Subclinical inflammation in children with Down syndrome: implications for preventive care

Article information

Ann Pediatr Endocrinol Metab. 2026;31(2):119-128

Publication date (electronic) : 2026 April 30

doi : https://doi.org/10.6065/apem.2550148.074

Charu Sharma¹, Muhammad Jawad Hashim², Tarek El Azzabi^3,4, Sania Al Hamad⁵, Ekhlass Mohammed⁵, Javed Yasin⁶, Yousef M. Abdulrazzaq⁵, Elhadi Husein Aburawi^,5

¹Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE

²Department of Family Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE

³Department of Pediatrics, Al Ain Hospital, Al Ain, UAE

⁴Department of Pediatrics, Sheikh Khalifa Medical City Hospital, Al Ain, UAE

⁵Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE

⁶Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE

Address for correspondence: Elhadi Husein Aburawi Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box 15551, Al Ain, UAE Email: e.aburawi@uaeu.ac.ae

Received 2025 May 5; Revised 2025 November 5; Accepted 2025 December 3.

Abstract

Highlights

· Children with Down syndrome exhibit elevated levels of subclinical inflammation, which are further exacerbated by advancing age, increased adiposity, and metabolic dysregulation.

· This inflammatory state is associated with metabolic parameters, including insulin levels, lipid profiles, and appetite-regulating hormones such as ghrelin.

· Early clinical monitoring and weight management strategies may mitigate the risk of adverse long-term health outcomes.

Introduction

Down syndrome (DS) is one of the most prevalent chromosomal disorders globally, and in the United Arab Emirates (UAE) has an estimated incidence of 1 in 374 live births [1]. Individuals with DS are predisposed to a range of health complications, including metabolic disorders, obesity, and immune system dysregulation [2,3]. Individuals with DS have an increased body fat percentage (BF%) and altered metabolic regulation, contributing to elevated levels of proinflammatory cytokines [4].

Studies have reported that chronic low-grade systemic inflammation plays a significant role in exacerbating metabolic dysfunction. Elevated levels of high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, are generally observed in individuals with DS, obesity, insulin resistance, and dyslipidemia [5]. Elevated hs-CRP level, even in the absence of overt infection, may be more reflective of metabolic rather than infectious inflammation [6,7]. Comparative analyses have shown a concurrent elevation of other inflammatory markers such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α in individuals with elevated hs-CRP, reinforcing that hs-CRP is a reliable indicator of baseline subclinical inflammation in different conditions [8].

Among metabolic regulators, ghrelin, a hormone primarily secreted by the stomach, plays a crucial role in appetite regulation [9]. Its anti-inflammatory properties and regulatory effects on energy metabolism may serve potential mediating roles in DS-associated metabolic inflammation. However, the specific role of ghrelin in DS-related inflammation and metabolic dysfunction remains poorly understood. While one study reported comparable ghrelin levels in individuals with DS and their peers [10], another found reduced ghrelin levels in obese individuals [11].

In the UAE, DS-specific growth charts for weight, height, and head circumference have been developed. Regional data indicate that children with DS are significantly shorter and heavier than typically developing peers and show disproportionately high rates of overweight and obesity. This reinforces the need for tailored growth and health monitoring tools [12]. This cohort of patients exhibits excess adiposity, which drives subclinical systemic inflammation (increased hs-CRP); ghrelin, due to its metabolic and anti-inflammatory roles, may act as a potential mediator of this relationship. Studies from this region have also examined health outcomes in children and adolescents with DS-including physical status, feeding behaviors, and oral health [13].

Our aim in this study was to investigate interrelationships among hs-CRP, ghrelin, adiposity, and metabolic dysfunction among UAE children with DS. Our findings contribute to a more comprehensive understanding of the inflammatory and metabolic profile of DS patients within the UAE population.

Materials and methods

Results

1. Anthropometric and metabolic profiles

Children with DS weighed significantly more (P=0.003) and were shorter (P<0.001) than controls (Table 1), but BMI differences were not significant. BF% was higher in DS children (P=0.096). Children with DS had lower weight-for-age percentiles and lower weight-for-age z-scores but higher BMI percentiles than controls. Other variables, such as consanguinity and sex, showed minor differences that were not statistically significant between the DS and normal control groups. Those with DS were not more likely to have consanguineous parents than healthy controls (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.31–4.2). Children with DS were more likely to have subclinical inflammation (elevated hs-CRP) than healthy controls (OR, 6.6; 95% CI, 1.7– 25.3). As expected, mothers of children with DS were older at the time of pregnancy: mean age 34.5 (±standard deviation [SD] 6.5) years versus 22.8 (±SD 5.1) years for mothers of healthy children (P<0.001; Cohen d=5.9). Comparison of family history between children with DS and healthy controls did not show higher rates of obesity, dyslipidemia, diabetes, or hypertension among parents of cases than parents of controls (Table 1).

