.
confirmatory study and therefore this report was excluded from our general analysis. In our study we identified that the number of male patients was higher than the number of female patients. Differences between genders in DS have been previously reported (14,19e27). Seth et al. (21) reported a 2.3:1 ratio, but slight variations may occur as in the case reported by Astete et al. (17) with a male:female ratio of 1:1.3. In the
present study, age of the parents for the different cytogenetic types of trisomy 21 varied according to the estimates previously reported in the literature (6,9,10). In 95.2% of the cytogenetic analyses, a trisomy 21 result was confirmed. When taking into consideration the number of karyotype results, this is the most extensive report in Mexico and is also one of the most extensive studies worldwide (Table 2). It is important to note that some of the
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Table 2. Cytogenetic analyses of patients with Down syndrome
Reference Country Years of study Patients confirmed Free T21 num (%) Non-contributory aberration num (%) rob þ rea(21;21) num (%) Mosaicism num (%) Other alterations Other contributory structural rearrangements num (%) Double or triple aneuploidies num (%)
Jyothy et al. Metneki et al. Chandra et al. Aboussair et al. 2010 (30) 2012 (31) 2002 (28) 2005 (29)a India ND 1021 892 (87.37)
Hungary 30 3390 3083 (90.94)
India 28 1020 855 (83.82) 1 (0.1)
Morocco 17 1095 1039 (94.88)
41 (4.01) 88 (8.62)
155 (4.58) 147 (4.33)
52 (5.1) 110 (10.78)
39 (3.56) 15 (1.37)
1 (0.03) 4 (0.12)
2 (0.2)
2 (0.18)
Morris et al. 2012 (10)a
Present study 2015
Total
England and Wales 20 29,255 27,943 (95.51) 64 (0.22)
Mexico 20 1921 1787 (93.02) 4 (0.21)
37,702 35,599 (94.42) 69 (0.18)
779 (2.66) 347 (1.19)
92 (4.79) 31 (1.61)
1158 (3.07) 738 (1.96)
38 (0.13)
5 (0.26)
44 (0.12)
84 (0.29)
2 (0.1)
94 (0.25)
ND, not determined. a Studies including prenatal diagnosis.
considered studies also included prenatal karyotyping diagnosis. The number of studied cases varies among the centers reporting the information in Mexico (15,32). An explanation for these differences may be that the health services offered in the mentioned centers are different among them. For example, our institution is a pediatric center and the other two institutions are a general care hospital and a university referral center for karyotype analysis. The most frequent cytogenetic abnormality in DS patients in the present study was a free trisomy 21, present in 93.02% of the cases and is within the range reported from other studies (95.51e83.82%) (Table 2). The discrepancy regarding the different percentages may be related to the number of metaphases analyzed. Other cytogenetic structural or numerical non-contributory aberrations have been previously reported in a range from 0 to 2.2%. In our study it was 0.21% (Table 2). In this work the frequency of Robertsonian translocations was within the previously reported range (2.66e5.1%) (Table 2). Our results are in accordance with reports that identified rob(14;21) and rea(21;21) as the most frequent translocations associated with trisomy 21 (10,14,21,22,24,27,30). It is interesting that up to 20% of the Robertsonian translocations identified in this study corresponded to inherited rearrangements. This situation underlines the importance of carrying out cytogenetic studies in the parents in order to offer adequate genetic assessment. The frequency of mosaic cases reported in our study is within the ample percentage variation observed in different studies and range from 1.19e10.78% (Table 2). An explanation for the differences found may be related once again to the number of analyzed cells per study. When carrying out the chromosomal formula review, we realized that among the results reported for this group of patients, there was a particularly interesting case where a postzygotic de
novo rea(21;21) was identified. To our knowledge this karyotype is very infrequently reported in DS patients and possibly implies a different mechanism of origin than the one responsible for its formation during maternal meiosis (33,34). Five cases were identified with other contributory structural rearrangements, corresponding to different abnormalities, all associated with a trisomy 21 syndrome phenotype that was the original indication for the cytogenetic study. This percentage is slightly higher than previously reported particularly when considering studies with O1000 individuals (Table 2). In our study in all hereditary patients with a Robertsonian translocation, the mother was the carrier. Most were associated with a rob(14;21). Interestingly, there were three carrier fathers, two of them corresponded to a noncontributory aberration, one had an inv (9) and another was a carrier of a t(1;15). This case has been reported (16). The last father of this group had an apparently balanced contributory rearrangement, 46,XY,t(21;?) (q22;?), that could not be appropriately characterized. We compared our data with several published series of karyotype studies belonging to different populations of DS patients (Table 2) and concluded that the most frequent karyotype alteration reported in DS is the free trisomy 21 with 94.42%, followed by Robertsonian translocations with 3.07% and in third place were the mosaics with 1.96%. Other contributory structural rearrangements corresponded to 0.12%, the cases with double or triple aneuploidies corresponded to 0.25%. In general terms, percentages of the different cytogenetic abnormalities reported here are in accordance with the reports in the literature. In conclusion, the present work reports the experience of a Mexican referral center regarding the karyotype diagnosis of patients with DS. The number of studies reported corresponds to the most extensive study regarding Mexican DS
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patients and is one of the most extensive studies reported so far. The free 21 trisomy karyotype was the most frequent result identified corresponding to 93.02%, followed by Robertsonian translocations with 4.79% and mosaics were in third place with 1.61%. These last two results are slightly different when compared with the analyzed accumulated data; however, in general terms a similar tendency was observed among the different reports. This study also reflects the important percentage that for our laboratory represents the karyotype analysis of DS patients and offers us an insight about the requirements that this population of patients may need including genetic assessment.
15.
16.
17. 18.
Acknowledgments
19.
CPG received a PROBEI scholarship from C.C.I.N.S.H.A.E, Health Secretariat, Mexico for participating in the protocol HIMFG 2012/073.
20. 21. 22.
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