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Current Diabetes Reports

, 18:58 | Cite as

Monogenic Diabetes in Children and Adolescents: Recognition and Treatment Options

  • May Sanyoura
  • Louis H. Philipson
  • Rochelle Naylor
Pediatric Type 2 and Monogenic Diabetes (PS Zeitler and O Pinhas-Hamiel, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Pediatric Type 2 and Monogenic Diabetes

Abstract

Purpose of Review

We provide a review of monogenic diabetes in young children and adolescents with a focus on recognition, management, and pharmacological treatment.

Recent Findings

Monogenic forms of diabetes account for approximately 1–2% of diabetes in children and adolescents, and its incidence has increased in recent years due to greater awareness and wider availability of genetic testing. Monogenic diabetes is due to single gene defects that primarily affect beta cell function with more than 30 different genes reported. Children with antibody-negative, C-peptide-positive diabetes should be evaluated and genetically tested for monogenic diabetes. Accurate genetic diagnosis impacts treatment in the most common types of monogenic diabetes, including the use of sulfonylureas in place of insulin or other glucose-lowering agents or discontinuing pharmacologic treatment altogether.

Summary

Diagnosis of monogenic diabetes can significantly improve patient care by enabling prediction of the disease course and guiding appropriate management and treatment.

Keywords

Monogenic diabetes Maturity-onset diabetes of the young Syndromic diabetes Type 1 diabetes Type 2 diabetes Genetic testing 

