Syndromic Causes of Congenital Hyperinsulinism

  • Jennifer M. KalishEmail author
  • Jean-Baptiste Arnoux
Part of the Contemporary Endocrinology book series (COE)


Understanding the genetic etiology of hyperinsulinism has been a focus of investigation for a number of years; in addition to specific genes identified related to mechanisms within the pancreatic beta cell, several genetic syndromes have been linked to hyperinsulinism. These include Beckwith-Wiedemann syndrome, Sotos syndrome, Kabuki syndrome, and Turner syndrome. All of these syndromes have been noted to occur with subtle presentations with hyperinsulinism being a clue toward diagnosis of the syndrome, and given there are additional medical management recommendations for patients with these syndromes, it is important to consider possible syndromic etiology as part of the evaluation for patients with hyperinsulinism.


Beckwith-Wiedemann syndrome Sotos syndrome Kabuki syndrome Turner syndrome 


  1. 1.
    Aasland R, Gibson TJ, Stewart AF. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem Sci. 1995;20(2):56–9.CrossRefGoogle Scholar
  2. 2.
    Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet. 2004;67(3):209–19. Scholar
  3. 3.
    Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JPT, Boyd AE 3rd, Gonzalez G, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science. 1995;268(5209):423–6.CrossRefGoogle Scholar
  4. 4.
    Al-Zubeidi H, Gottschalk ME, Newfield RS. Successful use of long acting octreotide in two cases with Beckwith-Wiedemann syndrome and severe hypoglycemia. Int J Pediatr Endocrinol. 2014;2014(1):18. Scholar
  5. 5.
    Alkhayyat H, Christesen HB, Steer J, Stewart H, Brusgaard K, Hussain K. Mosaic Turner syndrome and hyperinsulinaemic hypoglycaemia. J Pediatr Endocrinol Metab. 2006;19(12):1451–7.CrossRefGoogle Scholar
  6. 6.
    Bakalov VK, Cheng C, Zhou J, Bondy CA. X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J Clin Endocrinol Metab. 2009;94(9):3289–96. Scholar
  7. 7.
    Bonfig W, Salem NJ, Heiliger K, Hempel M, Lederer G, Bornkamm M, et al. Recurrent hypoglycemia due to growth hormone deficiency in an infant with Turner syndrome. J Pediatr Endocrinol Metab. 2012;25(9–10):991–5. Scholar
  8. 8.
    Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an International Consensus Statement. Nat Rev Endo. 2017. In press.Google Scholar
  9. 9.
    Calton EA, Temple IK, Mackay DJ, Lever M, Ellard S, Flanagan SE, et al. Hepatoblastoma in a child with a paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p causing focal congenital hyperinsulinism. Eur J Med Genet. 2013;56(2):114–7. Scholar
  10. 10.
    Carrasco Salas P, Palma Milla C, Lezana Rosales JM, Benito C, Franco Freire S, Lopez Siles J. Hyperinsulinemic hypoglycemia in a patient with an intragenic NSD1 mutation. Am J Med Genet A. 2016;170A(2):544–6. Scholar
  11. 11.
    Cole TR, Hughes HE. Sotos syndrome. J Med Genet. 1990;27(9):571–6.CrossRefGoogle Scholar
  12. 12.
    Cole TR, Hughes HE. Sotos syndrome: a study of the diagnostic criteria and natural history. J Med Genet. 1994;31(1):20–32.CrossRefGoogle Scholar
  13. 13.
    de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, et al. Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest. 1997;100(4):802–7. Scholar
  14. 14.
    DeBaun MR, King AA, White N. Hypoglycemia in Beckwith-Wiedemann syndrome. Semin Perinatol. 2000;24(2):164–71.CrossRefGoogle Scholar
  15. 15.
    Geneviève D, Amiel J, Le Merrer M, Sanlaville D, Uritzberea A, Gérard M, et al. Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet. 2004;129A(1):64–8. Scholar
  16. 16.
    Gibson CE, Boodhansingh KE, Li C, Conlin L, Chen P, Becker SA, Bhatti T, Bamba V, Adzick NS, De Leon DD, Ganguly A, Stanley CA. Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency. Horm Res Paediatr. 2018;89(6):413–422. Epub 2018 Jun 14.
