It has become increasingly apparent over the last few years that the seemingly ubiquitous auto-immune aetiology to pre-pubertal diabetes does not apply to those diagnosed under 6 months of age. In this age group, disease appears, in the vast majority of cases, to be conferred by single gene disorders mainly related to pancreatic development. The unravelling of these disorders has resulted in a far greater understanding of pancreatic development and some startling changes in treatment, resulting in improved quality of life and diabetes control. The progress made in our scientific and clinical understanding of these extremely rare diseases is a perfect example of how studying seemingly rare illnesses can improve our overall knowledge of much more common conditions.

1.
Kitselle: Jb Kinderheilk 1852;18.
2.
Iafusco D, Stazi MA, Cotichini R, et al: Permanent diabetes mellitus in the first year of life. Diabetologia 2002;45:798–804.
3.
Shield JP, Gardner RJ, Wadsworth EJ, et al: Aetiopathology and genetic basis of neonatal diabetes. Arch Dis Child Fetal Neonatal Ed 1997;76:F39–F42.
4.
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF: Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106–110.
5.
Stoffers DA, Stanojevic V, Habener JF: Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. J Clin Invest 1998;102:232–241.
6.
Hani EH, Stoffers DA, Chevre JC, et al: Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest 1999;104:R41–R48.
7.
Schwitzgebel VM, Mamin A, Brun T, et al: Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab 2003;88:4398–4406.
8.
Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP: Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes 2000;49:1359–1366.
9.
Slingerland AS, Hattersley AT: Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment. Ann Med 2005;37:186–195.
10.
Temple IK, James RS, Crolla JA, et al: An imprinted gene(s) for diabetes? Nat Genet 1995;9:110–112.
11.
Temple IK, Gardner RJ, Robinson DO, et al: Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23. Hum Mol Genet 1996;5:1117–1121.
12.
Cave H, Polak M, Drunat S, Denamur E, Czernichow P: Refinement of the 6q chromosomal region implicated in transient neonatal diabetes. Diabetes 2000;49:108–113.
13.
Gardner RJ, Mackay DJ, Mungall AJ, et al: An imprinted locus associated with transient neonatal diabetes mellitus. Hum Mol Genet 2000;9:589–596.
14.
Ma D, Shield JP, Dean W, et al: Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM. J Clin Invest 2004;114:339–348.
15.
Polychronakos C, Xiaoyu D: Graded Overexpression of ZAC Impairs Glucose Stimulated Insulin Secretion in Beta-Cells. Washington, American Diabetes Association, 2006, 190-OR.
16.
Valerio G, Franzese A, Salerno M, et al: Beta-cell dysfunction in classic transient neonatal diabetes is characterized by impaired insulin response to glucose but normal response to glucagon. Diabetes Care 2004;27:2405–2408.
17.
Senee V, Vattem KM, Delepine M, et al: Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 2004;53:1876–1883.
18.
Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C: EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000;25:406–409.
19.
Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D: Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 2000;5:897–904.
20.
Harding HP, Zeng H, Zhang Y, et al: Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 2001;7:1153–1163.
21.
Brunkow ME, Jeffery EW, Hjerrild KA, et al: Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001;27:68–73.
22.
Wildin RS, Ramsdell F, Peake J, et al: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001;27:18–20.
23.
Wildin RS, Smyk-Pearson S, Filipovich AH: Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2002;39:537–545.
24.
Ruemmele FM, Brousse N, Goulet O: Autoimmune enteropathy: molecular concepts. Curr Opin Gastroenterol 2004;20:587–591.
25.
Baud O, Goulet O, Canioni D, et al: Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N Engl J Med 2001;344:1758–1762.
26.
Mazzolari E, Forino C, Fontana M, et al: A new case of IPEX receiving bone marrow transplantation. Bone Marrow Transplant 2005;35:1033–1034.
27.
Njolstad PR, Sovik O, Cuesta-Munoz A, et al: Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001;344:1588–1592.
28.
Njolstad PR, Sagen JV, Bjorkhaug L, et al: Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 2003;52:2854–2860.
29.
Porter JR, Shaw NJ, Barrett TG, Hattersley AT, Ellard S, Gloyn AL: Permanent neonatal diabetes in an Asian infant. J Pediatr 2005;146:131–133.
30.
Gloyn AL, Ellard S, Shield JP, et al: Complete glucokinase deficiency is not a common cause of permanent neonatal diabetes. Diabetologia 2002;45:290.
31.
Gloyn AL, Pearson ER, Antcliff JF, et al: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004;350:1838–1849.
32.
Gloyn AL, Reimann F, Girard C, et al: Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 2005;14:925–934.
33.
Hattersley AT, Ashcroft FM: Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 2005;54:2503–2513.
34.
Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM: Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA 2004;101:17539–17544.
35.
Sagen JV, Raeder H, Hathout E, et al: Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2:patient characteristics and initial response to sulfonylurea therapy. Diabetes 2004;53:2713–2718.
36.
Klupa T, Edghill EL, Nazim J, et al: The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of beta cell function among carriers of the R201H mutation. Diabetologia 2005;48:1029–1031.
37.
Pearson EFI, Njolstad P, Malecki M, Flanagan S, Larkin B, Ashcroft F, Klimes I, Codner E, Iotova V, Slingerland A, Shield J, Robert J-J, Holst J, Clark P, Ellard S, Sovik O, Polak M, Hattersley A: Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. New Engl J Med 2006;355:467–477.
38.
Hoveyda N, Shield JP, Garrett C, et al: Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet 1999;36:700–704.
39.
Sellick GS, Barker KT, Stolte-Dijkstra I, et al: Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2004;36:1301–1305.
40.
Yorifuji T, Kurokawa K, Mamada M, et al: Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism. J Clin Endocrinol Metab 2004;89:2905–2908.
41.
Mitchell J, Punthakee Z, Lo B, et al: Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome. Diabetologia 2004;47:2160–2167.
42.
Verwest AM, Poelman M, Dinjens WN, et al: Absence of a PDX-1 mutation and normal gastroduodenal immunohistology in a child with pancreatic agenesis. Virchows Arch 2000;437:680–684.
43.
Ashraf A, Abdullatif H, Hardin W, Moates JM: Unusual case of neonatal diabetes mellitus due to congenital pancreas agenesis. Pediatr Diabetes 2005;6:239–243.
44.
Senee V, Chelala C, Duchatelet S, et al: Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006;38:682–687.
45.
Jeha GS, Venkatesh MP, Edelen RC, Kienstra KA, Karaviti L, Fernandes CJ: Neonatal diabetes mellitus: patient reports and review of current knowledge and clinical practice. J Pediatr Endocrinol Metab 2005;18:1095–1102.
46.
Polak M, Shield J: Neonatal and very-early-onset diabetes mellitus. Semin Neonatol 2004;9:59–65.
47.
Fosel S: Transient and permanent neonatal diabetes. Eur J Pediatr 1995;154:944–948.
48.
Sperling MA: Neonatal diabetes mellitus: from understudy to center stage. Curr Opin Pediatr 2005;17:512–518.
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