Notes

Compliance with Ethical Standards

Conflict of Interest

May Sanyoura, Louis H. Philipson, and Rochelle Naylor declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. 1.
    Flannick J, Johansson S, Njølstad PR. Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nat Publ Group. 2016;12(7):1–13.  https://doi.org/10.1038/nrendo.2016.50. CrossRefGoogle Scholar
  2. 2.
    Vaxillaire M, Froguel P. Monogenic forms of diabetes mellitus: an update. Endocrinol Nutr. 2009;56S4:26–9.  https://doi.org/10.1016/S1575-0922(09)73513-2.PubMedCrossRefGoogle Scholar
  3. 3.
    Alkorta-Aranburu G, Carmody D, Cheng YW, Nelakuditi V, Ma L, Dickens JT, et al. Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab. 2014;113(4):315–20.  https://doi.org/10.1016/j.ymgme.2014.09.007.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    • Hattersley AT, Patel KA. Precision diabetes: learning from monogenic diabetes. Diabetologia. 2017;60(5):1–9.  https://doi.org/10.1007/s00125-017-4226-2. Provides a review of the success of a precision medicine approach using monogenic forms of diabetes as an example. CrossRefGoogle Scholar
  5. 5.
    Kleinberger JW, Pollin TI. Personalized medicine in diabetes mellitus: current opportunities and future prospects. Ann N Y Acad Sci. 2015;1346(1):45–56.  https://doi.org/10.1111/nyas.12757.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Ehtisham S, Hattersley AT, Dunger DB, Barrett TG, Group BSfPEaDCT. First UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child. 2004;89(6):526–9.  https://doi.org/10.1136/adc.2003.027821.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Fendler W, Borowiec M, Baranowska-Jazwiecka A, Szadkowska A, Skala-Zamorowska E, Deja G, et al. Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign. Diabetologia. 2012;55(10):2631–5.  https://doi.org/10.1007/s00125-012-2621-2.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Irgens HU, Molnes J, Johansson BB, Ringdal M, Skrivarhaug T, Undlien DE, et al. Prevalence of monogenic diabetes in the population-based Norwegian Childhood Diabetes Registry. Diabetologia. 2013;56(7):1512–9.  https://doi.org/10.1007/s00125-013-2916-y.
  9. 9.
    Pihoker C, Gilliam LK, Ellard S, Dabelea D, Davis C, Dolan LM, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab. 2013;98(10):4055–62.  https://doi.org/10.1210/jc.2013-1279.
  10. 10.
    •• Shepherd M, Shields B, Hammersley S, Hudson M, McDonald TJ, Colclough K, et al. Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatric diabetes population with monogenic diabetes. Diabetes Care. 2016;39(11):1879–88.  https://doi.org/10.2337/dc16-0645. The study proposes the use of biomarkers in addition to clinical criteria as a useful approach to better identify cases of monogenic diabetes. PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kanakatti Shankar R, Pihoker C, Dolan LM, Standiford D, Badaru A, Dabelea D, et al. Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for Diabetes in Youth Study. 2013;14(3):174–80.  https://doi.org/10.1111/pedi.12003.
  12. 12.
    Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes. 1975;24(1):44–53.  https://doi.org/10.2337/diabetes.24.1.44.PubMedCrossRefGoogle Scholar
  13. 13.
    Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care. 2011;34(8):1878–84.  https://doi.org/10.2337/dc11-0035.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Bellanné-Chantelot C, Lévy DJ, Carette C, Saint-Martin C, Riveline J-P, Larger E, et al. Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene. J Clin Endocrinol Metab. 2011;96(8):E1346–51.  https://doi.org/10.1210/jc.2011-0268.PubMedCrossRefGoogle Scholar
  15. 15.
    Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010;53(12):2504–8.  https://doi.org/10.1007/s00125-010-1799-4.PubMedCrossRefGoogle Scholar
  16. 16.
    •• Kleinberger JW, Copeland KC, Gandica RG, Haymond MW, Levitsky LL, Linder B, et al. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Nat Publ Group. 2017:1–8.  https://doi.org/10.1038/gim.2017.150. This study shows that a monogenic cause should be considered in children and adolescents with atypical diabetes regardless of BMI.
  17. 17.
    Harjutsalo V, Lammi N, Karvonen M, Groop P-H. Age at onset of type 1 diabetes in parents and recurrence risk in offspring. Diabetes. 2010;59(1):210–4.  https://doi.org/10.2337/db09-0344.PubMedCrossRefGoogle Scholar
  18. 18.
