Multiple definitions of the MS have been proposed for adults by the WHO,⁷ the National Cholesterol Education Program's Adult Treatment Panel III,⁸ the European Group for the Study of Insulin Resistance⁹ and the International Diabetes Federation,¹⁰ which all agreed on the essential components (glucose intolerance, central obesity, hypertension and dyslipidaemia) but differed in the detail.^4,11 These definitions were adapted for children and adolescents by different authors, who also used widely varying criteria (table 1​1).^12,13,14,15 Conversely, a uniform internationally accepted definition of the MS in childhood and adolescence would allow comparison of the prevalence data in different studies and populations.

Paediatricians have “diagnosed” the MS increasingly in recent years to describe the cardiovascular risk.^12,13,14,15 Furthermore, the MS seems to affect the management of the overweight child,¹⁶ since the MS is based on the concept that the clustering of risk factors is predictive for CVD above and beyond the risk associated with its individual components.^4,11 Conversely, the concept of the MS has never been proven in childhood and adolescence.

There are very limited data on the variation in the MS prevalence in overweight children and adolescents using different proposed definitions. Furthermore, little is known concerning the factors influencing the frequency of the MS in childhood. Therefore, the aims of this study were to compare the prevalence of the MS according to the different existing definitions in a large sample of overweight children and adolescents, and to analyse the impact of degree of overweight, insulin resistance and pubertal stage on the frequency of the MS.

Overweight was defined according the International Task Force of Obesity in Childhood (IOTF).¹⁷ The degree of overweight was quantified using Cole's least mean square method, which normalised the body mass index (BMI) skewed distribution in childhood and expressed BMI as a standard deviation score (SDS‐BMI).¹⁸ Reference data for German children were used since the IOTF percentiles did not allow us to calculate SDS‐BMI.^17,19

The pubic hair stage was determined according to Marshall and Tanner. The pubertal developmental stage was categorised into three groups based on pubic hair and genital stages (prepubertal: boys with pubic hair stage I and gonadal stage I, girls with pubic hair stage I and breast stage I; pubertal: boys with pubic hair stage II or gonadal stage II and girls with pubic hair stage II or breast stage II; late/postpubertal: girls with menarche and boys with change of voice).

Serum fasting triglyceride, HDL‐cholesterol, total cholesterol and glucose concentrations were measured using commercially available test kits (HDL‐C Plus, Roche Diagnostics, Mannheim, Germany; Vitros analyser, Ortho Clinical Diagnostics, Neckargemuend, Germany; MEIA, Abbott, Wiesbaden, Germany). Fasting insulin concentrations were measured by high‐specific microparticle enhanced immunometric assay (MEIA Abbott, Wiesbaden, Germany). Intra‐ and interassay variations were less than 5% in all methods. Homeostasis model assessment (HOMA) was used to detect the degree of insulin resistance.²⁰ The resistance can be assessed from the fasting glucose and insulin concentrations by the formula: resistance (HOMA)=(insulin (mU/l)×glucose (mmol/l))/22.5.

An oral glucose tolerance test (oGTT) was performed in obese children and adolescents with at least two risk factors (first degree relatives with type 2 diabetes mellitus, dyslipidaemia, hypertension, acanthosis nigricans) according to the recommendations of the American Diabetes Association.²¹

Blood pressure was measured according to the guidelines of the National High Blood Pressure Education Program (NHBPEP).²² Systolic and diastolic blood pressure were measured twice at the right arm after a 10 min rest in the supine position using a calibrated sphygmomanometer and averaged. The cuff size, which was based on the length and circumference of the upper arm, was chosen to be as large as possible without having the elbow skin crease obstruct the stethoscope.²²

The MS was defined according to the criteria of Weiss,¹² Viner,¹⁴ De Ferranti,¹⁵ Cook,¹³ WHO,⁷ EGIR,⁹ ATPIII⁸ and IDF.¹⁰ Following the German guidelines for overweight children,²³ we used BMI percentiles of German children¹⁹ to define the 95th and 97th BMI percentiles in the definition of Viner and Weiss, the age‐ and height‐related percentiles of NHBPEP for blood pressure,²² the cut‐off points of lipids for German children²³ in the definition of Weiss, and the percentiles of Dutch children for waist circumferences.²⁴ Impaired fasting glucose was defined as fasting serum glucose 100 mg/dl according to the new WHO definition.²⁵ Impaired glucose tolerance was defined as 2 h serum glucose >140 mg/dl in the oGTT. Since oGTT was not performed in every child but impaired glucose tolerance was part of the definition in some proposed definitions for the MS, we alternatively used the following definition for disturbed glucose metabolism based on the proposal of Viner.¹⁴ Disturbed glucose metabolism was defined as impaired fasting glucose, hyperinsulinaemia (15 mU/l for prepubertal children, 30 mU/l for pubertal children, 20 mU/l for postpubertal children) or impaired glucose tolerance.

