Diabetes Mellitus in Children and Adolescents with Genetic Syndromes

Abstract

Background:

Several genetic syndromes are associated with diabetes mellitus (DM). This study aimed to analyse data from the DPV database with regard to frequency, treatment strategies and long-term complications in paediatric DM patients with genetic syndromes, including Turner syndrome (TS), Prader-Willi syndrome (PWS), Friedreich ataxia (FA), Alström syndrome (AS), Klinefelter syndrome (KS), Bardet-Biedl syndrome (BBS), Berardinelli-Seip syndrome (BSS) and Down syndrome (DS).

Methods:

Longitudinal data for 43 521 patients with DM onset at age <20 years were collected from 309 treatment centres in Germany and Austria using the DPV software. Data included anthropometric parameters, type of diabetes, mean age, age at diabetes onset, daily insulin dose, HbA_1c, micro- and macroalbuminuria, retinopathy and dyslipidaemia. Descriptive statistics and standard statistical tests were used for data analysis.

Results:

In total, 205 DM patients had one of the following syndromes: DS (141 patients), TS (24), PWS (23), FA (5), AS (5), KS (4), BBS (2) and BSS (1). Diabetes-specific antibodies were positive in the majority of patients with DS, TS and FA.

Conclusion:

Despite the well-known association between DM and certain syndromic disorders, the number of affected patients in the German and Austrian paediatric diabetic population is very low. Nevertheless, physicians should be aware of syndromic forms of diabetes. Joint multicentre analyses are needed to draw relevant conclusions.

Key words

Turner syndrome - Prader-Willi syndrome - Friedreich ataxia - Alström syndrome - Klinefelter syndrome - Pediatric diabetology

*

^*  These authors contributed equally as senior authors.

