Clinical and Cytogenetic Profile in Patients with Down Syndrome in Duhok Province, Iraq

Dian Jamel Salih,Nizar Bakir,Adil Abo Azeez Eissa,Nasir A. Al-Allawi
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Keywords : Down syndrome, karyotypes, mosaic, nondisjunction.
Medical Journal of Babylon  14:2 , 2017 doi:1812-156X-14-2
Published :28 October 2017

Abstract

Down syndrome is the most common Aneuploidy in humans which is associated with developmental delay, mental retardation and several characteristic physical features. This study is aimed to determine the proportion and types of chromosomal abnormalities in patients with Down syndrome in Duhok province, Iraq, and to study the clinical profile of these patients. A retrospective analysis was performed on the case records of 86 patients confirmed clinically as Down syndrome from October 2014 to April 2015, for all enrolled cases cytogenetic analysis had done at Research Centre at College of Medicine\ University of Duhok. Among the 86 cases of Down syndrome presented over a period of 6 months, non-disjunction was present in 79 (91.9%) cases, translocation in 5 (5.8%) cases and Mosaicism in 2 (2.3%) cases. The age of the enrolled patients were ranged from 1 day to 35 years, from these patients, 37 (43%) were males and 49 (57%) were females with male to female ratio of 1:1.3. The maternal ages at the time of delivery of index babies were ranged from 21 years to 47 years. The most prominent characteristic features noted were epicanthic folds (80.2%), upslanting palpebral fissures (70.9%), protruding tongue (67.4%), sandal gap (64%), depressed nasal bridge (62.8%), and flat facial features (58.1%). Congenital heart disease seen in (26.7%) and hypothyroidism seen in (10.5%) Down syndrome mostly result from non-disjunction and efforts to establish early diagnosis and a proper screening for high association with systemic anomalies should be undertaken among the Down syndrome patients in our population.

Introduction

Down syndrome (DS) is the most common autosomal chromosomal aneuploidy in human and the best known of all malformation syndromes associated with developmental delay, mental retardation and several characteristic physical features [1,2]. In addition, people with DS have an increased risk for Congenital Heart Diseases, leukemia, gastro interstitial tract abnormalities, immunological impairments, and Alzheimer disease [3]. The birth prevalence of DS is approximately 1 in 650-1000 live-born children world-wide which make the syndrome the most common cause of mental retardation [4]. Generally, DS can be caused by three types of chromosomal abnormalities: trisomy 21 (non-disjunction), translocation, or mosaicism. More than 95% of DS individuals have trisomy 21 which results from non-disjunction error during gameto-genesis in chromosome 21. About 2-4% results from a translocation of chromosome 21, while only 1-2% is mosaicism that showing a normal cell line additionally to trisomy [5]. Mosaic DS individuals may be phenotypically less severely affected than Individuals in trisomy or translocation, but their conditions are indistinguishable in all other aspects [6]. Down syndrome due to non-disjunction is typically not inherited. Mosaic DS is also not inherited, but is the result of random error during cell division, resulting in some cells having an extra copy of the chromosome. Translocation DS may be inherited [7]. Down syndrome is associated with variable phenotypes. However, mental retardation, neonatal hypotonia, hypocellular brain and minor facial dysmorphic features such as small nose, upslanting palpebral fissures, speckling of iris (Brushfield spots), wide gap between the first and second toes, flat facial profile, low set ears, single palm crease and shortened 5th finger can be seen in almost all individuals with DS [8]. In addition, individuals with DS are at an increased risk for several congenital anomalies and some health problems such as congenital heart defects, Leukemia, Alzheimer’s disease, Hypothyroidism and Gastrointestinal track anomalies [9,10]. But these Individuals are different in their health situations, not every person will suffer serious health problems. Many of associated conditions and health problems can be treated with surgery, certain medications or some interventions [11]. Cytogenetic investigation is an important technique to confirm clinical diagnosis and to determinate the recurrence risks of DS [12]. The purpose of this study was to found the proportion of chromosomal abnormalities in patients with Down syndrome in Duhok province, as well as to study their clinical features.