Among the normal weight children, six (7%) demonstrated fasting insulin levels above the threshold suggested by Viner.¹⁴ None of the normal weight children had glucose levels >100 mg/dl. Two (2%) children had blood pressure values >90th percentile, but none were >97th percentile. One child (1%) demonstrated HDL‐cholesterol below 40 mg/dl, but none had cholesterol levels >95th percentile. Nine children (11%) had triglycerides >110 mg/dl and four (5%) >150 mg/dl. None of the 84 normal weight children fulfilled any of the proposed definitions of the MS. Regardless of the type of definition, the MS was observed significantly (p<0.001) more frequently in overweight children as compared with normal weight children.

The different prevalences of the MS and the frequencies of the used criteria in the 1205 overweight children according to the different definitions for children and adolescents are shown in table 2​2.. In table 3​3,, the frequencies of the MS based on the definition for adults are shown. The frequency of the MS varied significantly (p<0.001) between the different definitions. A total of 114 (9%) children fulfilled the criteria of the MS in all proposed definitions for children and 22 (2%) fulfilled the criteria of the MS in all proposed definition including the definition for adults. A total of 1170 (97%) children demonstrated at least one criterion and 990 (82%) had at least two of the criteria used to define the MS.

We performed an oGTT in 194 obese children and detected impaired glucose tolerance in 27 (14%) of these children. If only impaired glucose tolerance was used as the criterion and not the alternative definition of disturbed glucose metabolism, 13% of the children fulfilled the definition of Weiss and 1% of the children fulfilled the definition of the WHO for the MS.

Degree of overweight and insulin resistance were significantly associated with occurrence of the MS regardless of the definition and after adjustment for age and sex (table 4​4).

The frequencies of the MS based on definitions for children and adolescents separated into gender and pubertal stage are shown in fig 1​1.. In each proposed definition, the differences in the frequency of the MS between the prepubertal, pubertal and late/postpubertal girls were not significant. In the definitions of Cook and De Ferranti but not in the definitions of Viner and Weiss, the MS was detected significantly more frequently in pubertal than in prepubertal boys (fig 1​1).). Analysing prepubertal, pubertal and late/postpubertal children separately, the frequency of the MS varied significantly (p<0.001) between the different definitions.

The correlation matrix between the criteria systolic blood pressure, waist circumference, BMI and levels of fasting glucose, total cholesterol, HDL‐cholesterol, triglycerides and insulin showed high correlation coefficients (r>0.4) only for BMI and insulin levels with r=0.49.

Not only did the prevalence of the MS vary widely between the different definitions, but also the impact of puberty on the prevalence of the MS varied widely as well. De Ferranti and Cook reported a 3–5‐fold higher prevalence of the MS in pubertal adolescents compared with prepubertal children.^13,15 Using their definition, we also found a higher prevalence of the MS in pubertal adolescents but only in boys and not in girls. Conversely, the other definitions of the MS proposed for childhood and adolescence demonstrated no influence of pubertal stage on the MS. The proposed definitions of the MS for children and adolescents differed widely in their criteria and the thresholds of their components. These facts likely explained the difference in frequencies of the MS and the different effect of pubertal stage on the MS.

PCA demonstrated that total cholesterol, triglycerides and waist circumference explained most of the variance between the analysed children and adolescents. Therefore, inclusion of these criteria in the definition of the MS helps to differentiate the children.