    Warram JH, Krolewski AS, Gottlieb MS, Kahn CR. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med. 1984;311(3):149–52.  https://doi.org/10.1056/NEJM198407193110304.PubMedCrossRefGoogle Scholar
  19. 19.
    McDonald TJ, Shields BM, Lawry J, Owen KR, Gloyn AL, Ellard S, et al. High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes. Diabetes Care. 2011;34(8):1860–2.  https://doi.org/10.2337/dc11-0323.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Bacon S, Kyithar MP, Rizvi SR, Donnelly E, McCarthy A, Burke M, et al. Successful maintenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort. Diabet Med. 2016;33(7):976–84.  https://doi.org/10.1111/dme.12992.PubMedCrossRefGoogle Scholar
  21. 21.
    Pearson ER, Liddell WG, Shepherd M, Corrall RJ, Hattersley AT. Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes. Diabet Med. 2000;17(7):543–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Shepherd M, Pearson ER, Houghton J, Salt G, Ellard S, Hattersley AT. No deterioration in glycemic control in HNF-1alpha maturity-onset diabetes of the young following transfer from long-term insulin to sulphonylureas. Diabetes Care. 2003;26(11):3191–2.PubMedCrossRefGoogle Scholar
  23. 23.
    Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1Adiabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med. 2009;26(4):437–41.  https://doi.org/10.1111/j.1464-5491.2009.02690.x.PubMedCrossRefGoogle Scholar
  24. 24.
    Greeley SAW, John PM, Winn AN, Ornelas J, Lipton RB, Philipson LH, et al. The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes. Diabetes Care. 2011;34(3):622–7.  https://doi.org/10.2337/dc10-1616.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Naylor RN, John PM, Winn AN, Carmody D, Greeley SAW, Philipson LH, et al. Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications. Diabetes Care. 2014;37(1):202–9.  https://doi.org/10.2337/dc13-0410.PubMedCrossRefGoogle Scholar
  26. 26.
    •• Nguyen HV, Finkelstein EA, Mital S, Gardner DS-L. Incremental cost-effectiveness of algorithm-driven genetic testing versus no testing for Maturity Onset Diabetes of the Young (MODY) in Singapore. J Med Genet. 2017;54(11):747–53.  https://doi.org/10.1136/jmedgenet-2017-104670. This study provides another important example of the cost-effectiveness of genetic testing for MODY. PubMedCrossRefGoogle Scholar
  27. 27.
    Schnyder S, Mullis PE, Ellard S, Hattersley AT, Flück CE. Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment. Swiss Med Wkly. 2005;135(23–24):352–6.PubMedGoogle Scholar
  28. 28.
    Kleinberger JW, Pollin TI. Undiagnosed MODY: Time for action. Current Diabetes Reports. 2015;15(12):458–11.  https://doi.org/10.1007/s11892-015-0681-7. CrossRefGoogle Scholar
  29. 29.
    Naylor R, Philipson LH. Who should have genetic testing for maturity-onset diabetes of the young? Clin Endocrinol. 2011;75(4):422–6.  https://doi.org/10.1111/j.1365-2265.2011.04049.x.CrossRefGoogle Scholar
  30. 30.
    Shepherd M, Sparkes AC, Hattersley AT. Genetic testing in maturity onset diabetes of the young (MODY): a new challenge for the diabetic clinic. Practical Diabetes International. Pract Diabetes Int 2001;18(1):16–21.  https://doi.org/10.1002/pdi.108.
  31. 31.
    Carroll R, Murphy R. Monogenic diabetes: a diagnostic algorithm for clinicians. Genes (Basel). 2013;4(4):522–35.  https://doi.org/10.3390/genes4040522.CrossRefGoogle Scholar
  32. 32.
    Vaxillaire M, Froguel P. Monogenic diabetes: implementation of translational genomic research towards precision medicine. Journal of Diabetes. 2016;8(6):782–95.  https://doi.org/10.1111/1753-0407.12446.PubMedCrossRefGoogle Scholar
  33. 33.
    McDonald TJ, Ellard S. Maturity onset diabetes of the young: identification and diagnosis. Ann Clin Biochem. 2013;50(Pt 5):403–15.  https://doi.org/10.1177/0004563213483458. PubMedCrossRefGoogle Scholar
  34. 34.
    Matschinsky FM. Regulation of pancreatic β-cell glucokinase: from basics to therapeutics. Diabetes. 2002;51(suppl 3):S394–404.  https://doi.org/10.2337/diabetes.51.2007.S394.PubMedCrossRefGoogle Scholar
  35. 35.
    Stride A, Vaxillaire M, Tuomi T, Barbetti F, Njølstad PR, Hansen T, et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia. 2002;45(3):427–35.  https://doi.org/10.1007/s00125-001-0770-9.PubMedCrossRefGoogle Scholar
  36. 36.