Table 1.

Clinical characteristics of children with Down syndrome compared to healthy controls

2. Analyses within the DS group

Further analysis within the DS group (n=49) revealed a near-equal distribution of male (n=25) and female (n=24) participants. Mean age of males (9.6 years) and females (7.2 years) was similar (P=0.092). There was a significant difference in weight between males and females (P= 0.045). Additionally, BMI was positively correlated with age (r=0.64, P<0.001). Fig. 1 shows obesity levels in children with DS. The marginal difference in fat-free mass (FFM) (P=0.056) and muscle mass (P=0.058) between the genders was not statistically significant. Other variables such as consanguinity and parental medical history showed differences, but these differences did not reach statistical significance (Table 2).

Fig. 1.

Obesity in children with Down syndrome. CDC, Centers for Disease Control and Prevention; IOTF, International Obesity Task Force; WHO, World Health Organization.

Table 2.

Comparison of male and female children with Down syndrome (n=49).

3. Inflammatory markers

hs-CRP levels were significantly higher in DS children than controls (P=0.030). Apolipoprotein B (Apo B) levels were also significantly higher in DS children (P<0.001), whereas adiponectin levels were significantly lower (P= 0.004). Ghrelin levels were significantly correlated positively with hs-CRP (r=0.30, P=0.012) but significantly negatively correlated with Apo B (r=-0.41, P<0.001) (Table 3). All biochemical assays performed were within the limits of variation (<7.8% for both inter- and intra-assay variability). Fig. 2 shows the effect of increased levels of inflammatory biomarkers and obesity with increasing age in children with DS (N=49). Fig. 3 shows the effect of weight, ghrelin and insulin levels in cases with high hs-CRP levels among 49 children with DS. Fig. 4 shows adjusted means of different biomarkers; these means were adjusted for differences in age, sex, and weight-forage centiles in the 2 groups.

Table 3.

Metabolic biomarkers in children with Down syndrome (DS) and controls

Fig. 2.

Increase in levels of inflammatory biomarkers and obesity with increasing age in children with Down syndrome (N=49). (A) C-reactive protein (high-sensitivity CRP). (B) Weight percentile. (C) Low-density lipoprotein (LDL) cholesterol. (D) Insulin. (E) Gamma-glutamyl transferase (GGT). (F) Vitamin D.

Fig. 3.

Greater weight, ghrelin, and insulin levels in cases with high hs-CRP levels among 49 children with DS. (A) Weight percentile. (B) Ghrelin. (C) Insulin. Children with DS were divided into 2 groups: an inflamed group (hs-CRP levels > 1.0 mg/L; n=24) and a not-inflamed group (hs-CRP levels<1.0 mg/L; n=23). hs-CRP, high-sensitivity C-reactive protein; DS, Down syndrome.

Fig. 4.

Adjusted comparison of inflammatory biomarkers between children with Down syndrome and healthy controls. The graph shows adjusted means (estimated marginal means) obtained using a univariate general linear model with age, sex, and weight-for-age centile as covariates. *Ghrelin values were divided by 100 to be able to show them on the same scale. Adiponectin levels were inversely correlated with inflammation: lower values indicate greater inflammation. hs-CRP, high-sensitivity C-reactive protein; GGT, gamma-glutamyl transferase; LDL, low-density lipoprotein.

4. Metabolic dysregulation

LDL and triglyceride levels were significantly higher in DS children than controls (P<0.001). Insulin resistance markers were significantly correlated with inflammation (insulin-hs-CRP: r=0.35, P=0.008). Vitamin D levels were significantly lower in children with DS and declined with age (r=-0.356, P=0.003) (Table 3). The metabolic biomarkers in children with DS with increased inflammation as determined by an elevated CRP level is tabulated in Table 4.

Table 4.

Metabolic biomarkers in children with Down syndrome (DS) with increased inflammation as determined by an elevated CRP level