One major difference between the proposed criteria for the MS was the definition of insulin resistance. Insulin levels without respect to glucose concentrations are not a good predictor of insulin resistance.²⁷ Furthermore, values of fasting insulin levels are limited by great intra‐ and interindividual variability.²⁷ Accurate assessment of insulin resistance as suggested by the WHO requires a complicated test (eg, the hyperinsulinaemic euglycyaemic clamp technique).⁷ Its application in children is invasive and impractical, so clinicians prefer simple tools such as fasting glucose. Conversely, only 1% of the overweight children demonstrated impaired fasting glucose even if we used the new WHO definition.²⁵ However, the insulin resistance index HOMA was associated with the MS in all definitions for children and adolescents. Moreover, previous longitudinal studies reported that insulin resistance was more closely related to components of the MS as compared with degree of overweight.^4,28

Furthermore, central obesity is one major element in the definition of the MS in adults^7,8,9,10 and not the degree of overweight as used in some proposals for children.^12,14 However, the cut‐offs of the waist circumference percentiles for European children do not seem to be very specific since the majority of our overweight children had waist circumferences above the proposed thresholds.

Most importantly, the entire concept of the MS is controversial.^4,11 A major concern in the definition of the MS refers to the use of cut‐off points for the various risk factors, thus implying that the values above the specified thresholds are associated with an excess risk, yet the rationale for the different cut‐off points has never been delineated.¹¹ Moreover, the dichotomous use of continuous data such as lipids, waist circumference and blood pressure values, seems inaccurate since they are not all‐or‐nothing values. In fact, the relationship is not even linear which makes it all the more difficult and opens up the issue of how risk in this conglomeration of the “syndrome” might be weighted more appropriately.

Finally, the MS is based on the concept that the clustering of risk factors is predictive for CVD above and beyond the risk associated with its individual components. In overweight children, dyslipidaemia, hypertension and disturbed glucose metabolism were related to intima‐media thickness (IMT) of the common carotid artery,^29,30 which is predictive and related to the severity of CVD.^31,32 Therefore, the integration of these factors in the definition of the MS seems meaningful. However, it has not yet been determined whether the clustering of these risk factors is associated with an increased of CVD in childhood above the risk of the individual components. Without evidence of an increased risk in the MS beyond the sum of its parts, it may be better to pay individual attention to the well documented individual risk factors.

The frequencies of the cardinal factors of the MS (disturbed glucose metabolism, hypertension and dyslipidaemia) were similar to those found in previous studies in Caucasian children.^2,3,33,34 Most overweight and obese children had one or two of these cardiovascular risk factors. It was found that 6–14% children and adolescents fulfilled the criteria for the different definitions of the MS used in adulthood, underlining the fact that the components of the MS are already present in some children.

The overall prevalence of the MS was lower in our overweight children and adolescents as compared with the studies of Weiss (39% vs 12%) and Viner (33% vs 18%).^12,14 However, in our sample the overall prevalence of the MS was similar to that found in the study of Cook (29% vs 21%) and more frequent than that reported by De Ferranti (10% vs 39%).^13,15 Different age ranges, races, degrees of overweight, referral practices, geographical variation in obesity and epigenetic factors might explain these differences. While the subjects in our study and those of Viner and Weiss were recruited in specialised obesity/endocrine clinics, which probably meant the frequency of the MS was overestimated, the cohorts of Cook and De Ferranti originated from general populations and had a tendency to a lower prevalence of the MS. We analysed only Caucasian children, while the studies with the highest prevalence of the MS also included subjects of Hispanic, African and Asian origin, who are suggested to have a higher frequency of the MS.^12,14

This study has a few potential important limitations. Data from clinical samples may not be representative of the general population, and selection and referral bias may have influenced our estimate of the prevalence of the MS. Furthermore, oGTT was not performed in every child. Finally, consideration of pubertal stage instead of dividing children into prepubertal, pubertal and late/postpubertal groups would be the ideal way to analyse the effect of puberty on the prevalence of the MS. Conversely, performing such a study needs a very large sample size since children have not only to be divided according to different pubertal stage but also according to gender. Additionally, division into groups according to pubic hair and breast stages partially depends on the investigator.

In summary, definitive criteria for the MS for childhood and adolescence have not yet been determined. The MS was related to insulin resistance and weight status, and was independent of the pubertal stage in most definitions. The prevalence of the MS was quite different depending on the proposed definitions for children and adolescents. An internationally accepted uniform definition of the MS is needed to allow comparisons between different studies and populations. Furthermore, the concept of the MS that the clustering of risk factors is predictive for CVD above and beyond the risk associated with its individual components has to be proven in childhood and adolescence.