    Steele AM, Wensley KJ, Ellard S, Murphy R, Shepherd M, Colclough K, et al. Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies. PLoS One. 2013;8(6):e65326.  https://doi.org/10.1371/journal.pone.0065326.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Spégel P, Ekholm E, Tuomi T, Groop L, Mulder H, Filipsson K. Metabolite profiling reveals normal metabolic control in carriers of mutations in the glucokinase gene (MODY2). Diabetes. 2013;62(2):653–61.  https://doi.org/10.2337/db12-0827.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA. 2014;311(3):279–86.  https://doi.org/10.1001/jama.2013.283980.PubMedCrossRefGoogle Scholar
  39. 39.
    Chakera AJ, Steele AM, Gloyn AL, Shepherd MH, Shields B, Ellard S, et al. Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care. 2015;38(7):1383–92.  https://doi.org/10.2337/dc14-2769.PubMedCrossRefGoogle Scholar
  40. 40.
    Dickens LT, Naylor RN. Clinical management of women with monogenic diabetes during pregnancy. Curr Diab Rep. 2018;18(3):12.  https://doi.org/10.1007/s11892-018-0982-8.PubMedCrossRefGoogle Scholar
  41. 41.
    Stride A, Shields B, Gill-Carey O, Chakera AJ, Colclough K, Ellard S, et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57(1):54–6.  https://doi.org/10.1007/s00125-013-3075-x.PubMedCrossRefGoogle Scholar
  42. 42.
    Carmody D, Naylor RN, Bell CD, Berry S, Montgomery JT, Tadie EC, et al. GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated. Acta Diabetol. 2016;53(5):703–8.  https://doi.org/10.1007/s00592-016-0859-8.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB. Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta -cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem. 2000;275(46):35953–9.  https://doi.org/10.1074/jbc.M006612200.PubMedCrossRefGoogle Scholar
  44. 44.
    Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A. 1997;94(24):13209–14.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Colclough K, Bellanné-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat. 2013;34(5):669–85.  https://doi.org/10.1002/humu.22279.PubMedCrossRefGoogle Scholar
  46. 46.
    Pontoglio M, Prié D, Cheret C, Doyen A, Leroy C, Froguel P, et al. HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep. 2000;1(4):359–65.  https://doi.org/10.1093/embo-reports/kvd071.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Bellanné-Chantelot C, Carette C, Riveline J-P, Valéro R, Gautier J-F, Larger E, et al. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes. 2008;57(2):503–8.  https://doi.org/10.2337/db07-0859.PubMedCrossRefGoogle Scholar
  48. 48.
    Shih DQ, Bussen M, Sehayek E, Ananthanarayanan M, Shneider BL, Suchy FJ, et al. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet. 2001;27(4):375–82.  https://doi.org/10.1038/86871.PubMedCrossRefGoogle Scholar
  49. 49.
    Steele AM, Shields BM, Shepherd M, Ellard S, Hattersley AT, Pearson ER. Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene. Diabet Med. 2010;27(2):157–61.  https://doi.org/10.1111/j.1464-5491.2009.02913.x.PubMedCrossRefGoogle Scholar
  50. 50.
    Thanabalasingham G, Shah N, Vaxillaire M, Hansen T, Tuomi T, Gašperíková D, et al. A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia. 2011;54(11):2801–10.  https://doi.org/10.1007/s00125-011-2261-y.PubMedCrossRefGoogle Scholar
  51. 51.
    Jeannot E, Mellottee L, Bioulac-Sage P, Balabaud C, Scoazec J-Y, Tran Van Nhieu J, et al. Spectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage. Diabetes. 2010;59(7):1836–44.  https://doi.org/10.2337/db09-1819.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, et al. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families. J Clin Endocrinol Metab. 2004;89(3):1476–80.  https://doi.org/10.1210/jc.2003-031552.PubMedCrossRefGoogle Scholar
  53. 53.
    Tuomi T, Honkanen EH, Isomaa B, Sarelin L, Groop LC. Improved prandial glucose control with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with maturity-onset diabetes of the young type 3. Diabetes Care. 2006;29(2):189–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Becker M, Galler A, Raile K. Meglitinide analogues in adolescent patients with HNF1A-MODY (MODY 3). Pediatrics. 2014;133(3):e775–9.  https://doi.org/10.1542/peds.2012-2537.PubMedCrossRefGoogle Scholar
  55. 55.
    Ostoft SH, Bagger JI, Hansen T, Pedersen O, Faber J, Holst JJ, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37(7):1797–805.  https://doi.org/10.2337/dc13-3007. PubMedCrossRefGoogle Scholar
  56. 56.
