Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center
-
Katharina Warncke
,
Franziska Falco
Abstract
Background:
Congenital hyperinsulinism (CHI) is a rare disease with an estimated incidence of 1:40,000 live births. Here, we characterize 11 patients treated at Munich Children’s Hospital Schwabing.
Methods:
We analyzed data on birth, treatment and laboratory results including genetic testing and evaluated the long-term course with a follow-up visit.
Results:
All patients had severe, diazoxide-(DZX)-resistant hypoglycemia, beginning immediately after birth. Two patients were treated by medical therapy, eight underwent subtotal pancreatectomy and one had a partial resection. Both patients who had medical therapy still suffer from occasional hypoglycemia. Six patients with subtotal pancreatectomy were affected by mild hypoglycemia. Seventy-five percent of patients who had surgical treatment developed diabetes mellitus (DM) at a median age of 10.5 (8–13) years. In 89% of patients with available genetic testing, mutations of the ABCC8 gene were detected.
Conclusions:
The majority of CHI-patients not responding to DZX underwent surgery. After subtotal pancreatectomy, patients typically developed diabetes around early puberty.
Acknowledgments
We thank all participating patients and their families. We acknowledge Prof. Dr. F. Höpner who performed surgery, and Dr. F. Prantl who performed the histopathological investigations.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. W.B. and F.F. conceived the study, designed it and organized and carried out the follow-up visits. I.E., W.R., J.S., D. F, K.W. and S.B. treated the CHI patients and gave major input for this publication. K.W. wrote the draft of the manuscript, which was reviewed and revised by all authors. This work forms part of the dissertation of F.F. (Technische Universität München).
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. de Lonlay P, Fournet JC, Touati G, Groos MS, Martin D, et al. Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases. Eur J Pediatr 2002;161:37–48.10.1007/s004310100847Search in Google Scholar PubMed
2. Mohnike K, Wieland I, Barthlen W, Vogelgesang S, Empting S, et al. Clinical and genetic evaluation of patients with K-ATP channel mutations from the German registry for congenital hyperinsulinism. Horm Res Paediatr 2014;81:156–68.10.1159/000356905Search in Google Scholar PubMed
3. Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ. Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 2004;84:239–75.10.1152/physrev.00022.2003Search in Google Scholar PubMed
4. Rahier J, Guiot Y, Sempoux C. Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 2000;82:F108–12.10.1136/fn.82.2.F108Search in Google Scholar PubMed PubMed Central
5. Mohnike W, Barthlen W, Mohnike K, Blankenstein O. Positron emission tomography/computed tomography diagnostics by means of fluorine-18-L-dihydroxyphenylalanine in congenital hyperinsulinism. Semin Pediatr Surg 2011;20:23–7.10.1053/j.sempedsurg.2010.10.007Search in Google Scholar PubMed
6. Otonkoski T, Näntö-Salonen K, Seppänen M, Veijola R, Huopio H, et al. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 2006;55:13–8.10.2337/diabetes.55.01.06.db05-1128Search in Google Scholar
7. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, et al. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol 2013;168:557–64.10.1530/EJE-12-0673Search in Google Scholar PubMed PubMed Central
8. Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab 2013;98:E355–63.10.1210/jc.2012-2169Search in Google Scholar PubMed PubMed Central
9. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;268:426–9.10.1126/science.7716548Search in Google Scholar PubMed
10. de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, 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;100:802–7.10.1172/JCI119594Search in Google Scholar PubMed PubMed Central
11. Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, et al. Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 1998;102:1286–91.10.1172/JCI4495Search in Google Scholar PubMed PubMed Central
12. Kapoor RR, James C, Hussain K. Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. Nat Clin Pract Endocrinol Metab 2009;5:101–12.10.1038/ncpendmet1046Search in Google Scholar PubMed
13. Barthlen W, Mohnike W, Mohnike K. Techniques in pediatric surgery: congenital hyperinsulinism. Horm Res Paediatr 2011;75:304–10.10.1159/000323532Search in Google Scholar PubMed
14. Beltrand J, Caquard M, Arnoux JB, Laborde K, Velho G, et al. Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care 2012;35:198–203.10.2337/dc11-1296Search in Google Scholar PubMed PubMed Central
15. Arya VB, Senniappan S, Demirbilek H, Alam S, Flanagan SE, et al. Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism. PLoS One 2014;9:e98054. doi: 10.1371/journal.pone.0098054.Search in Google Scholar PubMed PubMed Central
16. Meissner T, Wendel U, Burgard P, Schaetzle S, Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol 2003;149:43–51.10.1530/eje.0.1490043Search in Google Scholar PubMed
17. Bellanné-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, et al. ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. J Med Genet 2010;47:752–9.10.1136/jmg.2009.075416Search in Google Scholar PubMed
