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Middle East Journal of Medical Genetics:
doi: 10.1097/01.MXE.0000407733.93781.7a
Original articles

A review of 1125 cases referred for cytogenetic analysis in Syria

Mahayri, Zeina N.; Monem, Fawza S.

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Author Information

Clinical Laboratories, Assad University Hospital, Damascus, Syria

Correspondence to Zeina Mahayri, Cytogenetics Unit, Clinical Laboratories, Assad University Hospital, 17th Nissan Street. Damascus, Syria Tel: +963 11 212 6500 x 2329; fax: +963 11 213 9441; e-mail: zeina.mahayri@gmail.com

Received January 17, 2011

Accepted May 15, 2011

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Abstract

Introduction: The aim of this review is to evaluate the pattern of referral for cytogenetic analysis and to determine the frequency of chromosomal abnormalities in different groups of referrals, and then to compare these figures with similar studies.

Patients and methods: This review included 1125 cases referred between 2007 and 2010 to the Cytogenetic Unit, Clinical Laboratories, Assad University Hospital in Damascus, Syria. The referrals fall under two categories: hematological disorders (HD) and constitutional chromosomal aberrations.

Subjects and methods: All samples were subjected to standard cytogenetic procedures, followed by G-banding using trypsin and giemsa, and some were subjected to fluorescence in-situ hybridization according to the probe manufacturer’s protocol.

Results and discussion: In HD group there were 847 samples. The chronic myelogenous leukemia group consisted of the largest number of referrals. The next subgroup in number of referrals was acute myelogenous leukemia. The myelodysplastic syndrome group came next, followed by acute lymphoblastic leukemia, and then chronic lymphocytic leukemia. Cytogenetic results were either recurring aberrations with important diagnostic significance (e.g. Philadelphia chromosome) or other aberrations with less clear significance. In the constitutional chromosomal aberrations group, 278 samples were analyzed. Significant statistical differences between the current study and other studies from Turkey, Saudi Arabia, and Jordan were seen in the referring frequencies. The Turner syndrome group had the highest frequency of referrals, followed by the reproductive problems group, which had abnormal results in frequencies similar to previous reports. The Down syndrome suspect group was next in the number of referrals, but it had the highest number of abnormal karyotypes. Then came the chromosomal syndrome suspect group, followed by the Klinefelter group, and the sex determination group with the lowest referral rates.

Conclusion: This study highlights the importance of considering cytogenetic test during the management of HDs, and demonstrates the importance of incorporating it in evaluation plans for congenital abnormalities, sexual development problems, and reproductive problems.

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Introduction

It is estimated that more than 1 million cytogenetic and molecular cytogenetic analyses are performed per year for patients suffering from cancers, congenital malformations, mental diseases, or reproductive problems (Vorsanova et al., 2010).

In hematological disorders (HDs), cytogenetic analysis has provided fundamental insights into molecular pathogenesis. It has proven to be an extremely valuable diagnostic tool providing definite diagnosis, supporting the cytomorphologic diagnosis and providing prognostic information (Maciejewski and Mufti, 2008).

In contrast, cytogenetics plays a major role in diagnosing congenital abnormalities, evaluating patients with puberty and secondary sexual development problems, and for couples suffering from reproductive problems including infertility, recurrent miscarriage, or congenital abnormalities in the offspring.

Recognizing the key role of cytogenetic analysis mandates providing this diagnostic service, while revising the data obtained from this service may draw the attention of clinicians to its importance.

The aim of this study is to evaluate the pattern of referrals for cytogenetic analysis in our laboratory and to determine the frequency of chromosomal abnormalities in the different groups of referrals, and then comparing them with the figures in similar studies.

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Patients and methods

The cytogenetic findings from 1125 cases obtained between 2007 and 2010 were reviewed. The cases were referred to the Cytogenetic Unit, Clinical Laboratories, Assad University Hospital in Damascus, Syria. A detailed interview was conducted with all patients before cytogenetic analysis, and a detailed medical history was obtained.

Referrals to our laboratory fall under one of the two categories: (a) HDs; (b) constitutional chromosomal aberration suspects.

In the HDs group, aspirated bone marrow samples were collected from the patients into heparinized tubes. Peripheral blood samples were collected instead of bone marrow aspirates when the aspiration yielded a dry tap, although peripheral blood samples were not of use unless blast cells appear in sufficient numbers in the circulation.

