Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous <i>KCNJ11</i> mutation

Korula, Sophy; Chapla, Aaron; Priyambada, Leena; Mathai, Sarah; Simon, Anna

doi:10.1515/jpem-2017-0238

Cited by 8 publications

(7 citation statements)

References 9 publications

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“…Sirolimus has been reported to be an effective and safe drug for severe, diazoxide unresponsive, diffuse CHI with no major side effects ( 147 ). Following the first report, significant numbers of cases have been reported ( 148 , 149 , 150 , 151 , 152 , 153 , 154 ). As sirolimus has potentially adverse effects (perhaps related to dose) arising from its immunosuppressive effects, measurement of the blood levels is vitally important for reaching an optimal therapeutic level.…”

Section: Introductionmentioning

confidence: 99%

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Demirbilek¹,

Hussain²

2018

Jcrpe

105

112

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Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate secretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH. In HH due to the inhibitory effect of insulin on lipolysis and ketogenesis there is suppressed ketone body formation in the presence of hypoglycaemia thus leading to increased risk of hypoglycaemic brain injury. Therefore, a prompt diagnosis and immediate management of HH is essential to avoid hypoglycaemic brain injury and long-term neurological complications in children. Advances in molecular genetics, imaging techniques (18F-DOPA positron emission tomography/computed tomography scanning), medical therapy and surgical advances (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This review article provides an overview to the background, clinical presentation, diagnosis, molecular genetics and therapy in children with different forms of HH.

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Section: Introductionmentioning

confidence: 99%

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Demirbilek¹,

Hussain²

2018

Jcrpe

105

112

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Section: Discussionmentioning

confidence: 99%

“…A study from India has reported successful use of sirolimus in an infant with hyperinsulinism with diffuse pancreatic involvement and a novel KCNJ11 mutation 10. The genetic testing by next generation sequencing reported by Korula et al was a novel homozygous KCNJ11 variant (c.758C>A, p.Ala253Asp) 10. Another case series describing 10 subjects with congenital hyperinsulinism reported that mTOR inhibitor treatment in severe diffuse CHI was successful only in a minority (30%) of patients and concluded that they are unlikely to involve a decrease in islet cell proliferation 11.…”

Section: Discussionmentioning

confidence: 99%

Response to sirolimus in a case of diffuse congenital hyperinsulinaemic hypoglycaemia due to homozygousKCNJ11mutation

2022

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We present a case of a male neonate with refractory and persistent neonatal hypoglycaemia not responding to octreotide. On evaluation for hypoglycaemia, his cortisol was within the reference range while the serum insulin concentrations were high. Gallium-68 dotatate scan (GA-68 DOTA) showed diffuse pancreatic involvement. Genetic diagnosis of congenital hyperinsulinaemic hypoglycaemia due toKCNJ11mutation was made. He was started on tablet sirolimus, after which the child was off all other medication and was euglycaemic. However, he developed bilateral pneumonia leading to acute respiratory distress syndrome with refractory shock. Our case highlights the response to sirolimus in a case of congenital hyperinsulinaemia (CHI) due toKCNJ11mutation and severe adverse event thereafter.

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“…Because complications mainly developed while combined with other medications, the latter may also be held responsible of some of these. For instance, the CHI case published by Korula et al [32] had a nonfermenting gram-negative bacilli sepsis before sirolimus treatment and had not had any infections or side effects in the 14 months of treatment on sirolimus. Further studies analyzing the long-term use of sirolimus in children with CHI are needed.…”

Section: Discussionmentioning

confidence: 99%

Sirolimus: Efficacy and Complications in Children With Hyperinsulinemic Hypoglycemia: A 5-Year Follow-Up Study

Güemes

Dastamani

Ashworth

et al. 2019

Journal of the Endocrine Society

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IntroductionSirolimus, a mammalian target of rapamycin inhibitor, has been used in congenital hyperinsulinism (CHI) unresponsive to diazoxide and octreotide. Reported response to sirolimus is variable, with high incidence of adverse effects. To the best of our knowledge, we report the largest group of CHI patients treated with sirolimus followed for the longest period to date.MethodsRetrospective study of CHI patients treated with sirolimus in a tertiary service and review of the 15 publications reporting CHI patients treated with mammalian target of rapamycin inhibitors. Comparison was made between the findings of this study with those previously published.ResultsTwenty-two CHI patients treated with sirolimus were included in this study. Twenty showed partial response, one showed complete response, and one was unresponsive. Five of the partially/fully responsive patients had compound heterozygous ABCC8 mutations and five had heterozygous ABCC8 mutations. A total of 86.4% (19/22) developed complications, with infection being the most frequent (17/22), of which 11 were of bacterial etiology, followed by persistent diarrhea (3/22) and hyperglycemia (2/22). Seventeen patients stopped sirolimus: 13 from infections; 2 from hyperglycemia; and 2 from alternative treatment (lanreotide) response. Compared with data previously published, our study identified a higher number of partially sirolimus-responsive CHI cases, although the high rate of complications while on this medication limited its potential usefulness.ConclusionSirolimus candidates must be carefully selected given its frequent and potentially life-threatening side effects. Its use as a short-term, last-resort therapy until normoglycemia is achieved with other agents such as lanreotide could avoid pancreatectomy. Further studies evaluating the use of sirolimus in patients with CHI are required.

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Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous KCNJ11 mutation

Abstract: We report the successful use of sirolimus in the management of diazoxide unresponsive congenital hyperinsulinism with diffuse pancreatic involvement. We believe this is the youngest patient to be initiated on sirolimus so far.

Cited by 8 publications

References 9 publications

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Response to sirolimus in a case of diffuse congenital hyperinsulinaemic hypoglycaemia due to homozygousKCNJ11mutation

Sirolimus: Efficacy and Complications in Children With Hyperinsulinemic Hypoglycemia: A 5-Year Follow-Up Study

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