    Hohendorff J, Szopa M, Skupien J, Kapusta M, Zapala B, Platek T, et al. A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus. Endocrine. 2017;57(2):272–9.  https://doi.org/10.1007/s12020-017-1341-2.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Carette C, Dubois-Laforgue D, Saint-Martin C, Clauin S, Beaufils S, Larger E, et al. Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies. Diabet Med. 2010;27(12):1454–8.  https://doi.org/10.1111/j.1464-5491.2010.03115.x.
  58. 58.
    Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384(6608):458–60.  https://doi.org/10.1038/384458a0.PubMedCrossRefGoogle Scholar
  59. 59.
    Dusátková P, Pruhova S, Sumnik Z, Kolousková S, Obermannova B, Cinek O, et al. HNF1A mutation presenting with fetal macrosomia and hypoglycemia in childhood prior to onset of overt diabetes. J Pediatr Endocrinol Metab. 2011;24(5–6):377–9.PubMedGoogle Scholar
  60. 60.
    Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118.  https://doi.org/10.1371/journal.pmed.0040118.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HAJ, Lumb PJ, et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection. Diabetologia. 2005;48(5):878–85.  https://doi.org/10.1007/s00125-005-1738-y.PubMedCrossRefGoogle Scholar
  62. 62.
    Bellanne-Chantelot C, Clauin S, Chauveau D, Collin P, Daumont M, Douillard C, et al. Large genomic rearrangements in the hepatocyte nuclear factor-1 (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes. 2005;54(11):3126–32.  https://doi.org/10.2337/diabetes.54.11.3126.PubMedCrossRefGoogle Scholar
  63. 63.
    Chambers C, Fouts A, Dong F, Colclough K, Wang Z, Batish SD, et al. Characteristics of maturity onset diabetes of the young in a large diabetes center. 2015;17(5):360–7.  https://doi.org/10.1111/pedi.12289.
  64. 64.
    Pearson ER, Badman MK, Lockwood CR, Clark PM, Ellard S, Bingham C, et al. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1a and -1b mutations. Diabetes Care. 2004;27(5):1102–7.  https://doi.org/10.2337/diacare.27.5.1102.PubMedCrossRefGoogle Scholar
  65. 65.
    Bellanné-Chantelot C, Chauveau D, Gautier J-F, Dubois-Laforgue D, Clauin S, Beaufils S, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140(7):510–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum. Nat Publ Group. 2014;11(2):102–12.  https://doi.org/10.1038/nrneph.2014.232.CrossRefGoogle Scholar
  67. 67.
    Weber S, Moriniere V, Knuppel T, Charbit M, Dusek J, Ghiggeri GM, et al. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol. 2006;17(10):2864–70.  https://doi.org/10.1681/ASN.2006030277.PubMedCrossRefGoogle Scholar
  68. 68.
    Heidet L, Decramer S, Pawtowski A, Moriniere V, Bandin F, Knebelmann B, et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol. 2010;5(6):1079–90.  https://doi.org/10.2215/CJN.06810909. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Bingham C, Hattersley AT. Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant. 2004;19(11):2703–8.  https://doi.org/10.1093/ndt/gfh348. PubMedCrossRefGoogle Scholar
  70. 70.
    Edghill EL, Bingham C, Ellard S, Hattersley AT. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet. 2006;43(1):84–90.  https://doi.org/10.1136/jmg.2005.032854. PubMedCrossRefGoogle Scholar
  71. 71.
    Yu DD, Guo SW, Jing YY, Dong YL, Wei LX. A review on hepatocyte nuclear factor-1beta and tumor. Cell Biosci. 2015;5:58.  https://doi.org/10.1186/s13578-015-0049-3.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Sun M, Tong P, Kong W, Dong B, Huang Y, Park IY, et al. HNF1B loss exacerbates the development of chromophobe renal cell carcinomas. Cancer Res. 2017;77(19):5313–26.  https://doi.org/10.1158/0008-5472.CAN-17-0986.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Wang CC, Mao TL, Yang WC, Jeng YM. Underexpression of hepatocyte nuclear factor-1beta in chromophobe renal cell carcinoma. Histopathology. 2013;62(4):589–94.  https://doi.org/10.1111/his.12026.PubMedCrossRefGoogle Scholar
  74. 74.
    Ferre S, Bongers EM, Sonneveld R, Cornelissen EA, van der Vlag J, van Boekel GA, et al. Early development of hyperparathyroidism due to loss of PTH transcriptional repression in patients with HNF1beta mutations? J Clin Endocrinol Metab. 2013;98(10):4089–96.  https://doi.org/10.1210/jc.2012-3453.PubMedCrossRefGoogle Scholar
  75. 75.