The cell count was determined manually, and then the sample volume to be added to 10 ml of culture medium was calculated. For each patient, a minimum of two cultures were incubated. Samples were incubated in a complete culture medium (Marrowmax Gibco, California, USA) at 37°C for 24 h for chronic myelogenous leukemia (CML) cases and for 24–48 h for other cases.

Metaphases were harvested by adding 50 µm of 10 µg/ml colcemid (Euroclone, Milano, Italy) for 30 min followed by hypotonic KCl (0.075 mol/l) treatment for 20 min and then fixation using a standard 3 : 1 methanol–acetic acid fixative. Slides were prepared from the cell suspension and left to dry till the next day when the needed banding steps were applied.

The karyotype of each patient was determined by G-banding using trypsin and giemsa (Seabright, 1971). At least 20 cells were analyzed. The best metaphases were photographed to determine the karyotype.

Samples were subjected to the fluorescence in-situ hybridization (FISH) method in the following cases:

The clinician requested it before starting treatment of patients with CML on tyrosin kinase inhibitors (TKIs) or treatment of acute myelogenous leukemia (AML)-M3 (acute promyelocytic leukemia) with all-trans-retinoic acid and for monitoring the treatment response.

Culture failure or absence of good quality metaphases.

Unusual chromosomal aberration was detected and needed to be confirmed.

Slides were prepared as mentioned previously. The pretreatment, hybridization, and posthybridization steps were all according to the recommended procedures of the probe manufacturer (Kreatech diagnostics, Amsterdam, Netherlands) with some modifications. The dry slides were subjected to pretreatment steps first, which included incubation in 2XSSC for 30 min, followed by dehydrating the slides in ethanol series (70–85% absolute ethanol); the slides were then left to dry at room temperature. Five to 10 microns of the chosen probe/probes were applied, and codenaturation of the probe and the sample was carried out by heating the slide on a hot plate at 95°C for 5 min. The probe was left for hybridization overnight at 37°C in a closed hybridization chamber supplied with a wet cloth for humidification. Posthybridization washes consisted of soaking the slides in Wash Buffer II (Kreatech diagnostics) at room temperature for coverslip removal, 2 min wash in Wash Buffer I (Kreatech diagnostics) at 72°C, and then 5 min wash in wash buffer II (Kreatech diagnostics) at 37°C. After letting the slides to dry at room temperature, they were counterstained by adding 10–15 µm of 4′, 6-diamidino-2-phenylindole (DAPI) counterstain.

Locus-specific probes, whole-chromosome painting libraries, and α-satellite DNA probes were used. All probes were supplied from Kreatech diagnostics. Fifty to 250 cells were examined in case of interphase FISH; otherwise, all available metaphases were examined.

In the constitutional chromosomal aberrations group, the volume of the cultured sample was determined as in the HDs group. For each patient, a minimum of three cultures were incubated. Samples were incubated in complete culture medium supplemented with phytohemaglutinin (Karyomax Gibco, California, USA/Chromosome medium A Biochrome, Berlin, Germany) at 37°C for 72 h. Metaphases were harvested and karyotypes were determined as mentioned above.

FISH was applied as described previously, but in the following situations:

Suspicion of a microdeletion syndrome.

Confirmation of a suspected aberration.

Identification of the origin of the extrachromosomal material.

All karyotype descriptions were reported according to the International System for Human Cytogenetic Nomenclature recommendations (Shaffer and Tommerup 2005).

For result analysis in both groups, the relative referral frequency of each diagnostic group was calculated, and the percentage of abnormal cases and the distribution of the numerical and structural abnormalities were determined. In the constitutional chromosomal abnormalities group, the frequencies were compared with similar studies using the Z-test for comparison of two frequencies with unequal variance.

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Results

Hematological disorders group

Eight hundred and forty-seven samples were analyzed. Table 1 shows the different categories of patients in this group. In the CML subgroup, there were 200 samples from patients on TKIs who had the test in our laboratory at frequent intervals (3–6 months) for response monitoring. After subtracting samples coming from the same patient, the total patient count in this group comes to 647 patients; 46% were females and 54% were males. The age of patients ranged from 15 to 81 years, with a mean of 44 years (SD=15). All samples from subgroups other than CML were pretreatment samples.