• References

• 1 Rohrer TR, Hennes P, Thon A et al. DPV Initiative. Down’s syndrome in diabetic patients aged <20 years: an analysis of metabolic status, glycaemic control and autoimmunity in comparison with type 1 diabetes. Diabetologia 2010; 53: 1070-1075
• 2 Gravholt CH, Juul S, Naeraa RW et al. Morbidity in Turner syndrome. J Clin Epidemiol 1998; 51: 147-158
• 3 Hjerrild BE, Holst JJ, Juhl CB et al. Delayed β-cell response and glucose intolerance in young women with Turner syndrome. BMC Endocr Disord 2011; 11: 6
• 4 Butler JV, Whittington JE, Holland AJ et al. Prevalence of, and risk factors for, physical ill-health in people with Prader-Willi syndrome: a population-based study. Dev Med Child Neurol 2002; 44: 248-255
• 5 Brambilla P, Crinò A, Bedogni G et al. Genetic Obesity Study Group of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) . Metabolic syndrome in children with Prader-Willi syndrome: the effect of obesity. Nutr Metab Cardiovasc Dis 2011; 21: 269-276
• 6 Schulz JB, Boesch S, Bürk K et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol 2009; 5: 222-234
• 7 Wais S, Salvati E. Klinefelter’s syndrome and diabetes mellitus. Lancet 1966; 2: 747-748
• 8 Ota K, Suehiro T, Ikeda Y et al. Diabetes mellitus associated with Klinefelter’s syndrome: a case report and review in Japan. Intern Med 2002; 41: 842-847
• 9 Waters AM, Beales PL. Bardet-Biedl Syndrome. In: Pagon RA, Bird TC, Dolan CR, Stephens K. (eds.). GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2003 Jul 14 [updated 2010 Nov 18]
• 10 Marshall JD, Hinman EG, Collin GB et al. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Hum Mutat 2007; 28: 1114-1123
• 11 Beltrand J, Beregszaszi M, Chevenne D et al. Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy. Pediatrics 2007; 120: 291-296
• 12 Bergholdt R, Eising S, Nerup J et al. Increased prevalence of Down’s syndrome in individuals with type 1 diabetes in Denmark: a nationwide population-based study. Diabetologia 2006; 49: 1179-1182
• 13 Forbes AB, Engel E. The high incidence of diabetes mellitus in 41 patients with gonadal dysgenesis, and their close relatives. Metabolism 1963; 12: 428-439
• 14 Gravholt CH. Epidemiological, endocrine and metabolic features in Turner syndrome. Eur J Endocrinol 2004; 151: 657-687
• 15 World Health Organization . Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. World Health Organization; 1999
• 16 Burch PR. Klinefelter’s syndrome, dizygotic twinning and diabetes mellitus. Nature 1969; 221: 175-177
• 17 Horsthemke B, Wagstaff J. Mechanisms of imprinting of the Prader-Willi/Angelman region. Am J Med Genet A 2008; 146: 2041-2052
• 18 Haqq AM, Farooqi IS, O’Rahilly S et al. Serum Ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome. J Clin Endocrinol Metab 2003; 88: 174-178
• 19 Erdie-Lalena CR, Holm VA, Kelly PC et al. Ghrelin levels in young children with Prader-Willi syndrome. J Pediatr 2006; 149: 199-204
• 20 Al-Mahdawi S, Pinto RM, Varshney D et al. GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology. Genomics 2006; 88: 580-590
• 21 Marshall JD, Beck S, Maffei P et al. Alström syndrome. Eur J Hum Genet 2007; 15: 1193-1201
• 22 Berardinelli W. An undiagnosed endocrinometabolic syndrome: report of two cases. J Clin Endocrinol Metab 1954; 14: 193-204
• 23 Seip M. Lipodystrophy and gigantism with associated endocrine manifestation: a new diencephalic syndrome?. Acta Paediatr 1959; 48: 555-574
• 24 Garg A. Acquired and inherited lipodystrophies. New Engl J Med 2004; 350: 1220-1234
• 25 Oral EA, Simha V, Ruiz E et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346: 570-578
• 26 Grabert M, Schweiggert F, Holl RW. A framework for diabetes documentation and quality management in Germany: 10 years of experience with DPV. Comput Methods Programs Biomed 2002; 69: 115-121
• 27 Bingley PJ, Bonifacio E, Mueller PW. Diabetes Antibody Standardization Program: first assay proficiency evaluation. Diabetes 2003; 52: 1128-1136
• 28 Warncke K, Fröhlich-Reiterer EE, Thon A et al. DPV Initiative of the German Working Group for Pediatric Diabetology, German BMBF Competence Network for Diabetes Mellitus . Polyendocrinopathy in children, adolescents, and young adults with type 1 diabetes: a multicenter analysis of 28 671 patients from the German/Austrian DPV-Wiss database. Diabetes Care 2010; 33: 2010-2012
• 29 Schwab KO, Doerfer J, Marg W et al. DPV Science Initiative and the Competence Network Diabetes mellitus . Characterization of 33 488 children and adolescents with type 1 diabetes based on the gender-specific increase of cardiovascular risk factors. Pediatr Diabetes 2010; 11: 357-363
• 30 Lurbe E, Cifkova R, Cruickshank JK et al. European Society of Hypertension . Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens 2009; 27: 1719-1742
• 31 The Diabetes Control and Complications Trial Research Group . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-986
• 32 Gerstl EM, Rabl W, Rosenbauer J et al. Metabolic control as reflected by HbA1c in children, adolescents and young adults with type-1-diabetes mellitus: combined longitudinal analysis including 27 035 patients from 207 centers in Germany and Austria during the last decade. Eur J Pediatr 2008; 167: 447-453
• 33 Cole TJ, Bellizzi MC, Flegal KM et al. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 2000; 320: 1240-1243
• 34 Kromeyer-Hauschild K, Wabisch M, Kunze D et al. Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschr Kinderheilkd 2001; 149: 807-818
• 35 Jørgensen KT, Rostgaard K, Bache I et al. Autoimmune diseases in women with Turner’s syndrome. Arthritis Rheum 2010; 62: 658-666
• 36 Bakalov VK, Cheng C, Zhou J et al. X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J Clin Endocrinol Metab 2009; 94: 3289-3296
• 37 Diene G, Mimoun E, Feigerlova E et al. French Reference Centre for PWS. Endocrine disorders in children with Prader-Willi syndrome – data from 142 children of the French database. Horm Res Paediatr 2010; 74: 121-128
• 38 Bojesen A, Juul S, Birkebaek NH et al. Morbidity in Klinefelter Syndrome: A Danish Register Study Based on Hospital Discharge Diagnoses. J Clin Endocrinol Metab 2006; 91: 1254-1260
• 39 Bassali R, Hoffmann WH, Chen H et al. Hyperlipidemia, insulin-dependent diabetes mellitus, and rapidly progressive diabetic retinopathy and nephropathy in Prader-Willi Syndrome with Del (15) (q11.2q13). Am J Med Genetic 1997; 71: 267-270
• 40 Reinehr T, Schober E, Wiegand S et al. B-cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification?. Arch Dis Child 2006; 91: 473-477
• 41 Dabelea D, Pihoker C, Talton JW et al. SEARCH for Diabetes in Youth Study . Etiological approach to characterization of diabetes type. Diabetes Care 2011; 34: 1628-1633
• 42 Mortensen KH, Cleemann L, Hjerried BE et al. Increased prevalence of autoimmunity in Turner syndrome – influence of age. Clin Exp Immunol 2009; 156: 205-210
• 43 Chang P, Tsai WY, Hou JW et al. Autoimmune thyroiditis in children with Turner syndrome. J Formos Med Assoc 2000; 99: 823-886
• 44 Gillett PM, Gillett HR, Israel DM et al. Increased prevalence of celiac disease in girls with Turner syndrome detected using antibodies to endomysium and tissue transglutaminase. Can J Gastroenterol 2000; 14: 915-918
• 45 Wooten N, Bakalov VK, Hill S et al. Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome. J Clin Endocrinol Metab 2008; 93: 2109-2114