    Loirat C, Bellanne-Chantelot C, Husson I, Deschenes G, Guigonis V, Chabane N. Autism in three patients with cystic or hyperechogenic kidneys and chromosome 17q12 deletion. Nephrol Dial Transplant. 2010;25(10):3430–3.  https://doi.org/10.1093/ndt/gfq380.PubMedCrossRefGoogle Scholar
  76. 76.
    Raile K, Klopocki E, Holder M, Wessel T, Galler A, Deiss D, et al. Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young. J Clin Endocrinol Metab. 2009;94(7):2658–64.  https://doi.org/10.1210/jc.2008-2189.PubMedCrossRefGoogle Scholar
  77. 77.
    Clissold RL, Shaw-Smith C, Turnpenny P, Bunce B, Bockenhauer D, Kerecuk L, et al. Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder. Kidney Int. 2016;90(1):203–11.  https://doi.org/10.1016/j.kint.2016.03.027.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Brissova M, Shiota M, Nicholson WE, Gannon M, Knobel SM, Piston DW, et al. Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J Biol Chem. 2002;277(13):11225–32.  https://doi.org/10.1074/jbc.M111272200.PubMedCrossRefGoogle Scholar
  79. 79.
    Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 1993;12(11):4251–9.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Fajans SS, Bell GI, Paz VP, Below JE, Cox NJ, Martin C, et al. Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. Transl Res. 2010;156(1):7–14.  https://doi.org/10.1016/j.trsl.2010.03.003.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Hansen L. Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in Caucasians. J Clin Endocrinol Metab. 2000;85(3):1323–6.  https://doi.org/10.1210/jc.85.3.1323. PubMedCrossRefGoogle Scholar
  82. 82.
    Flanagan SE, Patch AM, Mackay DJG, Edghill EL, Gloyn AL, Robinson D, et al. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007;56(7):1930–7.  https://doi.org/10.2337/db07-0043.PubMedCrossRefGoogle Scholar
  83. 83.
    Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. 2009;350(18):1838–49.  https://doi.org/10.1056/NEJMoa032922.
  84. 84.
    Kapoor RR, Flanagan SE, James CT, McKiernan J, Thomas AM, Harmer SC, et al. Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations. Diabetologia. 2011;54(10):2575–83.  https://doi.org/10.1007/s00125-011-2207-4.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Bonnefond A, Philippe J, Durand E, Dechaume A, Huyvaert M, Montagne L, et al. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One. 2012;7(6):e37423–8.  https://doi.org/10.1371/journal.pone.0037423.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Bowman P, Flanagan SE, Edghill EL, Damhuis A, Shepherd MH, Paisey R, et al. Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia. 2011;55(1):123–7.  https://doi.org/10.1007/s00125-011-2319-x.PubMedCrossRefGoogle Scholar
  87. 87.
    Ovsyannikova AK, Rymar OD, Shakhtshneider EV, Klimontov VV, Koroleva EA, Myakina NE, et al. ABCC8-related maturity-onset diabetes of the young (MODY12): clinical features and treatment perspective. Diabetes Ther. 2016;7(3):591–600.  https://doi.org/10.1007/s13300-016-0192-9.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Molven A, Ringdal M, Nordbø AM, Ræder H, Støy J, Lipkind GM, et al. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes. 2008;57(4):1131–5.  https://doi.org/10.2337/db07-1467.PubMedCrossRefGoogle Scholar
  89. 89.
    Boesgaard TW, Pruhova S, Andersson EA, Cinek O, Obermannova B, Lauenborg J, et al. Further evidence that mutations in INS can be a rare cause of maturity-onset diabetes of the young (MODY). BMC Med Genet. 2010;11(1):42.  https://doi.org/10.1186/1471-2350-11-42. PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Edghill EL, Flanagan SE, Patch A-M, Boustred C, Parrish A, Shields B, et al. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008;57(4):1034–42.  https://doi.org/10.2337/db07-1405.PubMedCrossRefGoogle Scholar
  91. 91.
    Meur G, Simon A, Harun N, Virally M, Dechaume A, Bonnefond A, et al. Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes. 2010;59(3):653–61.  https://doi.org/10.2337/db09-1091.PubMedCrossRefGoogle Scholar
  92. 92.
    Barrett TG. Differential diagnosis of type 1 diabetes: which genetic syndromes need to be considered? Pediatr Diabetes. 2007;8(Suppl 6):15–23.  https://doi.org/10.1111/j.1399-5448.2007.00278.x.PubMedCrossRefGoogle Scholar
  93. 93.
    Y-i G, Nonaka I, Horai S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348(6302):651–3.  https://doi.org/10.1038/348651a0.CrossRefGoogle Scholar
  94. 94.
    Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med. 2008;25(4):383–99.  https://doi.org/10.1111/j.1464-5491.2008.02359.x.PubMedCrossRefGoogle Scholar
  95. 95.
    Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12(4):537–77.  https://doi.org/10.1089/ars.2009.2531.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Supale S, Li N, Brun T, Maechler P. Mitochondrial dysfunction in pancreatic β cells. Trends Endocrinol Metab. 2012;23(9):477–87.  https://doi.org/10.1016/j.tem.2012.06.002. PubMedCrossRefGoogle Scholar
  97. 97.
    Maassen JA, Janssen GMC, Hart LM. Molecular mechanisms of mitochondrial diabetes (MIDD). Ann Med. 2009;37(3):213–21.  https://doi.org/10.1080/07853890510007188.CrossRefGoogle Scholar
  98. 98.
    Guillausseau PJ, Massin P, Dubois-Laforgue D, Timsit J, Virally M, Gin H, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med. 2001;134(9 Pt 1):721–8.PubMedCrossRefGoogle Scholar
  99. 99.
    Maassen JA, ‘T Hart LM, Van Essen E, Heine RJ, Nijpels G, Jahangir Tafrechi RS, et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes. 2004;53(Suppl 1):S103–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Suzuki Y, Kobayashi T, Taniyama M, Astumi Y, Oka Y, Kadowaki T, et al. Islet cell antibody in mitochondrial diabetes. Diabetes Res Clin Pract. 1997;35(2–3):163–5.  https://doi.org/10.1016/S0168-8227(97)01378-8.
  101. 101.
    Suzuki Y, Taniyama M, Shimada A, Atumi Y, Matsuoka K, Oka Y. GAD antibody in mitochondrial diabetes associated with tRNA(UUR) mutation at position 3271. Diabetes Care. 2002;25(6):1097–8.  https://doi.org/10.2337/diacare.25.6.1097.PubMedCrossRefGoogle Scholar
  102. 102.
    van ven Ouweland JMW, Cryns K, Pennings RJE, Walraven I, Janssen GMC, Maassen JA, et al. Molecular characterization of WFS1 in patients with Wolfram syndrome. The Journal of Molecular Diagnostics : JMD. 2003;5(2):88–95.CrossRefGoogle Scholar
  103. 103.
    Urano F. Wolfram syndrome iPS cells: the first human cell model of endoplasmic reticulum disease. Diabetes. 2014;63(3):844–6.  https://doi.org/10.2337/db13-1809.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Bonnycastle LL, Chines PS, Hara T, Huyghe JR, Swift AJ, Heikinheimo P, et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes. 2013;62(11):3943–50.  https://doi.org/10.2337/db13-0571.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Minton JAL, Rainbow LA, Ricketts C, Barrett TG. Wolfram syndrome. Rev Endocr Metab Disord. 2003;4(1):53–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Cano A, Rouzier C, Monnot S, Chabrol B, Conrath J, Lecomte P, et al. Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome. Am J Med Genet A. 2007;143A(14):1605–12.  https://doi.org/10.1002/ajmg.a.31809.PubMedCrossRefGoogle Scholar
  107. 107.
    Zmyslowska A, Borowiec M, Fichna P, Iwaniszewska B, Majkowska L, Pietrzak I, et al. Delayed recognition of Wolfram syndrome frequently misdiagnosed as type 1 diabetes with early chronic complications. Exp Clin Endocrinol Diabetes. 2014;122(1):35–8.  https://doi.org/10.1055/s-0033-1357160.PubMedCrossRefGoogle Scholar
  108. 108.
    Zmyslowska A, Fendler W, Szadkowska A, Borowiec M, Mysliwiec M, Baranowska-Jazwiecka A, et al. Glycemic variability in patients with Wolfram syndrome is lower than in type 1 diabetes. Acta Diabetol. 2015;52(6):1057–62.  https://doi.org/10.1007/s00592-015-0757-5.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Satman I, Yilmaz MT, Gürsoy N, Karşidağ K, Dinççağ N, Ovali T, et al. Evaluation of insulin resistant diabetes mellitus in Alström syndrome: a long-term prospective follow-up of three siblings. Diabetes Res Clin Pract. 2002;56(3):189–96.PubMedCrossRefGoogle Scholar
  110. 110.
    Marshall JD, Maffei P, Beck S, Barrett TG, Paisey R, Naggert JK. Clinical utility gene card for: Alström syndrome—update 2013. Eur J Hum Genet. 2013;21(11):3–4.  https://doi.org/10.1038/ejhg.2013.61.CrossRefGoogle Scholar
  111. 111.
    Marshall JD, Muller J, Collin GB, Milan G, Kingsmore SF, Dinwiddie D, et al. Alström syndrome: mutation spectrum of ALMS1. Hum Mutat. 2015;36(7):660–8.  https://doi.org/10.1002/humu.22796.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • May Sanyoura
    • 1
  • Louis H. Philipson
    • 1
  • Rochelle Naylor
    • 1
  1. 1.Section of Adult and Pediatric Endocrinology, Diabetes, and MetabolismThe University of ChicagoChicagoUSA

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