Congenital Hyperinsulinism Caused by Mutations in ABCC8 Gene Associated with Early-Onset Neonatal Hypoglycemia: Genetic Heterogeneity Correlated with Phenotypic Variability.

Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the ABCC8 and KCNJ11 genes that encode the ATP-sensitive potassium channel (KATP). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset HH caused by ABCC8 gene mutations. In the first patient, who presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the ABCC8 gene [deletion in the ABCC8 gene c.(2390+1_2391-1)_(3329+1_3330-1)del] that correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the ABCC8 gene c.1792C>T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of the focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine) positron emission tomography/computed tomography (PET/CT) was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.

[Congenital hyperinsulinism : contributions of chemistry, therapeutic response, genetics and imaging]. / Hyperinsulinisme congénital : apports de la biologie, de la réponse thérapeutique, de la génétique et de l'imagerie.

Congenital hyperinsulinism is the most common cause of recurrent hypoglycemia in newborns and children. Early diagnosis and rapid management are essential to avoid hypoglycaemic brain injury and later neurological complications. Management of those patients involves biological evaluation, molecular genetics, imaging techniques and surgical advances. We report the case of a newborn with recurrent hypoglycemia due to congenital hyperinsulinism (CHI) caused by a new variant in the ABCC8 gene. Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography (18F-DOPA PET/CT scan) reported a focal lesion at the isthmus of the pancreas which has been removed by laparoscopic surgery with a complete recovery for the patient.

L'hyperinsulinisme congénital est la cause la plus fréquente d'hypoglycémies récidivantes chez le nouveau-né et l'enfant. Un diagnostic et une prise en charge précoces sont primordiaux pour éviter les conséquences potentielles sur le développement neurologique. Ces derniers reposent sur la conjonction d'éléments biologiques, génétiques et d'imagerie. Nous rapportons le cas d'un nouveau-né présentant des hypoglycémies récidivantes. La mise au point mettra en évidence un hyperinsulinisme congénital (CHI) lié à un variant non encore décrit au sein du gène ABCC8. L'imagerie par Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography/Computed Tomography-scanner (18F-DOPA PET/CT scan) a mis en évidence une forme focale de l'hyperinsulinisme justifiant une prise en charge chirurgicale amenant à une guérison complète et à l'arrêt de tout traitement médicamenteux.

A homozygous exonic variant leading to exon skipping in ABCC8 as the cause of severe congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is genetically heterogeneous, caused by pathogenic variants in multiple known genes regulating insulin secretion from the pancreatic ß-cells. The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1), a key player in insulin secretion, and pathogenic variants in ABCC8 are the most common cause of CHI. With increased application of genetic testing in clinical practice, variants of unknown clinical significance (VUS) are commonly reported. Additional functional investigation for variant pathogenicity is fundamental in establishing definitive molecular diagnosis and in guiding clinical management. However, due to the lack of ubiquitous tissue expression of these genes, obtaining functional studies on affected tissue has been challenging. We present a case of severe congenital hyperinsulinism which required a near-total pancreatectomy. CHI gene sequencing identified a homozygous silent variant in ABCC8 located on the last nucleotide of exon 38, c.4608G>A (p.Ala1536Ala). The total RNA was isolated from pancreas resected at the time of pancreatectomy. RNA sequencing and expression analysis demonstrated exon 38 skipping and decreased RNA expression, which supports the pathogenicity of this variant. This case highlights the feasibility of functional studies of VUS on resected pancreatic tissue. The result expands the mutation spectrum in ABCC8 and allows precise genetic counseling to affected families.

Genotype-phenotype correlation of KATP channel gene defects causing permanent neonatal diabetes in Indian patients.

BACKGROUND: There are very few reports pertaining to Indian patients with neonatal diabetes mellitus (NDM). Activating or gain of function mutations of KATP channel genes namely KCNJ11 and ABCC8 are most predominant cause of permanent neonatal diabetes mellitus (PNDM). OBJECTIVES: To identify the genotype-phenotype correlation of KATP channel gene defects in a large series of (n = 181) Indian PNDM patients. METHODS: Direct sequencing of all exons of KCNJ11 and ABCC8 genes in all 181 patients with PNDM were performed. Clinical and biochemical data were collected. RESULTS: We have identified the molecular basis of KATP -NDM in 39 out of 181 patients (22%). Of these, 20 had KCNJ11 mutations and 19 had ABCC8 mutations, thus comprising 51% of KCNJ11 and 49% of ABCC8. There were four novel mutations (D1128Tfs*16, Y1287C, S1422T, and H1537R) in ABCC8 gene. Three patients with KCNJ11 mutations had developmental delay with DEND syndrome. In patients with ABCC8 mutations developmental delay was seen in seven out of 19 (36.8%). Of this, three patients (15.7%) had DEND phenotype and four (21%) had iDEND. Of the 39 patients, 33 (84%) patients were shifted to sulfonylurea therapy (glibenclamide). Of this, 19(57.5%) patients harbored KCNJ11 mutations and 14(42.1%) ABCC8 mutations. CONCLUSIONS: This is the first largest study in NDM patients in India demonstrating the importance of KATP channel gene mutation screening in PNDM and efficacy of glibenclamide for Indian patients with KATP -PNDM. The success rate of transfer is more in patients with KCNJ11 mutations compared with those with ABCC8 mutations.