Table 1
Table 1
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The number of samples with Philadelphia-positive karyotypes was 452 patients (70%) regardless of the percentage of positive clones and the phase of the disease in which the test was performed. Other chromosomal aberrations seen with t(9;22) are mentioned in Table 1. An extra Philadelphia chromosome [der (22) t(9;22)] was the most frequent one, followed by the loss of chromosome Y in male patients, and then trisomy 8. Seven samples presented with complex translocation involving a third chromosome with chromosomes 9 and 22.

The second largest group in number of referrals was the AML group. Forty-six patients (51%) had an abnormal karyotype and the most frequent chromosomal aberration presented was t(15;17). Other aberrations seen were either nonrandom aberrations compatible with one AML subclass, such as t(8;21) and inv(16), or aberrations that are not associated with a specific class and had variable indications and significance.

The myelodysplastic syndrome (MDS) patients group was the next most frequently referred. The most frequent aberrations seen were the loss of chromosome 7 or deletion of its long arm, and then the loss of chromosome 5 or deletion of its long arm.

Patients with acute lymphoblastic leukemia (ALL) were less frequently referred and had the highest frequency in culture failure.

The chronic lymphocytic leukemia (CLL) subgroup had the least number of patients and all had a normal karyotype.

Frequencies of all previous subgroups and the reported chromosomal aberrations are summarized in Table 1.

FISH was applied for some samples according to the previously mentioned circumstances. Indications and results are summarized in Table 2.

Table 2
Table 2
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Constitutional chromosomal abnormalities

Two hundred and seventy-eight samples were analyzed. Table 3 shows the different categories of patients in this group. Distribution of referrals and cytogenetic results of each subgroup were compared with similar studies performed in Turkey (Balkan et al., 2010), Saudi Arabia (Al Husain and Zaki, 1999), and Jordan (El Shanti and Al Alami, 2002). Table 4 summarizes this comparison.

Table 3
Table 3
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Table 4
Table 4
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The largest referral subgroup comprised of females suspected to have Turner syndrome. Seventy females with an age range from 1 to 27 years (mean 13.8 years, SD=4.7) were referred either because of growth retardation in younger patients or because of primary amenorrhea with short stature in older patients. Twenty-six (37%) of them had a karyotype explaining their clinical presentation. Two patients who had a 46, XY karyotype were subjected to FISH to confirm the presence of the Y chromosome. Sex-determining region Y gene (SRY gene) detection by PCR was recommended for other patients with an abnormal karyotype, but the results are not included here.

Thirty-one azoospermic males (age 15–40 years, mean 24.9, SD=6.8) were suspected to have Klinefelter syndrome; 14 of them (45%) had a 47, XXY karyotype explaining their clinical presentation.

In the Down syndrome subgroup, there were 43 children with an age range between 6 days and 7 years (mean 13.79 months, SD=19.516), of which 57.8% were males and 42.2% were females. Forty patients (93%) in this subgroup had trisomy 21 either in all examined metaphases or in mosaicism. Robertsonian translocation t(21;21) was seen in two cases. One patient had a 49, XXYY+21 karyotype.

The chromosomal syndrome suspect subgroup consisted of 38 patients who were 1 month to 21 years old (mean=5.5 year, SD=5.5) and had an equal sex distribution ratio (19 males/19 females). They were mentally retarded and/or had congenital malformations. One newborn female had a 5p deletion compatible with Cri du Chat syndrome. Another newborn female had trisomy 13 compatible with Patau syndrome. Two males and one female with mental retardation and obesity were suspected to have Prader–Willi (PW) syndrome but had a normal karyotype, and one of them proved to be negative for del(15)(q11-q13) by FISH. One 5-year-old boy had delayed growth milestones, and his karyotype revealed additional chromosomal material similar to the p arm of chromosome 9. The origin of this material was confirmed by FISH to be +9p. One male with mental retardation had a 47, XYY karyotype. Two patients were suspected to have 22q11 deletion syndrome, but they proved not to have this deletion by FISH. Another negative result appeared in the FISH study of one patient who was suspected to have Williams–Beuren syndrome. All other patients had a normal karyotype.