  17. 17.
    Goto M. Possible relationship between ring X chromosome and neonatal hypoglycemia. J Pediatr Endocrinol Metab. 2008;21(11):1103. Scholar
  18. 18.
    Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177(3):G1–G70. Scholar
  19. 19.
    Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol. 1998;51(2):147–58. Scholar
  20. 20.
    Hook EB, Reynolds JW. Cerebral gigantism: endocrinological and clinical observations of six patients including a congenital giant, concordant monozygotic twins, and a child who achieved adult gigantic size. J Pediatr. 1967;70(6):900–14.CrossRefGoogle Scholar
  21. 21.
    Hussain K, Cosgrove KE, Shepherd RM, Luharia A, Smith VV, Kassem S, et al. Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels. J Clin Endocrinol Metab. 2005;90(7):4376–82. Scholar
  22. 22.
    Kalish JM, Biesecker LG, Brioude F, Deardorff MA, Di Cesare-Merlone A, Druley T, et al. Nomenclature and definition in asymmetric regional body overgrowth. Am J Med Genet A. 2017; Scholar
  23. 23.
    Kalish JM, Boodhansingh KE, Bhatti TR, Ganguly A, Conlin LK, Becker SA, et al. Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith-Wiedemann syndrome. J Med Genet. 2016;53(1):53–61. Scholar
  24. 24.
    Kalish JM, Conlin LK, Mostoufi-Moab S, Wilkens AB, Mulchandani S, Zelley K, et al. Bilateral pheochromocytomas, hemihyperplasia, and subtle somatic mosaicism: the importance of detecting low-level uniparental disomy. Am J Med Genet A. 2013;161A(5):993–1001. Scholar
  25. 25.
    Kubota T, Wakui K, Nakamura T, Ohashi H, Watanabe Y, Yoshino M, et al. The proportion of cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X Turner syndrome females. Cytogenet Genome Res. 2002;99(1–4):276–84. Scholar
  26. 26.
    Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr. 1981;99(4):570–3. Scholar
  27. 27.
    Léger J, Zénaty D. PNDS – syndrome de Turner. Haute Autorité de Santé. 2008.Google Scholar
  28. 28.
    Leventopoulos G, Kitsiou-Tzeli S, Kritikos K, Psoni S, Mavrou A, Kanavakis E, Fryssira H. A clinical study of Sotos syndrome patients with review of the literature. Pediatr Neurol. 2009;40(5):357–64. Scholar
  29. 29.
    Matsumoto N, Niikawa N. Kabuki make-up syndrome: a review. Am J Med Genet C. 2003;117C(1):57–65. Scholar
  30. 30.
    Matsuo T, Ihara K, Ochiai M, Kinjo T, Yoshikawa Y, Kojima-Ishii K, et al. Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome. Am J Med Genet A. 2013;161A(1):34–7. Scholar
  31. 31.
    Meissner T, Rabl W, Mohnike K, Scholl S, Santer R, Mayatepek E. Hyperinsulinism in syndromal disorders. Acta Paediatr. 2001;90(8):856–9. Scholar
  32. 32.
    Michot C, Corsini C, Sanlaville D, Baumann C, Toutain A, Philip N, et al. Finger creases lend a hand in Kabuki syndrome. Eur J Med Genet. 2013;56(10):556–60. Scholar
  33. 33.
    Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, et al. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet. 2013;161A(9):2234–43. Scholar
  34. 34.
    Miyake N, Mizuno S, Okamoto N, Ohashi H, Shiina M, Ogata K, et al. KDM6A point mutations cause Kabuki syndrome. Hum Mutat. 2013;34(1):108–10. Scholar
  35. 35.
    Munns CF, Batch JA. Hyperinsulinism and Beckwith-Wiedemann syndrome. Arch Dis Child Fetal Neonatal Ed. 2001;84(1):F67–9.CrossRefGoogle Scholar
  36. 36.
    Mussa A, Di Candia S, Russo S, Catania S, De Pellegrin M, Di Luzio L, et al. Recommendations of the scientific committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. Eur J Med Genet. 2016;59(1):52–64. Scholar
  37. 37.
    Nakamura Y, Takagi M, Yoshihashi H, Miura M, Narumi S, Hasegawa T, et al. A case with neonatal hyperinsulinemic hypoglycemia: it is a characteristic complication of Sotos syndrome. Am J Med Genet A. 2015;167A(5):1171–4. Scholar
