title: 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.
  
  
  OBJECTIVE
  To evaluate the frequency of IGT and T2DM in a cohort of children and young patients with WBS.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Health Sciences, University of Florence, Chieti, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Stagi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lapi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cecchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiarelli
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: D'Avanzo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Seminara
authors.forename: Maurizio
authors.initials: M
authors.lastname: de Martino
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D000081410:Germinal Center Kinases; D005951:Glucose Tolerance Test; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D018980:Williams Syndrome / Q000097:blood / Q000150:complications / Q000235:genetics
chemical_list: D000081410:Germinal Center Kinases; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D017346:Protein Serine-Threonine Kinases