Twenty-nine patients were considered in the sex determination group. The majority of the patients in this group were 2 months to 6 years old (mean=24.2 months SD=20). Twenty-five percent were assigned as females, whereas 75% were assigned as males. Ten of them (34%) had results opposite to their assigned sex (six patients assigned as males had a female karyotype, and four assigned as females had a male karyotype). Other five cases were classified in this group. Three 17-year-old patients, a 14-year-old patient, and one 9-year-old patient were referred because of sexual development problems. All of them were assigned as females, and two had a 46, XY karyotype.

In the reproductive problems subgroup, 67 patients (49% males and 51% females), with an age range of 19–50 years (mean 32.35, SD=8), were referred because of subfertility, recurrent miscarriage, or congenital abnormalities in the offspring. Three patients had sex chromosome abnormalities, including a female with recurrent miscarriages who had mosaic 45, X, a male with oligospermia and multiple failures in assisted reproduction who had mosaic 47, XXY, and the third patient who was referred with his wife because of having malformed offspring and he had a 47, XYY karyotype. Three other patients had autosomal chromosomal abnormalities including pericentric inversion in both chromosome 9 homologs in a male, an extramaterial on chromosome 15 in a male, and deleted material from chromosome 6q in a few metaphases in a female.

The cytogenetic results of patients in this group are all summarized in Table 3.

FISH was applied for some samples according to the previously mentioned circumstances. Indications and results are summarized in Table 5.

Table 5
Table 5
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Discussion

Hematological disorders group

The CML group consisted of the largest number of referrals; this is because our laboratory is accredited for monitoring these patients during their treatment with TKIs and cannot reflect the actual relevance of CML in comparison with other leukemia types in Syria. Patients were referred before starting treatment and then every 3–6 months till the achievement of a complete cytogenetic response that is compatible with international recommendations (Baccarani et al., 2006; Hughes and Branford, 2009).

The presence of t(9;22) in its classical form or its variants was determined besides the presence of any other cytogenetic changes and the percentage of each clone. The evaluation of retrieved results must take into consideration the phase of the disease at which the test was performed, ‘chronic, accelerated, or blastic phase’ and other patient-related factors such as patient age. This is out of the scope of our study and it suggests conducting a retrospective study.

Complex translocation involving a third chromosome besides chromosomes 9 and 22 was found in seven (1.5%) Philadelphia-positive cases, which is less than the previously reported percentage of Philadelphia chromosome variants (5–10%) (El Zimaity et al., 2004). However, several studies confirmed that the presence of these variants does not affect either the clinical and hematological features or the response to TKIs (El Zimaity et al., 2004; Valencia et al., 2009).

The total number of samples with other chromosomal abnormalities were 47 out of 461 Philadelphia-positive cases (10%). This percentage cannot be compared with previous studies because of the limitations of the current study. In general, several studies concluded that the evolution of cytogenetic clonal abnormalities in Ph-positive patients is considered as an independent poor prognostic factor for survival (Cortes et al., 2003), even though it was not found to diminish the good response to TKI therapy (O’Dwyer et al., 2002).

Trisomy 8 was the most frequent ‘common’ anomaly seen in patients with CML, MDS, and AML. Although it is thought to be of no prognostic significance in CML, it is an intermediate or poor prognostic indicator in AML and it is associated with median survival in MDS (Huret, 2007).

Loss of chromosome Y in male patients was found in the current study in males from CML, MDS, and AML subgroups. However, it is still considered controversial as to whether Y chromosome loss is an age-related phenomenon or a cytogenetic marker indicating a malignant change, but it is widely accepted that it is related to the malignant clone in MDS/AML patients with a neutral prognostic impact when present as a single anomaly (Zhang et al., 2007).

FISH was requested for monitoring the treatment response in patients with CML treated by TKIs. Interphase FISH was applied for those patients, which facilitated studying a large number of cells. The use of dual fusion probes reduced rates of false-positive cells. Applying FISH as an alternative to routine cytogenetics for cytogenetic response monitoring in patients with CML is considered reasonable, especially as it can be applied on peripheral blood samples (Kantarjian et al., 2008).

Other patients with CML were subjected to FISH to identify the identity of a marker chromosome and to confirm an uncommon translocation. The identity of the marker chromosome was not revealed after using several probes and no further investigations were performed.

