Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy

Abstract

Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.Congenital hyperinsulinism (CHI) is a condition characterized by severe hypoglycemia related to inappropriate insulin secretion by pancreatic b cells. Its typical presentation is the presence of seizures in infants, and it is associated with the risk of brain damage. 1 The most common causes of CHI are mutations in the ABCC8 and KCNJ11 genes, which encode the sulfonylurea receptor (SUR1) and the inwardly rectifying potassium subunit (Kir6.2) of the pancreatic adenosine triphosphate-sensitive potassium channel (KATP). 2 CHI can manifest as either focal or diffuse: 18 F-Ldihydroxyphenylalanine positron emission tomography allows for differentiation between the 2 to choose the correct treatment strategy. 3 The management of diffuse, severe CHI is challenging: diazoxide (administered in doses of 10-15 mg/kg per day) is the drug of choice, 4 followed by octreotide; when medical therapy is ineffective, subtotal pancreatectomy should be considered to ensure normoglycemia, even if there is a high risk of postoperative diabetes mellitus or persistent hyperinsulinemic hypoglycemia. 5 The successful use of the mammalian target of rapamycin (mTOR) inhibitor sirolimus has been recently reported to be effective and safe for the severe, diffuse form of CHI. 6 We report the case of an 8-year-old white boy with severe diffuse CHI due to a biallelic heterozygous ABCC8 gene mutation who was successfully treated with sirolimus. CASE REPORTWe present the case of an 8-year-old white boy affected by CHI that was diagnosed in the first days of life due to severe and persistent hypoglycemia (35 mg/dL; 1.94 mmol/L) and high insulin blood levels (25 mU/mL; 166.7 pmol/L). The patient was born at 36 weeks' gestational age, after a pregnancy complicated by insulinindependent maternal diabetes, and

The difficult management of persistent, non‐focal congenital hyperinsulinism: A retrospective review from a single, tertiary center

“…The conservative treatment constitutes primarily of diazoxide, or octreotide, as first choice, but a significant number of the patients are unresponsive or only partially responsive to medical treatment . Alternatively, continuous glucagon, sirolimus or nifedipine among others have been used, however with variable success . If responsive to octreotide, long acting somatostatin analogues may be preferred …”

The Effectiveness of Sirolimus Treatment in Two Rare Disorders with Nonketotic Hypoinsulinemic Hypoglycemia: The Role of mTOR Pathway

“…In both patients hypoglycemia has been controlled with Sirolimus treatment. The reported side effects of Sirolimus treatment were immunosuppression effects, oral mucositis, renal dysfunction, pneumonitis, increased serum aminotransferase levels, hepatitis, and dyslipidemia (9,19). We observed only mild leucocytosis in Case 1 without any additional symptoms.…”

“…The only known and experienced agent to impact this pathway is mTOR inhibitor Sirolimus. Until now, Sirolimus has been succesfully used for the severe, diffuse form of CHI (9). In our cases, we decided to give Sirolimus to improve hypoglycemia in a patient with AKT2 mutation and another patient with PTEN tumoral hamartamatous syndrome caused by the inhibition of mTOR, which was the next step of PTEN/AKT signaling.…”

“…Besides, there is no therapetic implementation in case patients can not be fed for reasons such as; vomiting, gastrointestinal problems, anorexia etc. The mammalian target of rapamycin (mTOR) inhibitor Sirolimus has been used in hyperinsulinemic hypoglycemia which was unresponsive to other medical treatment (3,9). In the insulin signaling pathway, both AKT2 and PTEN play a role before mTOR.…”

A Novel Homozygous Mutation in the KCNJ11 Gene of a Neonate with Congenital Hyperinsulinism and Successful Management with Sirolimus

“…Kara et al (22) treated a newborn having CHI with sirolimus, but discontinued it due to hepatic and renal failure. Another report describes an 8-year-old boy with severe CHI due to a biallelic heterozygous ABCC8 mutation who exhibited a drastic improvement with sirolimus (23). Sirolimus therapy appears to be a feasible alternative to subtotal pancreatectomy, either alone or in combination with somatostatin analogues for selected patients with no contraindications.…”