Materials and methods

The current study was performed according to the cross-sectional descriptive study design.
A total of 86 Individuals with DS for cytogenetic analyses were collected from Hivi pediatric hospital in Duhok city and Awat institute for mental retardation children from October 2014 to April 2015. Cytogenetic analyses and karyotyping foe each individual was performed at the scientific research Centre in the College of medicine, University of Duhok. All patients were subjected to full clinical, laboratory examinations.
Before working, permission of Ethics Committee and permission from all children parents had been taken.
A questionnaire form was filled for each patient that included sociodemographic characteristics of individuals and their mothers, comorbidity, recurrent infections and Clinical features. The information’s about congenital heart disease has been taken from individual profiles in Hivi Hospital and Awat institute.
All steps for preparation of chromosome from lymphocytes cultured of peripheral blood and all solutions needed prepared according to Rooney [13].
Chromosomal culture was carried out by 1ml of peripheral whole blood collected in sodium heparinized tube each patient then added to a flat culture tube that containing 10ml of RPMI1640\L-glutamine, 2ml of  fetal bovine serum, 200µ of Phyto-haemagglutinin (10 ?g/ml), 200µ penicillin-streptomycin solution (10 ?g/ml).
After 72 hours of incubation at 37°C, 100µ of Colcemid was added, after 60 minutes, the cells were harvested by centrifugation 1500/rpmi for 7 min. Then, 10ml of 0.075M KCl solution was added and mixed and incubated at 37°C for 30 min. After centrifugation 1500/rpmi for 7 min, hypotonic supernatant was removed. Then, 10ml of cold, fresh fixative solution (3:1 methanol: glacial acetic acid) was added drop by drop for the first 2 ml to the cell pellet. Centrifugation was done afterward, and the supernatant was removed, last step was repeated until a clear pellet was obtained. Finally, cells obtained were dropped on clean distinct slides, staining with Giemsa stain.
Slides were examined and analyzed with bright field microscope using BX51 Olympus microscope and karyotyping were performed with the aid of computer based karyotyping system (Cytovision version 7.2 from Leica microsystem). At least 15-20 metaphase spread Captured by using a satellite capture station and the images transferred to an image analyser. For each patient 15-20 cells were counted and analyzed and finally designated the karyotype according to the ISCN (1995).
After completing karyotyping, data analysis was performed by using IBM SPSS Statistics software version 22. Descriptive data were presented for continuous variables as mean ± SD, while qualitative data description done by calculating number and percentage. t-test was used to compare between two means and Chi-square (x2) tests was used to compare between proportions, P value ? 0.05 considered statistically significant.




Results

All 86 cases included in this study were cytogenetically confirmed cases with a clinical diagnosis of Down syndrome, 37 (43%) were males and 49 (57%) were females with male to female ratio of 1:1.3 and the age of the enrolled patients ranged from 1 day to 35 years with a median age of 6.1 years (mean 8.3±7 years). The maternal ages at the time of delivery of index babies were ranged from 21 years to 47 years with a median age of 33 years (mean 32±5.8) and out of 86 DS individuals, 30 (34.9%) were born to mothers ?35 years of age, while 56 (64.1%) were born to mothers ?35 years of age. Also 31 (36.2%) mothers of affected child gave history of abortion, and majorities have 1-2 abortion and occasionally more than 2 abortions The orders of affected individuals were from 1stto 14th, the 3rdorder was the most common order constituting 14 (16.3%) individuals with DS. Consanguinity relationship showed that 44 (51.2%) couples were in a consanguinity relationship and 42 (48.8%) had no consanguinity. The cytogenetic results of the analysis of 86 cases of DS listed in table I, showed that the in Trisomy 21 was the most common type of abnormality detected in 79 (91.9%) of the cases, while there were 5 (5.8%) cases of Translocation and 2 (2.3%) cases of Mosaicism. These various karyo-gramsare shown in figures 1 and 2. Frequencies of clinical features listed in Table II, It shows that the craniofacial abnormalities comprised epicanthic folds was the most common feature among DS cases presenting in 69 (80.2%) cases, Upslanting palpebral fissures In 61(70.9%) cases, protruding tongue in 58 (67.4%) cases, short broad hand in 49 (57%) cases. On the other hand excessive skin folds on neck were the least common feature which only presented in 21 (24.4%) cases. About clinical complications, Congenital heart defect presented in 23 (26.7%) of cases, Hypothyroidism presented in 9 (10.5%) cases and under developed genitalia presented in 7 (8.1%) cases.