In the AML subgroup, the percentage of patients who presented with an abnormal karyotype was similar to those retrieved from studies conducted in the Middle East (Udayakumar et al., 2007). Chromosomal aberrations seen in patients with AML may be classified as recurring balanced translocations, particularly t(8;21), t(15;17), inv(16)/t(16;16), and other aberrations (Arber et al., 2003). Although the French-American-British cooperative group (FAB) does not incorporate cytogenetic results into its system, they are considered as major elements of the World Health Organization (WHO) classification (Arber et al., 2003). The presence of t(15;17) as the most frequent aberration in the current study is compatible with several studies but not with other studies that found t(8;21) the most prevalent abnormality in patients with AML (Udayakumar et al., 2007).

In AML patients, FISH was applied to exclude inv(16), as it is the most frequent aberration missed in metaphases of suboptimal quality (Frohling et al., 2002). A break apart probe was used for this purpose. A dual fusion probe was used to detect t(15;17); this was applied to detect low-level positivity.

The ALL subgroup had few referrals, which may be explained by the rarity of it in adults. Abnormalities were detected in seven patients only; this is lower than the supposed frequency of chromosomal abnormalities in patients with ALL, which is found to reach 79% in large studies (Moorman et al., 2007). This cannot be significant in such a small sample size; besides, many patients in our study were referred to cytogenetic analysis before completion of other investigations to confirm diagnosis, and so they might be classified incorrectly in this group. However, Philadelphia-positive cases comprised half of the observed abnormalities, which is compatible with its presence in other studies (Moorman et al., 2007; Pullarkat et al., 2008). The highest frequency of culture failure was seen in this group. This is a common observation an ALL sample that can be encountered by applying FISH using probes for the most recurrent aberrations.

Chromosomal abnormalities were seen in 49% of the patients who presented with MDS, which is very close to the incidence of these abnormalities in a review of the literature involving more than 3000 patients (Malcovati and Nimer, 2008). All chromosomal abnormalities found in this subgroup were previously reported and each has its prognostic significance according to the International Prognostic Scoring System and the WHO classification-based prognostic scoring system. The most frequent aberration found was -7/7q-, followed by -5/5q-, which is categorized by the WHO classification as a distinct type of MDS (5q- syndrome) (Malcovati and Nimer, 2008). FISH was used for two patients with MDS who had a few bad-quality metaphases to exclude 5q deletions, as this aberration has its effect on treatment options for patients with MDS. FISH can be used to exclude common chromosomal abnormalities in patients with MDS, but data about how much it may add to conventional cytogenetic results is controversial (Pinheiro and Chauffaille, 2009).

The CLL subgroup had the lowest referral rate. All results retrieved from these patients were normal. It is reported that clonal abnormalities are found in 50% of the patients with CLL by karyotyping and in 80% of the cases by FISH (Reddy, 2005). The few good quality samples may be behind the normal results retrieved in this subgroup. However, these results emphasize the importance of applying FISH for these patients using a probe panel that covers the most recurrent abnormalities.

In general, FISH panels for MDS, AML, ALL, and CLL must be established and offered as a second choice in cases of culture failure or a few good quality metaphases.

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Constitutional chromosomal abnormalities

In this group, we evaluated the pattern of referral for the cytogenetic study, and we compared it with other studies that were chosen because they applied methodologies similar to our study, and the cases were grouped into almost the same referrals. Significant statistical differences between the current study and the other studies were seen in the referring frequencies for almost all referral groups.

The highest frequency of referrals was in the Turner syndrome group, which was not the case in other studies. Abnormal cytogenetic results in this subgroup were significantly more than the Turkish sample, but were not significantly higher than the Saudi and the Jordanian samples. These figures reflect the increased expertise in recognizing this syndrome clinically before referring candidates for laboratory investigation. The high number of referrals and positive results may raise a question of high incidence of Turner syndrome in Syria. It cannot be confirmed unless a large study is conducted either on newborn females or on older females with delayed puberty or primary amenorrhea.

The classical type of Turner syndrome karyotype ‘45, X’ was the most predominantly seen between abnormal results (65%). Mosaicism and other chromosome X abnormalities were seen in frequencies similar to those retrieved from other studies.

The Klinefelter syndrome subgroup had a higher frequency of positive results than the same subgroup in the other studies. Screening for chromosome Y microdeletions (azoospermia factors) was recommended for patients who had normal karyotypes (Alkhalaf and Al-Shoumer, 2010).

