Williams-Beuren Syndrome Is a Genetic Disorder Associated with Impaired Glucose Tolerance and Diabetes in Childhood and Adolescence: New Insights from a Longitudinal Study

Abstract

Background: In adults with Williams-Beuren syndrome (WBS), a common endocrine abnormality is type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). However, few and sporadic data are available in children, adolescents, and young adults with WBS. Aim: To evaluate the frequency of IGT and T2DM in a cohort of children and young patients with WBS. Patients and Methods: We longitudinally evaluated 27 patients (9 males and 18 females, median age at study onset 13.6 years) with WBS. The median follow-up was 3.6 years. Variables of insulin resistance and β-cell function were evaluated in all subjects using an oral glucose tolerance test. The homeostasis model assessment (HOMA) of insulin resistance and the Matsuda index of insulin sensitivity were calculated. The study of the GCK and HNF1Α genes was performed in patients with glucose metabolism abnormalities. 45 age- and sex-matched healthy subjects and 51 age-, sex- and BMI-matched subjects were recruited as two control groups. Results: Considering nutritional status, 7 (25.9%) patients were obese, 9 (33.3%) overweight, and 11 (40.8%) normal-weight. One (3.1%) patient had acanthosis nigricans. IGT was diagnosed in 7 (25.9%) WBS patients and T2DM in 3 (11.1%). Considering all WBS patients, the median value of HOMA was 5.23 (range 2.93-14.89; insulin 24.73 ± 14.67 μU/ml; glucose 104.98 ± 16.06 mg/dl). Considering BMI values, HOMA was 11.00 (range 6.53-12.56), 5.64 (range 3.54-7.95), and 4.54 (range 3.21-5.43), and insulin was 34.53 ± 6.84, 22.76 ± 8.91, and 19.47 ± 6.01 μU/ml in obese, overweight, and normal-weight WBS patients, respectively. Comparing the results with the two control groups, WBS patients showed higher insulin values than healthy controls (p < 0.001), but similar values as the BMI-matched control group (p = n.s.). However, WBS patients showed significantly higher values of glycemia (healthy control group, p < 0.001; BMI-matched control group, p < 0.05) and HOMA (healthy control group, p < 0.001; BMI-matched control group, p < 0.05) than the two control groups. Finally, among WBS patients there was a higher number of subjects with IGT and T2DM than among healthy controls (p < 0.0001) and the BMI-matched control group (p = 0.0002). Conclusion: Our data strongly suggest that IGT and T2DM may be frequently discovered in children, adolescents, and young adults with WBS. WBS should be included among the genetic syndromes associated with T2DM. Further studies are necessary to evaluate the etiopathogenesis of this aspect.

Bone mineral status and metabolism in patients with Williams-Beuren syndrome

“…The classical phenotype included typical facial features, mental retardation/developmental delay, supravalvular aortic stenosis, other congenital heart disease, inguinal hernia, and hypercalcaemia, as previously reported. 5,9 Diagnosis was confirmed by fluorescent in situ hybridisation results for elastin deletion at 7q11.23. All subjects with WBS in this study exhibited the typical 1.55 Mb microdeletion.…”

“…2 WBS is characterised by cardiovascular disease, distinctive facies and personality, mild intellectual disability, connective tissue abnormalities, growth retardation, and endocrine disorders. [3][4][5] Among the endocrine abnormalities associated with WBS, the most frequently noted are short stature, early puberty and early menarche, thyroid diseases, diabetes mellitus, 4,5 and hypercalcaemia, which has received the most attention. 1 Hypercalcaemia has been reported in 5-50% of WBS patients and is generally mild and asymptomatic or associated with nonspecific symptoms.…”

Altered body composition, lipedema, and decreased bone density in individuals with Williams syndrome: A preliminary report

“…Given these differences, it will be important for future studies to assess the lower extremities of adults with WS by DXA or other imaging to confirm that excess adipose tissue is indeed responsible for the apparent lipedema and to elucidate any characteristics of this tissue that may differentiate it from typical subcutaneous adipose tissue. Future studies should also determine if this phenotype is associated with metabolic abnormalities, in light of the relatively high prevalence of impaired glucose tolerance and type 2 diabetes mellitus seen in WS [Cherniske and others 2004; Masserini and others 2011; Stagi and others 2014]. …”

Retrospective Evaluation of Metformin and/or Metformin Plus a New Polysaccharide Complex in Treating Severe Hyperinsulinism and Insulin Resistance in Obese Children and Adolescents with Metabolic Syndrome

“…A low HOMA-IR index indicates high insulin sensitivity, whereas a high HOMA-IR index indicates low insulin sensitivity (insulin resistance). HOMA-IR > 4.4 was considered as consistent with insulin resistance [30,31]. The Matsuda index [29] also provides a measure of insulin sensitivity and is calculated using the following equation: Matsuda index = 10,000/(square-root (FPG x FPI) × (meanPG x meanPI) …”