  38. 38.
    Nestorowicz A, Wilson BA, Schoor KP, Inoue H, Glaser B, Landau H, et al. Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet. 1996;5(11):1813–22.CrossRefGoogle Scholar
  39. 39.
    Ng SB, Bigham AW, Buckingham KJ. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42(9):790–3. Scholar
  40. 40.
    Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet. 1988;31(3):565–89. Scholar
  41. 41.
    Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr. 1981;99(4):565–9. Scholar
  42. 42.
    Pietzner V, Weigel JF, Wand D, Merkenschlager A, Bernhard MK. Low-level hyperinsulinism with hypoglycemic spells in an infant with mosaic Turner syndrome and mild Kabuki-like phenotype: a case report and review of the literature. J Pediatr Endocrinol Metab. 2014;21(1–2):165–70. Scholar
  43. 43.
    Rodríguez L, Diego-Alvarez D, Lorda-Sanchez I, Gallardo FL, Martínez-Fernández ML, Arroyo-Muñoz ME, Martínez-Frías ML. A small and active ring X chromosome in a female with features of Kabuki syndrome. Am J Med Genet A. 2008;146A(21):2816–21. Scholar
  44. 44.
    Schrander-Stumpel CT, Spruyt L, Curfs L, Defloor T, Schrander K, Schrander J. Kabuki syndrome: clinical data in 20 patients, literature review, and further guidelines for preventive management. Am J Med Genet A. 2005;132A(3):234–43. Scholar
  45. 45.
    Senniappan S, Ismail D, Shipster C, Beesley C, Hussain K. The heterogeneity of hyperinsulinaemic hypoglycaemia in 19 patients with Beckwith-Wiedemann syndrome due to KvDMR1 hypomethylation. J Pediatr Endocrinol Metab. 2015;28(1–2):83–6. Scholar
  46. 46.
    Smith AC, Shuman C, Chitayat D, Steele L, Ray PN, Bourgeois J, Weksberg R. Severe presentation of Beckwith-Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15. Am J Med Genet A. 2007;143A(24):3010–5. Scholar
  47. 47.
    Stankiewicz P, Thiele H, Giannakudis I, Schlicker M, Baldermann C, Krüger A, et al. Kabuki syndrome-like features associated with a small ring chromosome X and XIST gene expression. Am J Med Genet. 2001;102(3):286–92.CrossRefGoogle Scholar
  48. 48.
    Su PH, Kuo PL, Chen SJ, Chen JY, Yu JS, Liu YL, Kao IW. Kabuki make-up (Niikawa-Kuroki) syndrome with mosaicism ring chromosome X and incomplete XIST gene expression. Acta Paediatr Taiwan. 2007;48(1):28–31.PubMedGoogle Scholar
  49. 49.
    Subbarayan A, Hussain K. Hypoglycemia in Kabuki syndrome. Am J Med Genet. 2013;164(1):467–71. Scholar
  50. 50.
    Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S, et al.; Childhood Overgrowth C. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet. 2005:77(2):193–204. Scholar
  51. 51.
    Thomas PM, Cote GJ, Hallman DM, Mathew PM. Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet. 1995a;56(2):416–21.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995b;268(5209):426–9.CrossRefGoogle Scholar
  53. 53.
    Toda N, Ihara K, Kojima-Ishii K, Ochiai M, Ohkubo K, Kawamoto Y, et al. Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann, Sotos, and Kabuki syndromes: a nationwide survey in Japan. Am J Med Genet A. 2017;173(2):360–7. Scholar
  54. 54.
    Wellesley DG, Slaney S. Kabuki make-up and Turner syndromes in the same patient. Clin Dysmorphol. 1994;3(4):297–300.CrossRefGoogle Scholar
  55. 55.
    White SM, Thompson EM, Kidd A, Savarirayan R, Turner A, Amor D, et al. Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa–Kuroki) syndrome. Am J Med Genet A. 2004;127A(2):118–27. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Human Genetics, Center for Childhood Cancer Research, Department of PediatricsThe Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Reference Centre for Inherited Metabolic Diseases, Necker-Enfants Malades HospitalParis Descartes University, APHPParisFrance

Personalised recommendations