18. Ismail D, Werther G. Persistent hyperinsulinaemic hypoglycaemia of infancy: 15 years’ experience at the Royal Children’s Hospital (RCH), Melbourne. J Pediatr Endocrinol Metab 2005;18:1103–9.10.1515/JPEM.2005.18.11.1103Search in Google Scholar PubMed
19. Senniappan S, Alexandrescu S, Tatevian N, Shah P, Arya V, et al. Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014;370:1131–7.10.1056/NEJMoa1310967Search in Google Scholar PubMed
20. Shah P, Arya VB, Flanagan SE, Morgan K, Ellard S, et al. Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation. J Pediatr Endocrinol Metab 2015;28:695–9.10.1515/jpem-2014-0371Search in Google Scholar PubMed
21. Steinkrauss L, Lipman TH, Hendell CD, Gerdes M, Thornton PS, et al. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism. J Pediatr Nurs 2005;20:109–18.10.1016/j.pedn.2004.12.009Search in Google Scholar
22. Shilyansky J, Fisher S, Cutz E, Perlman K, Filler RM. Is 95% pancreatectomy the procedure of choice for treatment of persistent hyperinsulinemic hypoglycemia of the neonate? J Pediatr Surg 1997;32:342–6.10.1016/S0022-3468(97)90207-4Search in Google Scholar
23. Cherian MP, Abduljabbar MA. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI): long-term outcome following 95% pancreatectomy. J Pediatr Endocrinol Metab 2005;18:1441–8.10.1515/JPEM.2005.18.12.1441Search in Google Scholar
24. Leibowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, et al. Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of DM and persistent beta-cell dysfunction at long-term follow-up. J Clin Endocrinol Metab 1995;80:386–92.Search in Google Scholar
25. Wiegand S, Raile K, Reinehr T, Hofer S, Näke A, et al. Daily insulin requirement of children and adolescents with type 1 diabetes: effect of age, gender, body mass index and mode of therapy. Eur J Endocrinol 2008;158:543–9.10.1530/EJE-07-0904Search in Google Scholar PubMed
©2016 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- An update on thyroid-associated ophthalmopathy in children and adolescents
- Mini Review
- Systematic review and meta-analysis of the association between mumps during childhood and risk of type 1 diabetes mellitus
- Original Articles
- Glycemic variability predicts inflammation in adolescents with type 1 diabetes
- Prevalence and risk factors for diabetic retinopathy in a hospital-based population of Australian children and adolescents with type 1 diabetes
- One month of omega-3 fatty acid supplementation improves lipid profiles, glucose levels and blood pressure in overweight schoolchildren with metabolic syndrome
- The outcome of seven patients with hereditary tyrosinemia type 1
- Increased oxidative stress parameters in children with moderate iodine deficiency
- Relationship between 25(OH)D levels and circulating lipids in African American adolescents
- Endoglin and obestatin levels, cardiometabolic risk factors and subclinical atherosclerosis in children aged 10–18 years
- Lipoprotein-associated phospholipase A2 activity and low-density lipoprotein subfractions after a 2-year treatment with atorvastatin in adolescents with type 1 diabetes
- Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center
- Pituitary volume in children with growth hormone deficiency, idiopathic short stature and controls
- Case Reports
- A novel insulin receptor mutation in an adolescent with acanthosis nigricans and hyperandrogenism
- Primary hyperparathyroidism may masquerade as rickets-osteomalacia in vitamin D replete children
- Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity
- Severe malnutrition causing superior mesenteric artery syndrome in an adolescent with Triple A syndrome
- Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta
Articles in the same Issue
- Frontmatter
- Review
- An update on thyroid-associated ophthalmopathy in children and adolescents
- Mini Review
- Systematic review and meta-analysis of the association between mumps during childhood and risk of type 1 diabetes mellitus
- Original Articles
- Glycemic variability predicts inflammation in adolescents with type 1 diabetes
- Prevalence and risk factors for diabetic retinopathy in a hospital-based population of Australian children and adolescents with type 1 diabetes
- One month of omega-3 fatty acid supplementation improves lipid profiles, glucose levels and blood pressure in overweight schoolchildren with metabolic syndrome
- The outcome of seven patients with hereditary tyrosinemia type 1
- Increased oxidative stress parameters in children with moderate iodine deficiency
- Relationship between 25(OH)D levels and circulating lipids in African American adolescents
- Endoglin and obestatin levels, cardiometabolic risk factors and subclinical atherosclerosis in children aged 10–18 years
- Lipoprotein-associated phospholipase A2 activity and low-density lipoprotein subfractions after a 2-year treatment with atorvastatin in adolescents with type 1 diabetes
- Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center
- Pituitary volume in children with growth hormone deficiency, idiopathic short stature and controls
- Case Reports
- A novel insulin receptor mutation in an adolescent with acanthosis nigricans and hyperandrogenism
- Primary hyperparathyroidism may masquerade as rickets-osteomalacia in vitamin D replete children
- Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity
- Severe malnutrition causing superior mesenteric artery syndrome in an adolescent with Triple A syndrome
- Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta
