Clinical Efficacy Evaluation of Sirolimus in Congenital Hyperinsulinism

Background. Congenital hyperinsulinism (CHI) is a rare and life-threatening genetic disorder. Sirolimus as a mammalian target of rapamycin inhibitor may be helpful in patients with CHI who do not respond well to other treatments including diazoxide and octreotide. However, the safety and efficacy of this therapy are still unclear. This study aimed to evaluate the potential therapeutic effects of sirolimus in CHI patients with mutations in the ABCC8 and KCNJ11 genes. Methods. During the period of this follow-up study, every child with a confirmed diagnosis of unresponsive CHI underwent genetic evaluation. Among those who had positive genetic testing, six families agreed to participate in this study. The participants were evaluated for ABCC8, KCNJ11, or HNF4α gene mutations by polymerase chain reaction (PCR) sequencing. The participants who were unresponsive to diazoxide and octreotide therapy received 0.5 mg/m2/d of sirolimus, and the dose was gradually increased until a serum concentration of 5–15 ng/ml was achieved. Then, the participants were followed up for any possible complications. Results. Among the study participants, only one neonate was completely free of hypoglycemia after one year of follow-up, whereas three others experienced a partial reduction in hypoglycemic episodes over six months. One neonate underwent pancreatectomy despite receiving sirolimus. The oldest participant with a mutation in the ABCC8 gene responded well to sirolimus therapy after surgery and remained asymptomatic for 18 months. Conclusion. This study suggested that sirolimus therapy needs further evaluation to determine which patients will benefit the most. The genetic basis of CHI may have possible implications for determining the patient’s response.

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ADDRESS (ADministration of DRotrecogin alfa [activated] in Early stage Severe Sepsis) long-term follow-up: One-year safety and efficacy evaluation*

Critical Care Medicine ◽

10.1097/01.ccm.0000266588.95733.63 ◽

2007 ◽

Vol 35 (6) ◽

pp. 1457-1463 ◽

Cited By ~ 29

Author(s):

Pierre-Francois Laterre ◽

Edward Abraham ◽

Jonathan M. Janes ◽

Benjamin L. Trzaskoma ◽

Nancy L. Correll ◽

...

Keyword(s):

Severe Sepsis ◽

Drotrecogin Alfa ◽

Early Stage ◽

Efficacy Evaluation ◽

Safety And Efficacy ◽

Drotrecogin Alfa Activated ◽

Long Term Follow Up ◽

One Year

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Novel Compound Heterozygous Variants of the ABCC8 Gene Warrant Identification of Pancreatic Histology in Infant with Diazoxide-unresponsive Congenital Hyperinsulinism

Children ◽

10.3390/children8100836 ◽

2021 ◽

Vol 8 (10) ◽

pp. 836

Author(s):

Rana Al Balwi ◽

Dalal Bubshait ◽

Raed Al Nefily ◽

Omar Al Ghamdi

Keyword(s):

Autosomal Recessive ◽

Severe Hypoglycemia ◽

Katp Channels ◽

Compound Heterozygous ◽

Congenital Hyperinsulinism ◽

Abcc8 Gene ◽

Genes Encoding ◽

One Year ◽

The One ◽

Compound Heterozygous Variants

Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion, resulting in severe hypoglycemia. Mutations in the ABCC8 and KCNJ11 genes encoding KATP channels in beta cells of the pancreas are common among patients with CHI. Autosomal recessive CHI with diffuse involvement is the most common type of CHI among Saudi patients. It is relatively common for patients with autosomal recessive CHI to be medically unresponsive and undergo pancreatectomy. In this case report, we describe novel compound heterozygous variants in the ABCC8 gene in a Saudi infant that caused diazoxide-unresponsive CHI. The variants included a monoallelic paternally inherited variant that has been previously reported to cause a focal form of CHI and a maternally inherited variant of unknown significance (VUS). The severity of CHI in this patient was mild over the one-year follow-up period, with a near-optimal glycemic response on a low dose of octreotide. We suspected an atypical subtype of histological involvement in the patient. In this report, we highlight the phenotypic spectrum of novel compound heterozygous variants in a patient with CHI and consider that the report can help establish the pathogenicity of the VUS.

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Long-Term Follow-Up of Children With Congenital Hyperinsulinism on Octreotide Therapy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-1866 ◽

2014 ◽

Vol 99 (10) ◽

pp. 3660-3667 ◽

Cited By ~ 30

Author(s):

Huseyin Demirbilek ◽

Pratik Shah ◽

Ved Bhushan Arya ◽

Louise Hinchey ◽

Sarah E. Flanagan ◽

...

Keyword(s):

Congenital Hyperinsulinism ◽

Long Term Follow Up ◽

Octreotide Therapy

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Prolactinoma-associated headache and dopamine agonist treatment

Cephalalgia ◽

10.1177/0333102413515343 ◽

2013 ◽

Vol 34 (7) ◽

pp. 493-502 ◽

Cited By ~ 13

Author(s):

Mia-Maiken Kallestrup ◽

Helge Kasch ◽

Toke Østerby ◽

Edith Nielsen ◽

Troels S Jensen ◽

...

Keyword(s):

Dopamine Agonist ◽

Dopamine Agonists ◽

Tumor Volume ◽

Serum Prolactin ◽

Therapeutic Effects ◽

Average Tumor Volume ◽

Tumor Volume Reduction ◽

One Year

Aim The aim of this article is to investigate the phenotype and etiology of prolactinoma-associated headache as well as present and discuss the plausible pain-relieving effect of dopamine agonist treatment. Methods In this case-based audit we included 11 patients with prolactinomas and one patient with idiopathic hyperprolactinemia presenting with headache that subsequently improved or resolved after dopamine agonist treatment. Results A significant ipsilateral location of tumor mass and reported headache symptoms was observed ( p = 0.018). After dopamine agonist treatment seven out of 12 patients became pain free within 2.5 months; after one year of treatment 11 out of 12 reported headache improvement or resolution. Average tumor volume reduction after treatment was 47 ± 22% during 9.5 ± 8.4 months of follow-up. There was no significant association between headache relief and tumor shrinkage ( p = 0.43) or normalization of serum prolactin ( p = 1.00), respectively. Conclusions 1) The significant association between lateralization of tumor and headache suggests a mechanical origin of the headache, 2) headache responded to dopamine agonist treatment in most patients, and 3) our observations encourage future prospective controlled trials to investigate the role of hyperprolactinemia in the pathogenesis of headache as well as the therapeutic effects of dopamine agonists.

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ADDRESS LONG TERM FOLLOW UP: ONE YEAR SAFETY AND EFFICACY EVALUATION.

Critical Care Medicine ◽

10.1097/00003246-200512002-00529 ◽

2005 ◽

Vol 33 ◽

pp. A151

Author(s):

edward abraham ◽

Pierre-Francois Laterre ◽

Jonathan Janes ◽

Nancy Correll ◽

Benjamin Trzaskoma ◽

...

Keyword(s):

Efficacy Evaluation ◽

Safety And Efficacy ◽

Long Term Follow Up ◽

One Year

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Wiedemann-Steiner syndrome with a novel pathogenic variant in KMT2A: a case report

Colombia Medica ◽

10.25100/cm.v50i1.3555 ◽

2019 ◽

pp. 40-45 ◽

Cited By ~ 3

Author(s):

Diana Ramirez Montaño ◽

Harry Pachajoa

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

Specific Binding ◽

Genetic Disorder ◽

Low Frequency ◽

Clinical Findings ◽

Whole Exome ◽

One Year

Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.

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