Discussion

This study corroborates existing evidence that children with DS exhibit increased inflammatory responses, particularly in those with elevated BMI, older age, and signs of metabolic dysregulation. A comparative analysis involving 95 adolescents with DS and 113 typically developing controls revealed that the DS group had significantly higher BMI, waist-to-height ratio, waist circumference, and BF%. Additionally, children with DS displayed elevated inflammatory biomarkers, including complement factors C3 and C4, as well as total serum proteins [14]. Interestingly, this study found no significant differences in inflammatory markers based on gender; however, FFM and muscle mass showed significant differences between sexes, suggesting potential gender-related differences in body composition that merit further exploration. The present study identified early dyslipidemia in children with DS, a significant risk factor for cardiovascular disease. These findings are consistent with a case-control study involving 69 children (31 with DS and 38 controls), which revealed a distinct lipid profile in the DS group characterized by elevated triglyceride levels and HDL-C, alongside reduced LDL-C levels [15]. In a larger cross-sectional study of 386 children with DS aged 2–18 years, the most prevalent lipid abnormalities included low HDL-C (45.9%) and hypertriglyceridemia (26.2%). Notably, significant associations were observed between dyslipidemia, general obesity, and central adiposity [16], highlighting the critical need for early and regular lipid screening in children with DS to mitigate long-term cardiovascular risks.

The key predictors of systemic inflammation identified in this study were age, ghrelin levels, and BF%. Age was independently linked to increased hs-CRP levels in a previous study involving adult women [17]. Furthermore, evidence from pediatric cohorts suggests a temporal relationship between obesity and inflammation, with higher body fat percentiles correlating with elevated hs-CRP levels—an association that poses significant implications for chronic disease risk in later life [10]. The positive correlation between hs-CRP and obesity supports a proinflammatory state exacerbated by increased adiposity, as noted in previous literature [17].

Ghrelin appears to be involved in complex inflammatory processes through a compensatory physiological response, potentially linked to altered metabolic pathways [18]. This has been observed in inflammatory bowel diseases such as Crohn disease and ulcerative colitis [19,20]. A study among obese youth showed a negative correlation between fasting plasma ghrelin and insulin resistance, implying that elevated insulin may suppress ghrelin secretion [21]. Another study reported lower fasting ghrelin levels in obese children than normal weight children, indicating its regulatory role in energy balance [22]. However, despite the anticipated inverse relationship, we found a positive correlation between ghrelin and hs-CRP levels in this study. Despite limited studies on ghrelin in children with DS, this population is characterized by increased rates of obesity and chronic inflammation.

Inflammatory markers such as TNF-α and IL-6, which are elevated in obesity, may interfere with the regulation of appetite-related hormones like ghrelin. However, in the present study, we did not measure TNF-α and IL-6, but focused on other inflammatory markers such as ghrelin, hs-CRP, Apo B, insulin and insulin resistance, which were significantly different between the DS and control groups. Uric acid levels were significantly higher in the group with elevated hs-CRP levels than the normal hs-CRP-level group.

Additionally, we noted significant differences in Apo B levels between the DS and control groups. Elevated Apo B levels in individuals with DS further emphasize the increased risk of cardiovascular disease in this population [16], reinforcing the necessity for careful cardiovascular risk assessment. The findings of this study also suggest that DS may represent a state of early-onset insulin resistance, as evidenced by elevated serum insulin levels. This aligns with previous research indicating that obese children with DS have higher insulin levels and exhibit early markers of insulin resistance compared to their typically developing peers [23].

As a secondary finding, vitamin D did not differ between DS and controls overall (P=0.888), but within the DS group, those with an elevated CRP level (hs-CRP > 1 mg/L) had lower vitamin D levels than their peers with normal CRP levels (P=0.033). This pattern supports monitoring and optimizing vitamin D status in patients with DS, while keeping the primary emphasis on the ghrelin–inflammation axis.

An inverse correlation between serum vitamin D and hs-CRP levels was reported in an earlier study, highlighting its role in modulating inflammatory pathways in newborns [24]. These findings support early vitamin D supplementation as a preventive measure to reduce inflammation in this high-risk population.

In conclusion, this study demonstrated that children with DS have increased systemic inflammation influenced by age, obesity, and metabolic irregularities. Thus, routine assessment of inflammatory markers, lipid profiles, and vitamin D levels is essential in this population. Additionally, ghrelin was identified as a potential mediator of metabolic inflammation in DS, with its correlation to hs-CRP suggesting a compensatory role in the inflammatory state. Emphases on early screening and intervention strategies to address dyslipidemia, insulin resistance, and vitamin D deficiency should be mandatory. Further research is needed to understand the complex interplay between obesity, inflammation, and metabolic dysregulation in this vulnerable population.

The primary limitations of this study are its relatively small sample size, which may affect the generalizability of the findings, and the absence of longitudinal data to assess long-term health outcomes. The control group included a substantial number of overweight and obese children due to the high prevalence of childhood obesity in the region. While results of a subset analysis (after excluding overweight and obese children in the control group) were reported, matching or weighting techniques were not used to compare the 2 groups. Fasting sampling was not possible as parents with DS did not provide consent for this. Additionally, some patients in the DS group had elevated hs-CRP levels without any clinical explanation.

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