The highest frequencies of abnormal karyotypes were found among cases of Down syndrome suspect (93%) this reflects the ease of diagnosing this syndrome. This number was significantly higher than the numbers retrieved from other studies. The majority of the abnormal karyotypes presented as extra free chromosome 21 (90%), followed by mosaicism (4.7%) and Robertsonian translocation (4.7%). These were close to the frequencies reported in other reviews (Chandra et al., 2010). Patients in this group were the youngest among other groups; this is explained by the obvious clinical features of Down syndrome that can be recognized from the early days of life. One newborn had a 49, XXYY+21 karyotype, which has not been described before in the literature for a live born. No more data were available about this patient because of loss of contact with his parents.

In the chromosomal syndrome suspect group, a small number of abnormal karyotypes was retrieved and this was similar to what was found in other studies used for comparison. The cytogenetic results of Cri du Chat syndrome (female), Patau syndrome (female), and trisomy 9p syndrome (male) were all compatible with their clinical presentation. One boy had a 47, XYY karyotype, which is known to be associated with language and motor delay (Lenroot et al., 2009). The three patients who presented with PW syndrome phenotype did not show interstitial deletion of chromosome 15q11.2-q13 on karyotyping. One female who was suspected to be affected with PW syndrome had chromosome X monosomy compatible with Turner syndrome, but failed to prove the 15q deletion by FISH. However, the cooccurrence of Turner and PW syndromes in this female cannot be excluded, as a PW phenotype can be due to maternal imprinting that cannot be detected by cytogenetic techniques. The other two patients might be proved to have the deletion if FISH was offered to them (Cassidy and Schwartz, 2009).

Two patients were referred to exclude 22q11 deletion syndrome; they had normal karyotypes and normal signal patterns by FISH. The same results were retrieved in a patient referred as a Williams–Beuren Syndrome suspect. All other patients under the chromosomal syndrome suspect category were not referred to exclude any chromosomal syndrome, but they were referred as they had idiopathic mental retardation. Referral of many patients in this group was from physicians with limited experience in dysmorphology and genetic diseases. The evaluation by dymorphologist may guide to a microdeletion or a genetic syndrome, which show a normal karyotype and can be detected only by FISH or other molecular techniques. This may explain the limited information retrieved from this group.

The most important point to be discussed in the sex determination group is the age of presentation, which, in the majority of the cases, was considered to be late. Workup on these patients, including cytogenetic study as first-line testing, is recommended as soon as possible during the neonatal period to avoid psychological and social sequelae (Al Mutair et al., 2004; Lee et al., 2006). The delay in our group may in some cases be due to the low education of parents, but increasing parents’ awareness of the importance of early intervention remains the medical staff’s responsibility.

In the Reproductive problems group, two kinds of abnormalities were detected: sex chromosomes abnormalities and autosomal chromosomes abnormalities. In the first group, the reproductive problems are justified and associated with such abnormalities. Pericentric inversion of chromosome 9 in both homologs has been considered as a polymorphism in many reviews and it was considered to be associated with male infertility in other reports (Khaleghian and Azimi, 2006). Other autosomal chromosomal abnormalities observed needed further investigation to proof their origin and relation to the reproductive problem. The total number of abnormal karyotypes in this sample was small, but it is consistent with the estimated percentage of chromosomal factors in infertile males (2–8%) and females (about 5%) (Foresta et al., 2002).

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Conclusion

Our goal in the HDs group was to emphasize the diverse results that may be gained from cytogenetic analysis for these patients and how such results can affect treatment decisions. Because of the design of our study, interpretation of cytogenetic results is limited. Other clinical features, laboratory results, and patient factors (age, sex, previous treatment, etc.) have to be considered to obtain significant interpretation of the cytogenetic results.

However, we believe that this study highlighted the importance of considering cytogenetic tests during the management of patients with HD.

In the constitutional chromosomal disorders group, the high rates of chromosomal abnormalities found demonstrate the importance of cytogenetic analysis and emphasize the need to incorporate it in evaluation plans.

As these data are from a single clinical service, they do not represent population prevalence. However, the present study is the first cytogenetic data review from Syria that covers all these referral groups. We suppose it draws the attention of clinicians in our area of what cytogenetic services may provide to the evaluation and management of patients.

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Acknowledgements
Conflicts of interest

There are no conflicts of interest.

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Keywords:

constitutional chromosomal aberrations; cytogenetics; hematological disorders; karyotype; Syria

© 2012 Middle East Journal of Medical Genetics

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