Possible association between ABCC8 C49620T polymorphism and type 2 diabetes in a Nigerian population.

BACKGROUND: The association between ABCC8 gene C49620T polymorphism and type 2 diabetes (T2D) in populations of diverse ethnic backgrounds has been reported. However, such occurrence in an African population is yet to be established. This case-control study involving 73 T2D and 75 non-diabetic (ND) patients investigated the occurrence of this polymorphism among T2D patients in Nigeria and assessed its relationship with body lipids of patients. METHODS: Demographic and clinical characteristics of patients were collected and lipid profile indices including total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were assayed. Restriction fragment length polymorphism-PCR (RFLP-PCR) was employed to genotype the ABCC8-C49620T polymorphism using PstI restriction enzyme. RESULTS: This study revealed significantly (p < 0.05) higher prevalence of the T allele of the ABCC8 gene in T2D patients (33.1%) compared to ND patients (28.0%). The mutant TT genotype was also higher than the CC and CT genotypes in T2D patients compared to ND patients but did not show any significant risk (p>0.05) of T2D for the unadjusted codominant, dominant and recessive models. Following age adjustment, the mutant genotypes (CT and TT) showed significant (p<0.05) risk of T2D for all the models with the recessive model presenting the greatest risk of T2D (OR: 2.39, 95% CI: 1.16-4.91, p<0.018). The TT genotype significantly (p<0.05) associated with high level of HDL and reduced levels of TC, TG and LDL in non-diabetic patients but was not associated with any of the demographic and clinical characteristics among T2D patients. CONCLUSIONS: ABCC8 C49620T polymorphism showed possible association with T2D marked by predominance of the mutant TT genotype in T2D patients. However, the relationship between TT genotype and lipid abnormalities for possible beneficial effect on people suffering from T2D is unclear.

Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia.

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the ß-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling.

Association study of the ABCC8 gene variants with type 2 diabetes in south Indians.

BACKGROUND: The ABCC8 gene which encodes the sulfonylurea receptor plays a major role in insulin secretion and is a potential candidate for type 2 diabetes. The -3c → t (rs1799854) and Thr759Thr (C → T, rs1801261) single nucleotide polymorphisms (SNPs) of the ABCC8 gene have been associated with type 2 diabetes in many populations. The present study was designed to investigate the association of these two SNPs in an Asian Indian population from south India. MATERIALS AND METHODS: A total of 1,300 subjects, 663 normal glucose tolerant (NGT) and 637 type 2 diabetic subjects were randomly selected from the Chennai Urban Rural Epidemiology Study (CURES). The -3c → t and Thr759Thr were genotyped in these subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and a few variants were confirmed by direct sequencing. RESULTS: The frequency of the 't' allele of the -3c → t SNP was found to be 0.27 in NGT and 0.29 in type 2 diabetic subjects (P = 0.44). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetic group (P = 0.18). Neither the genotypic frequency nor the allele frequency of the Thr759Thr polymorphism was found to differ significantly between the NGT and type 2 diabetic groups. CONCLUSION: The -3c → t and the Thr759Thr polymorphisms of the ABCC8 gene were not associated with type 2 diabetes in this study. However, an effect of these genetic variants on specific unidentified sub groups of type 2 diabetes cannot be excluded.

Severe nephrotic syndrome and early end-stage diabetic kidney disease in ABCC8-MODY12: A case report.

A 24-year-old man with diabetes mellitus presented with advanced kidney disease and severe proteinuria. Genetic testing revealed ABCC8-MODY12 (OMIM 600509), and a kidney biopsy showed nodular glomerulosclerosis. He commenced dialysis shortly thereafter, and glycemic control improved on treatment with a sulfonylurea. Diabetic end-stage kidney disease in patients with ABCC8-MODY12 has not been reported until now. Thus, our case highlights the risk for early-onset and severe diabetic kidney disease in patients with ABCC8-MODY12 and the importance of timely genetic diagnosis in unusual cases of diabetes to allow for proper treatment and prevention of late sequelae of diabetes.

