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Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia

  • Mary B. Abraham EMAIL logo , Vinutha B. Shetty , Glynis Price , Nicholas Smith , Martin de Bock , Aris Siafarikas , Steven Resnick , Elizabeth Whan , Sian Ellard , Sarah E. Flanagan , Elizabeth A. Davis , Timothy W. Jones , Khalid Hussain and Catherine S. Choong EMAIL logo
Published/Copyright: July 30, 2015
Journal of Pediatric Endocrinology and Metabolism
From the journal Journal of Pediatric Endocrinology and Metabolism Volume 28 Issue 11-12

Abstract

Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured.

Keywords: hyperinsulinism; mTOR inhibitors; neonatal hypoglycaemia; sirolimus
Corresponding authors: Dr. Mary B. Abraham and Prof. Catherine S. Choong, Department of Endocrinology, Princess Margaret Hospital, Perth, Western Australia 6008, Australia; and School of Paediatrics and Child Health, The University of Western Australia, Perth, Australia, Phone: +61 8 93408090, Fax: +61 8 93408605, E-mail: (Mary B. Abraham); (Catherine S. Choong)

Acknowledgments

MA is the recipient of the Channel 7 Telethon Research Fellowship 2014.

Conflict of interest statement

Disclosure statement: The authors have nothing to disclose.

Authors’ contribution: MA collated the clinical information of the case and wrote the manuscript. VS, GP, MB, AS, ED, TJ, SR and EW provided the clinical details and offered critical input. KH, SE and SF provided the genetic analyses and additional expert opinion. CSC oversaw all aspects of the manuscript and edited the manuscript. All authors approved of the final version of the manuscript.

References

1. 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

2. Flanagan SE, Kapoor RR, Hussain K. Genetics of congenital hyperinsulinemic hypoglycemia. Semin Pediatr Surg 2011;20:13–7.10.1053/j.sempedsurg.2010.10.004Search in Google Scholar PubMed

3. Demirbilek H, Shah P, Arya VB, Hinchey L, Flanagan SE, et al. Long-term follow up of children with congenital hyperinsulinism on octreotide therapy. J Clin Endocrinol Metab 2014;99:3660–7.10.1210/jc.2014-1866Search in Google Scholar PubMed

4. Palladino AA, Stanley CA. A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism. Semin Pediatr Surg 2011;20:32–7.10.1053/j.sempedsurg.2010.10.008Search in Google Scholar PubMed

5. 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:e98054.10.1371/journal.pone.0098054Search in Google Scholar PubMed PubMed Central

6. Alexandrescu S, Tatevian N, Olutoye O, Brown RE. Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. Int J Clin Exp Pathol 2010;3:691–705.Search in Google Scholar

7. 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

8. Pape L, Ahlenstiel T. mTOR inhibitors in pediatric kidney transplantation. Pediatr Nephrol 2014;29:1119–29.10.1007/s00467-013-2505-9Search in Google Scholar PubMed

9. Frieden IJ. Infantile hemangioma research: looking backward and forward. J Invest Dermatol 2011;131:2345–8.10.1038/jid.2011.315Search in Google Scholar PubMed

10. Garcia A, Rack-Gomer AL, Bhavaraju NC, Hampapuram H, Kamath A, et al. Dexcom G4AP: an advanced continuous glucose monitor for the artificial pancreas. J Diabetes Sci Technol 2013;7:1436–45.10.1177/193229681300700604Search in Google Scholar PubMed PubMed Central

11. Crofton PM, Midgley PC. Cortisol and growth hormone responses to spontaneous hypoglycaemia in infants and children. Arch Dis Child 2004;89:472–8.10.1136/adc.2003.033431Search in Google Scholar PubMed PubMed Central

12. Le Quan Sang KH, Arnoux JB, Mamoune A, Saint-Martin C, Bellanne-Chantelot C, et al. Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol 2012;166:333–9.10.1530/EJE-11-0874Search in Google Scholar PubMed

13. Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 2000;49:1325–33.10.2337/diabetes.49.8.1325Search in Google Scholar PubMed

14. Fraenkel M, Ketzinel-Gilad M, Ariav Y, Pappo O, Karaca M, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008;57:945–57.10.2337/db07-0922Search in Google Scholar PubMed

15. General recommendations on immunization — Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011;60:1–64.Search in Google Scholar

16. Sindhi R, Seward J, Mazariegos G, Soltys K, Seward L, et al. Replacing calcineurin inhibitors with mTOR inhibitors in children. Pediatr Transplant 2005;9:391–7.10.1111/j.1399-3046.2005.00360.xSearch in Google Scholar PubMed

17. Kwon G, Marshall CA, Pappan KL, Remedi MS, McDaniel ML. Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. Diabetes 2004;53:S225–32.10.2337/diabetes.53.suppl_3.S225Search in Google Scholar PubMed

18. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69–76.10.1200/JCO.2009.24.2669Search in Google Scholar PubMed PubMed Central

19. Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 2009;360:195–7.10.1056/NEJMc0806740Search in Google Scholar PubMed

20. Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, et al. Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia. Eur J Endocrinol 2013;168:665–74.10.1530/EJE-12-1101Search in Google Scholar PubMed

21. 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

22. Blatt J, Stavas J, Moats-Staats B, Woosley J, Morrell DS. Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 2010;55:1396–8.10.1002/pbc.22766Search in Google Scholar PubMed

23. Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011;57:1018–24.10.1002/pbc.23124Search in Google Scholar PubMed

24. Kaylani S, Theos AJ, Pressey JG. Treatment of infantile hemangiomas with sirolimus in a patient with PHACE syndrome. Pediatr Dermatol 2013;30:e194–7.10.1111/pde.12023Search in Google Scholar PubMed

25. Kai L, Wang Z, Yao W, Dong K, Xiao X. Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 2014;140:471–6.10.1007/s00432-013-1549-3Search in Google Scholar PubMed

26. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, et al. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol 2009;4:135–42.10.1007/s11523-009-0107-zSearch in Google Scholar PubMed

27. Schachter AD, Benfield MR, Wyatt RJ, Grimm PC, Fennell RS, et al. Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co-therapy. Pediatr Transplant 2006;10:914–9.10.1111/j.1399-3046.2006.00541.xSearch in Google Scholar PubMed PubMed Central

28. Matthews K, Gossett J, Kappelle PV, Jellen G, Pahl E. Indications, tolerance and complications of a sirolimus and calcineurin inhibitor immunosuppression regimen: intermediate experience in pediatric heart transplantation recipients. Pediatr Transplant 2010;14:402–8.10.1111/j.1399-3046.2010.01306.xSearch in Google Scholar PubMed

Received: 2015-2-19
Accepted: 2015-7-8
Published Online: 2015-7-30
Published in Print: 2015-11-1

©2015 by De Gruyter

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https://doi.org/10.1515/jpem-2015-0094
Keywords for this article
hyperinsulinism; mTOR inhibitors; neonatal hypoglycaemia; sirolimus

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Turner syndrome
  3. Turner syndrome – working together with patients and their families
  4. Turner syndrome patients with bicuspid aortic valves and renal malformations exhibit abnormal expression of X-linked inhibitor of apoptosis protein (XIAP)
  5. Inhibin B in adolescents and young adults with Turner syndrome
  6. Mode of initial presentation and chromosomal abnormalities in Irish patients with Turner syndrome: a single-centre experience
  7. Retrospective evaluation of pubertal development and linear growth of girls with Turner Syndrome treated with oral and transdermal estrogen
  8. Turner syndrome in Albania and the efficacy of its treatment with growth hormone
  9. Review articles
  10. The relation of vitamin D status with metabolic syndrome in childhood and adolescence: an update
  11. Putting the pieces together: cryptorchidism – do we know everything?
  12. Original articles
  13. Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development
  14. Molecular diagnosis of maturity-onset diabetes of the young (MODY) in Turkish children by using targeted next-generation sequencing
  15. Association of physical activity level with depression, anxiety, and quality of life in children with type 1 diabetes mellitus
  16. Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment
  17. The effect of intraoperative administration of dexamethasone for PONV prophylaxis on perioperative blood glucose level in obese and normal weight children
  18. Are obesity and metabolic syndrome associated with plasma adropin levels in children?
  19. Carnitine insufficiency in children with inborn errors of metabolism: prevalence and treatment efficacy
  20. Comparison of energy expenditure, body composition, metabolic disorders, and energy intake between obese children with a history of craniopharyngioma and children with multifactorial obesity
  21. Effect of serum cholesterol on bone mineral density in normal-weight children and adolescents
  22. Assessment of bone turnover markers and bone mineral density in normal short boys
  23. Long-term treatment for hyperphenylalaninemia and phenylketonuria: a risk for nutritional vitamin B12 deficiency?
  24. Risk factors affecting the development of nephrocalcinosis, the most common complication of hypophosphatemic rickets
  25. Children with hyperthyroidism younger than age 7 require higher mg/kg doses of methimazole to normalize free T4 compared to older children
  26. Effects of bisphosphonates to treat osteoporosis in children with cerebral palsy: a meta-analysis
  27. AMH levels at central precocious puberty and premature thelarche: is it a parameter?
  28. Validating Paediatric Morphometrics: body proportion measurement using photogrammetric anthropometry
  29. Treatment of central precocious puberty and early puberty with GnRH analog in girls with Williams-Beuren syndrome
  30. Short communication
  31. Pilot study on the dietary habits and lifestyles of girls with idiopathic precocious puberty from the city of Rome: potential impact of exposure to flame retardant polybrominated diphenyl ethers
  32. Patient reports
  33. Hypomagnesemia due to two novel TRPM6 mutations
  34. A novel mutation of AMH in three siblings with persistent Mullerian duct syndrome
  35. Kocher-Debré-Semelaigne syndrome with rhabdomyolysis and increased creatinine
  36. Anaphylaxis to gonadorelin acetate in a girl with central precocious puberty
  37. Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia
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