Subjects with chromosomal disorders are at higher risk for cardiometabolic comorbidities that develop earlier than in the general population. Homocysteinemia has been emerged as an independent risk factor for cardiovascular diseases. Reports showed that about 40% of patients with cerebrovascular disorders have homocysteinemia. There are controversial reports regarding the relationship between homocysteine and lipid profile under several normal and pathological conditions 16. However, there is no sufficient data exploring the prevalence of homocysteinemia in children with chromosomal disorders and its relation to dyslipidemia.
There is controversy in the identification of the cutoff level of homocysteinemia in children and adolescents that varied according to age and ethnicity between 8.3 and 13.75 nmol/L. In the current study we relied on a cutoff level > 95th percentile for age and sex to identify homocysteinemia [17, 18].
The current study demonstrated higher homocysteine serum level in children with Klinefelter, Turner and Down syndromes in comparison to healthy children with positive correlation between homocysteine level and BMI. These findings could be partially explained by higher rate of overweight and obesity among children with chromosomal disorders especially those with Down syndrome. These findings are in accordance with Kumar et al. , who reported that among school aged children none of normal weight children had homocysteinemia while 37.5% of overweight children and 36.5% of obese children had homocysteinemia. However, the frequencies of homocysteinemia in obese children with chromosomal disorders much exceed that observed in healthy children.
However, further analysis of our results demonstrated that homocysteine level was significantly higher in normal weight children with chromosomal disorders when compared to normal weight healthy children suggesting the presence of other causes for homocysteinemia rather than increased BMI. This indicates that numerical chromosomal aberrations play a role in the development of homocysteinemia.
Schulze et al.  suggested that homocysteinemia in children with numerical chromosomal aberrations could be due to genetic polymorphisms, physical activity patterns, adiposity, and nutritional deficiency of folic acid and vitamin B12. In children with Turner syndrome, previous reports demonstrated that homocysteinemia may be related to female sex hormones deficiency. Estrogen deficiency caused by monosomy X chromosome may represent a possible cause for homocysteinemia in children with Turner syndrome . While homocysteinemia in children with Klinefelter syndrome may be related to increased muscle mass. Furthermore, previous evidence showed increased homocysteine level after treatment with testosterone in patients with Klinefelter syndrome .
Our results demonstrated higher levels of total cholesterol and LDL in children with homocysteinemia. Regression analysis revealed a significant association between homocysteinemia and LDL level. These findings are in accordance with previous studies that have shown strong association between homocysteinemia and dyslipidemia. This could be attributed to the effect of homocysteine that promotes the formation and secretion of cholesterol by the hepatocytes that may contribute to the direct correlation between cholesterol and homocysteine level . Experimental studies demonstrated that homocysteine thiolactone triggers the aggregation of LDL leading to the formation of foam cells in cultured human macrophages .
Several studies demonstrated the role of homocysteine in enhancement of low-density lipoprotein peroxidation. Dong et al.,  reported significant positive correlation between homocysteine and LDL level in patients with hypothyroidism, which is commonly associated with both Down syndrome and Turner syndrome. Furthermore, reduction of homocysteine level was associated with decreased LDL.
Our findings came in agreement with Yakub et al.  who reported that homocysteinemia directly correlated with hypertension, dyslipidemia, and obesity. Experimental studies have demonstrated that hypomethylation due to homocysteinemia may attribute to visceral fat accumulation. Furthermore, homocysteinemia may also alter the activity of some inhibitory enzymes which are involved in HDL metabolism .
On the other hand, previous studies reported an association between homocysteinemia and the metabolic syndrome. Additionally, it was reported that homocysteinemia has a thrombogenic and atherogenic effect that attribute to premature atherosclerosis leading to several cardiometabolic events including stroke and ischemic heart disease .
In conclusion, our findings suggest a strong association between homocysteinemia and dyslipidemia in children with non- mosaic numerical chromosomal disorders who are known to have high risk of cardiovascular morbidities. Furthermore, BMI positively correlated with homocysteinemia in children with numerical chromosomal aberrations but not in children with normal karyotypes. Thus, numerical chromosomal aberrations may play a role in increased BMI.
Further studies are required to understand the causes of homocysteinemia in such children. Moreover, longitudinal follow up studies are needed to prove a cause-effect relationship between homocysteinemia and dyslipidemia in children with non- mosaic numerical chromosomal aberrations and assess cardiovascular comorbidities related to homocysteinemia.