ABCC8-related maturity-onset diabetes of the young: switching from insulin to sulphonylurea therapy: how long do we need for a good metabolic control?

OBJECTIVES: Activating variants of the ABCC8 gene cause neonatal diabetes or maturity-onset diabetes of the young (MODY). We report three cases of MODY type 12 caused by variants in the ABCC8 encoding sulphonylurea receptor 1, and the experience of switching from insulin therapy to sulphonylurea therapy. CASE PRESENTATIONS: We describe a 12.5-year-old girl with permanent neonatal diabetes mellitus, and two diabetes mellitus cases with variants in the ABCC8 gene. Two of these cases were successfully switched from subcutaneous insulin to oral glibenclamide, with a marked improvement in glycemic control. In permanent neonatal diabetes case, glibenclamide dose was progressively increased to achieve a full dose (2 mg/kg/day) in 9 days. Nine months after starting oral sulphonylurea therapy, her blood glucose control dramatically improved and insulin therapy was discontinued. CONCLUSIONS: We conclude that patients with ABCC8 gene variants can successfully switch from insulin to sulphonylureas.

Maltodextrin May Be a Promising Treatment Modality After Near-total Pancreatectomy in Infants Younger Than Six Months with Persistent Hyperinsulinism: A Case Report

Persistent hypoglycemia in infants with congenital hyperinsulinism (CHI) can be challenging in approximately half of these cases, even after undergoing a near-total pancreatectomy. While maltodextrin has been recommended in the nutritional management of CHI cases younger than six months, information regarding its efficacy in managing hypoglycemia are not yet clear. Here, we present a male infant with CHI who experienced persistent hypoglycemia even after undergoing a near-total pancreatectomy and despite multiple medical treatments. The infant's hypoglycemic episodes were successfully controlled by adding maltodextrin to his diet.

Genetics and Natural History of Non-pancreatectomized Patients With Congenital Hyperinsulinism Due to Variants in ABCC8.

CONTEXT: Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomized patients. OBJECTIVE: This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomized patients with congenital hyperinsulinism due to variants in the ABCC8 gene. METHODS: Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were not pancreatectomized. Continuous glucose monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test was performed if hyperglycemia was detected in the CGM. RESULTS: Eighteen non-pancreatectomized patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, 8 (44.4%) compound heterozygous, 2 (11.1%) homozygous, and 1 patient carried 2 variants with incomplete familial segregation studies. Seventeen patients were followed up and 12 (70.6%) of them evolved to spontaneous resolution (median age 6.0 ± 4 years; range, 1-14). Five of these 12 patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. CONCLUSION: The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended, as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism-The UK Perspective.

Context: In focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic ß-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery. Objective: We describe surgical and nonsurgical outcomes of focal CHI in a national cohort. Methods: Patients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018. Results: Of 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose. Conclusion: Despite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management.

Case report: Congenital hyperinsulinemia with ABCC8 gene mutations.

Background: Congenital hyperinsulinemia (CHI) is an inherited disease of abnormal insulin secretion and is the main cause of persistent and intractable hypoglycemia in infants. The aim of this case report was to investigate the genetic mechanisms and treatment of CHI in an affected patient. Case summary: We collected clinical data from, and performed gene capture, high-throughput gene sequencing analysis, and Sanger sequencing validation, in a child with CHI and his family to identify the causative gene mutations. Two heterozygous pathogenic mutations in the ATP-binding cassette subfamily C member 8 (ABCC8) gene were detected in the child: c.863G>A (p.Trp288Ter) in exon 6 and c.2506C>T (p.Arg836Ter) in exon 21. Sanger sequencing showed that c.863G>A was inherited from heterozygous mutations in the paternal line and c.2506C>T from heterozygous mutations in the maternal line. Conclusion: The child was a CHI with a biallelic recessive heterozygous mutations in ABCC8 resulting in impairment of its encoded ATP-sensitive potassium (KATP) channel, poor response to diazoxide treatment, and developed diabetes after subtotal pancreatectomy.

Identification of a compound heterozygous inactivating ABCC8 gene mutation responsible for young-onset diabetes with exome sequencing.

Activating mutations in the ABCC8 gene cause diabetes and inactivating mutations usually cause hyperinsulinemic hypoglycemia in infancy. Patients with hypoglycemia in infancy due to a heterozygous inactivating mutation have been reported to occasionally progress to diabetes later in life. We explored the gene responsible for diabetes in two brothers, who were suspected to have diabetes at 15 and 18 years-of-age, respectively, with whole exome sequencing, and identified a compound heterozygous ABCC8 gene mutation (p.Arg168Cys and p.Arg1421Cys). Although their father and mother were heterozygous carriers of the p.Arg168Cys and the p.Arg1421Cys mutation, respectively, neither parent had diabetes. These mutations have been reported to be responsible for hypoglycemia in infancy and function as an inactivating mutation. Our results suggest that the inactivating ABCC8 gene mutation is also important in the etiology of diabetes.