Discussions

Several factors had been claimed to be associated with increased incidence of DS including: advanced maternal age, birth order of the affected children, consanguinity, and number of maternal miscarriage [14-16]. Down syndrome frequently encountered in our area with 1/960 being affected and this figure somewhat similar to that reported from Malaysia, Egypt and Germany [17-19], higher than United states, Singapore, England and Wales [20-22], but lower than India, most Arab countries, Iran and South Africa [23-25,5] and this mostly related to cultural factors as multiparity and probably exposure to environmental pollution including radiation. Ages of the enrolled patients ranged from 1 day to 35 years with a mean of 8.3±7.6 years (Median 6.1 years) and this figure is slightly higher than many international studies as about 46 enrolled patients were already diagnosed clinically and they were registered at Awat institute for mental retardation and because of the absence of routine cytogenetic techniques for such disorders. El-Gilany et al [26] reported a mean age of diagnosis of 12.2 months among 712 Egyptian DS individuals, Azman et al [19] reported a mean age of diagnosis of 10.6 months among 149 Malaysian DS individuals and Kava [27] reported a mean age of diagnosis of 18 months among 524 Indian DS individuals. Al-Harasi [28] reported almost 90% of 680 cases of DS children born in Oman were diagnosed cytogenetically within 6 months after birth. Females are predominant in the current study with sex ratio of (M:F =1:1.3) and this is relatively compatible with the data from small numbers of patients from Jordan which was (M:F =1:1.2) [29] but different to most other results from the region including that previously done in Duhok city based on clinical features only which was 1.5:1 [30]. Mehdipour [24] reported sex ratio of 1.5:1 in 150 Iranian DS individuals, El-Gilany et al [26] reported sex ratio of 1.14:1 among 712 Egyptian DS individuals and Frennyin [31] reported sex ratio of 2.3:1 among 382 Indian DS individuals. In spite of decades of research, the variability sex distribute in DS individuals is still unclear. Several hypotheses have been discussed, such as not-optimal timing of insemination in relation to ovulation [32], the joint segregation of chromosome 21 with the Y chromosome in spermatogenesis or chromosomal non-disjunction during meiotic division of oogenesis which is caused by Y chromosome-bearing spermatozoa [33-35] Affection of female more frequently in the current study remained unclear. The mean maternal age for DS individuals in our study was 32±5.8 years, which is slightly but significantly lower from the 34.4 years age in Western countries [36,37], this indicates that there is a clear effect of advanced maternal age on the DS birth prevalence in Duhok province and this difference may be related to younger age at marriage in our region or underestimation of maternal age as the females do not mention their real ages correctly. Down syndrome mostly observed among multiparous women with the birth order of second, third and fifth birth order and particularly the 3rd order. When individuals were stratified by karyotypes, mosaic DS were significantly associated with higher parity and these results are relatively compatible with data of few studies in Egypt, Iran and India [38,16,39]. On the other hand, Murthy et al [25] reported that an individual with DS were mostly the last one or second last one. Several studies suggest that there is an increasing risk with increasing parity as Doria-Rose et al [40] suggested that higher parity is associated with an increased risk of giving birth to a DS child, both for women aged more than 35 years and for women under 35 years of age, while Chan et al [41] reported that there is no increased risk noted with increased parity. It has been suggested that the consanguinity among parents of DS individuals is associated with the higher rate of DS in some Arab countries including Iraq [15]. Consanguineous marriages are favored by the Kurds and Arab communities in the Middle East especially the first cousin marriages due to some social and economic reasons and to maintain the family properties [42]. Increased consanguinity rate of DS parents as compared to the general population was observed in the current study (51.2%) and those data are comparable to that reported from Oman [43] and this may be due to a higher probability of carrying rare recessive alleles influencing non-disjunction that could result in an increased aneuploidy rate of the progeny specially in the younger aged mothers [44,45] or recessive genes, possibly preventing the loss of the trisomy 21 fetus [46,47]. Miscarriage was observed with higher rate among mothers of DS children in the current study (36.2%) in comparison to the general population (14.3%) [48] and this may be due to inherited risk for chromosomal aneuploidy that commonly ended with abortion in the previous pregnancies [14]. Also abortion rate was higher than most other studies at 8.6% [28] and this might be due to higher rate of abortion in the region [48]. Regarding clinical profiles, craniofacial features considered to be the most important indicators of clinical suspicion of DS [49]. Among the craniofacial features studied in the current study, epicanthic fold was the most frequent feature observed in 69 (80.2%) cases, which is compatible with the study of Erika et al [12]who reported it in (79%) among DS individuals in southeast of Brazil, but this was quite different from that reported from southeast Asia with prevalence of only (17.5%) from northeast Malaysia and (59.6%) from India [27,19]. The major five clinical features present in more than 60% of the total cases were the epicanthic fold, upslanting palpebral fissures, protruding tongue, sandal gap and depressed nasal bridge which are comparable to the other studies in Table 5.1. Regarding complications and associated co-morbidities, congenital heart defect was encountered in 23 (26.7%) cases and this figure was smaller than that previously reported by Garjess and Muhsin [30] in Duhok province who reported CHD in 44 (55%) out of 80 cases with DS and this mostly due to inclusion of older patients from Awat institute and randomly selected patients from different region of Duhok who lack CHD and survived longer than those who suffered from CHD and pass away in the early childhood. The figure was also lower than that reported from Brazil, Malaysia and India (49%, 56% and 49% respectively) [19,12,50] and mostly due to the same reason mentioned above. Thyroid dysfunction observed more frequently (10.5%) among enrolled patients with DS than general population at 0.13% as revealed from the recent study from Duhok and these data are in concordance with other studies which all show higher prevalence of thyroid dysfunction among DS patients [51,50]. About 15% of adolescents with Down syndrome are hypothyroid, and there is evidence for a steady decline in thyroid function as age increases [52]. Hypothyroidism was significantly more frequent among non-disjunction individuals in comparison to those with translocation.

Conclusions

1. This study is a first record of cytogenetic analysis and karyotyping for Down syndrome individuals in Duhok province, Iraq. 2. Nondisjunction of Trisomy 21 was the most common karyotype followed by translocation and mosaicism. Down syndrome among Duhok province population was more frequent in females than males. 3. A high rate of consanguinity has been reported among parents of children with Down syndrome. Among the craniofacial features studied, epicanthic fold was the most frequent, while excessive skin fold on neck was the least common.

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