Neonatal diabetes caused by the heterozygous Pro1198Leu mutation in the ABCC8 gene in a male infant: 6-year clinical course.

Neonatal diabetes is a rare disease, often caused by a monogenic abnormality. A male infant patient developed diabetic ketoacidosis at 2 months-of-age due to the heterozygous ABCC8 gene mutation (p.Pro1198Leu). After genetic diagnosis, insulin therapy was successfully transitioned to oral sulfonylurea therapy. For >6 years, oral sulfonylurea therapy has been safe and effective, and the required amount of sulfonylureas has progressively decreased. The mutation was transmitted in an autosomal-dominant fashion across three generations of his family, but the severity of diabetes varied among members from neonatal diabetes to mild diabetes. One family member had normal glucose tolerance despite having the mutation. This case presentation could help in the understanding of neonatal diabetes caused by the ABCC8 gene mutation.

ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): A Report of a Chinese Family.

Maturity-onset diabetes mellitus of the young (MODY) is a monogenic diabetes characterized by autosomal dominant inheritance. Its atypical clinical features make diagnosis difficult and it can be misdiagnosed as type 1 or type 2 diabetes. Fourteen subtypes of MODY have been diagnosed so far, of which MODY12 is caused by mutation of the ABCC8 (ATP Binding Cassette Subfamily C Member 8) gene, which is rarely reported in China. This paper reports a Chinese family of MODY12 caused by a rare missense mutation on the ABCC8 gene, which has not been reported to be associated with MODY in China or in other countries, with the aim of increasing clinicians' awareness and attention to the disease.

A novel de novo mutation at the ABCC8 gene in a newborn with transient diabetes mellitus.

Neonatal diabetes mellitus is a monogenic disease that can present with hyperglycemia, dehydration, failure to thrive, and ketoacidosis within the first six months of life. Neonatal diabetes mellitus can be transient or permanent. Here, we describe a 10-week-old infant with transient neonatal diabetes mellitus who presented with diabetic ketoacidosis and was found to have heterozygous a de novo mutation, p.Thr1381Asn in the ABCC8 gene, which encodes the SUR1 protein. There was no family history of diabetes mellitus and the parents were negative for the mutation at ABCC8. The patient started on insulin therapy and remission of diabetes occurred at 4 months of age. The patient remained euglycemic over a 2-year follow-up period without necessitating any medicine.

The use of glimepiride for the treatment of neonatal diabetes mellitus caused by a novel mutation of the ABCC8 gene.

OBJECTIVES: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that is usually diagnosed in the first six months of life. CASE PRESENTATION: We report on a male infant with neonatal diabetes who presented with diabetic ketoacidosis at two months and 16 days. A novel homozygous missense mutation (c.259T>G) was identified in the ABCC8 gene. In this case, insulin was replaced with glimepiride at a dosage of 0.49 mg/kg/day at five months, and this achieved metabolic control and satisfactory growth as observed at follow-up. CONCLUSIONS: This report improves our understanding of the mutational spectrum of ABCC8, which is normally associated with NDM, and shows that the treatment regimen for this condition can be successfully switched from insulin therapy to the use of sulfonylurea.

Clinical and genetic predictors of secondary sulfonylurea failure in Type 2 diabetes patients: the SUCLINGEN study.

Background: Due to several limitations in the study designs of sulfonylurea pharmacogenomics studies, we investigated the clinical and genetic predictors of secondary sulfonylurea failure in Type 2 diabetes patients. Materials & methods: Patients receiving the maximum sulfonylurea and metformin doses for >1 year were enrolled. Secondary sulfonylurea failure was defined as HbA1c >7.0% (>53 mmol/mol) after a 12-month follow-up. Results: By multivariate analysis, increased insulin resistance (HOMA2-IR), baseline HbA1c >7.0%, residing in eastern Peninsular Malaysia, and the CC genotype of rs757110 ABCC8 gene polymorphism were independent predictors of secondary sulfonylurea failure (p < 0.05) while sulfonylurea-induced hypoglycemia was protective against such failure (p < 0.05). Conclusion: Sulfonylurea does not benefit patients with an increased risk of secondary sulfonylurea failure.

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

INTRODUCTION: Sirolimus, 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. METHODS: Retrospective 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. RESULTS: Twenty-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. CONCLUSION: Sirolimus 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.