Focal Hyperinsulinism Research Articles

Focal congenital hyperinsulinism

In congenital hyperinsulinemic hypoglycemia - the most common cause of persistent hypoglycemia in infancy - a focal lesion can be identified in 50% of the cases. With appropriate medical care based upon early diagnosis, these patients can be cured by the resection of the lesion rendering unnecessary long time medical care, and avoiding serious brain damage from recurrent hypoglycemic episodes. Genetic testing and 18F-fluoro-dihydroxyphenylalanine PET/CT imaging are essential for determining the best possible treatment. We report 2 cases of focal congenital hyperinsulinism - both male infants: 22 and 2 months of age - treated successfully with enucleation of the pancreas lesion (Semmelweis University, Budapest). Both patients had the pathognomonic mutation of the ABCC8 gene of the ATP-sensitive potassium channel. Radiologic imaging and histology confirmed the diagnosis, and after the operation, pharmacological treatment was terminated in both cases. During the follow-up period (5 and 1.5 years, respectively) they are euglycemic, with no morbidities attributed to the operation. We believe that these two operations for focal hyperinsulinism - diagnosed and localised by the above detailed genetic and specific radiological testing - were the first of their kind in Hungary. Based on the acquired experience, every necessary examination can be achieved in our country to improve patient care, reduce morbidity and medical costs. Orv Hetil. 2023; 164(47): 1877-1884.

Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

Recent updates in the management of infants and children with hyperinsulinism.

To highlight recent advances in early diagnosis and the changing treatment paradigm for hyperinsulinism (HI) which can result in shorter hospitalizations, higher rates of cure and improved neurological outcome. Recent literature has shown that following publication of the pediatric endocrinology society guidelines for diagnosing hypoglycemia there have been higher rates of diagnosis of acquired and genetic HI. Studies of neurological outcome have found that poor outcomes are associated with delay between initial hypoglycemia and instigation of treatment for HI, hypoglycemic seizures and frequency of glucose <20 mg/dL. Rapid genetic testing can decrease the time from the discovery of diazoxide unresponsiveness to referral to multidisciplinary centers with the availability of 18-F-L 3,4-Dihydroxyphenylalanine positron emission tomography (18F-DOPA PET). Proper selection of patients for 18F-DOPA PET and careful interpretation of the images can result in greater than 90% cure for patients with focal HI. Recent advances in the early diagnosis of HI and rapid turnaround genetic testing can lead to prompt transfer to centers with multidisciplinary care teams where proper selection of patients for 18F-DOPA PET scan gives the best opportunity for cure for patients with focal disease. Minimizing severe hypoglycemia maximizes the opportunity for improved neurological outcome.

Coexistence of paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p hyperinsulinism

BackgroundBeckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome with variable clinical phenotype and complex molecular aetiology. It is mainly caused by dysregulation of the chromosome 11p15 imprinted region, which results in overgrowth in multiple tissues, often in a mosaic manner.Case presentationA large-for-gestational-age infant without any other somatic features of BWS presented with medically refractory hyperinsulinism (HI) requiring 80% pancreatectomy. Next generation sequencing with congenital HI sequencing panel identified a pathogenic ABCC8:c.1792C > T (p.Arg598Ter) variant of paternal origin, suggestive of focal HI. However, pancreatic histology revealed atypical findings of coalescing nests and trabeculae of adenomatosis scattered with islets with isolated enlarged, hyperchromatic nuclei scattered throughout the pancreas. Methylation analysis, SNP-based chromosomal microarray and short tandem repeat markers analysis revealed mosaic segmental paternal uniparental disomy (UPD) 11p15.5-p15.1 in the pancreatic tissue, but not the peripheral blood, suggestive of BWS/BW-spectrum HI.ConclusionsThis case highlights the importance of integrating the clinical presentation and subsequent clinical course, together with radiological, genetic and histological findings in the definitive diagnosis of this rare yet clinically important entity. In addition, this is the first report that demonstrated the level of paternal inherited c.1792 T pathogenic variant in the pancreatic tissue being directly correlated to the mosaic level of pUPD.

Synthesis of high-molar-activity [18F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor.

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.

Congenital hyperinsulinism disorders: Genetic and clinical characteristics.

Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.

Laparoscopic resection of pancreatic neck lesion with Roux-en-Y pancreatico-jejunostomy

Abstract Background Congenital hyperinsulinism is a rare disease and patients not responding to medical treatment need near-total or partial pancreatectomy, dependent on whether they have diffuse or focal hyperinsulinism, respectively. While laparoscopic technique for distal and for total pancreatectomy has been developed, minimally invasive resection of the pancreatic neck with pancreatico-jejunostomy has not been reported in children before. Case summary A 2-year old boy suffered from congenital hyperinsulinism, which was refractory to high-dose medical treatment. The nuclear-medicine scan revealed a focal lesion of the pancreatic neck, hence partial pancreatectomy was indicated. On laparoscopy, a slightly prominent tissue mass was apparent in the area of the pancreatic neck. We proceeded with laparoscopic mobilisation of the pancreas from the underlying splenic vessels and resected the pancreatic neck and adjacent parts of the body and the head. After macroscopic resection of the mass, the patient's intraoperative blood glucose levels increased to a point where insulin had to be substituted. To drain the pancreatic tail, we formed an end-to-side anastomosis in the proximal Jejunum and brought the open end to the pancreatic tail and performed a laparoscopic pancreatico-jejunostomy. The patient tolerated the procedure well and had no remaining signs or symptoms of hyperinsulinism. Conclusion This is the first report of a laparoscopic middle-segmental pancreatic resection with laparoscopic assisted Roux-en-Y pancreatico-jejunostomy in a child. For benign pancreatic lesions proximal to the body and tail, the described minimally invasive technique should be considered.

Surgical treatment of congenital hyperinsulinism: Results from 500 pancreatectomies in neonates and children

BackgroundCongenital Hyperinsulinism (HI) causes severe hypoglycemia in neonates and children. We reviewed our experience with pancreatectomy for the various types of HI. MethodsFrom 1998 to 2018, 500 patients with HI underwent pancreatectomy: 246 for focal HI, 202 for diffuse HI, 37 for atypical HI (16 for Localized Islet Nuclear Enlargement [LINE], 21 for Beckwith-Wiedemann Syndrome), and 15 for insulinoma. Focal HI neonates were treated with partial pancreatectomy. Patients with diffuse HI who failed medical management underwent near-total (98%) pancreatectomy. Atypical HI patients had pancreatectomies tailored to the PET scan and biopsy findings. ResultsThe vast majority of pancreatectomies for focal HI were < 50%, and many were 2%–10%. 97% of focal HI patients are cured. For diffuse disease patients, 31% were euglycemic, 20% were hyperglycemic, and 49% required treatment for hypoglycemia; the incidence of diabetes increased with long-term follow-up. All 15 insulinoma patients were cured. ConclusionsOur approach to patients with focal HI can distinguish focal from diffuse HI, localize focal lesions, and permit partial pancreatectomy with cure in almost all focal patients. Surgery does not cure diffuse disease but can help prevent severe hypoglycemia and brain damage. Surgery can be curative for insulinoma and for some cases of atypical HI. Level of evidenceLevel IV.

Genetic characteristics of patients with congenital hyperinsulinism.

Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children. Early and appropriate recognition and treatment of hypoglycemia is vital to minimize neurocognitive impairment. There are at least 11 known monogenic forms of hyperinsulinism and several associated syndromes. Molecular diagnosis allows for prediction of the effectiveness of diazoxide and the likelihood of focal hyperinsulinism. Inactivating mutations in the genes encoding the ATP-sensitive potassium channel (KATP hyperinsulinism) account for 60% of all identifiable mutations, including 85% of diazoxide-unresponsive cases. Syndromes or disorders associated with hyperinsulinism include Beckwith-Wiedemann syndrome, Kabuki syndrome, Turner syndrome, and congenital disorders of glycosylation. Although focal hyperinsulinism can be cured by resection of the lesion, therapeutic options for nonfocal hyperinsulinism remain limited and include diazoxide, octreotide, long-acting somatostatin analogs, and near-total pancreatectomy. Although sirolimus has been reported to improve glycemic control in infants with diazoxide-unresponsive hyperinsulinism, the extent of improvement has been limited, and significant adverse events have been reported. Identification of the cause of congenital hyperinsulinism helps guide management decisions. Use of therapies with limited benefit and significant potential risks should be avoided.

Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders.

Congenital hyperinsulinism (HI) is the most common cause of hypoglycemia in children. The risk of permanent brain injury in infants with HI continues to be as high as 25-50% due to delays in diagnosis and inadequate treatment. Congenital HI has been described since the birth of the JCEM under various terms, including "idiopathic hypoglycemia of infancy," "leucine-sensitive hypoglycemia," or "nesidioblastosis." In the past 20 years, it has become apparent that HI is caused by genetic defects in the pathways that regulate pancreatic β-cell insulin secretion. There are now 11 genes associated with monogenic forms of HI (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1), as well as several syndromic genetic forms of HI (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes). HI is also the cause of hypoglycemia in transitional neonatal hypoglycemia and in persistent hypoglycemia in various groups of high-risk neonates (such as birth asphyxia, small for gestational age birthweight, infant of diabetic mother). Management of HI is one of the most difficult problems faced by pediatric endocrinologists and frequently requires difficult choices, such as near-total pancreatectomy and/or highly intensive care with continuous tube feedings. For 50 years, diazoxide, a KATP channel agonist, has been the primary drug for infants with HI; however, it is ineffective in most cases with mutations of ABCC8 or KCNJ11, which constitute the majority of infants with monogenic HI. Genetic mutation testing has become standard of care for infants with HI and has proven to be useful not only in projecting prognosis and family counseling, but also in diagnosing infants with surgically curable focal HI lesions. (18)F-fluoro-L-dihydroxyphenylalanine ((18)F-DOPA) PET scans have been found to be highly accurate for localizing such focal lesions preoperatively. New drugs under investigation provide hope for improving the outcomes of children with HI.

Abstract 3293: Molecular evidence for a parent of origin effect in pediatric insulinomas

Abstract Insulinomas are well-differentiated pancreatic endocrine tumors that cause abnormal beta cell proliferation and hyperinsulinimic hypoglycemia. With an incidence of 2-4 cases per million per year, insulinomas are rare in adults and even less common in children. Since congenital focal hyperinsulinism, another developmental lesion, is associated with paternal isodisomy for the imprinted 11p15 locus, we sought to characterize the role of this region and of mutations in MEN1 on 11q13 in pediatric insulinoma cases. We identified 13 pediatric insulinoma cases, which is the largest pediatric series reported, and performed immunohistochemical analysis for the maternally expressed tumor suppressor marker p57 located in 11p15. Using blood and tumor DNA, we tested 9 candidate genes associated with congenital hyperinsulinism including ABCC8, KCNJ11 and the MEN1 tumor suppressor. We performed methylation analysis of imprint control regions (ICR) that included the paternally expressed IGF2 (ICR1) and maternally expressed CDKN1C (ICR2) located on 11p15 and genome-wide SNP array analysis with tumor DNA. MEN1 mutations were found in 4 cases and suspected in one (MEN1 group); all 5 tumors stained negative for p57 and were hypermethylated at ICR1 and hypomethylated at ICR2 indicating loss of the maternal allele. SNP arrays confirmed loss of heterozygosity (LOH) of entire chromosome 11 in 4 cases. Four out of the 6 remaining non-MEN1 cases also stained negative for p57; in confirmation, 2 of the 4 cases carried mosaic copy number abnormality of chromosome 11. SNP array data demonstrated extensive genome-wide aneuploidy in MEN1 and non-MEN1 cases; however interstitial changes were not present in any of the cases. Notably, MEN1 cases carried only entire chromosome changes, while non-MEN1 cases carried whole arm changes in addition whole chromosome changes. In conclusion, MEN1 mutations are more common in pediatric insulinomas than in adult insulinoma cases (40% in this study vs. 8% in adults). Compared to adult cases, our pediatric insulinoma cases had smaller sized tumors and a shorter median duration of symptoms, suggesting that these tumors are rapidly growing and that the most common chromosome gains and losses very likely represent early events in insulinoma development. Mechanistically, our data suggest that loss of p57 expression, in conjunction with loss of either MEN1 and/or additional imprinted genes on 11p, play a role in the pathogenesis of most insulinomas. In cases with a germ-line MEN1 mutation, we identified a previously unreported paternal parent-of-origin effect that is unique to pediatric insulinomas but not to other MEN1 endocrine tumors (e.g., prolactinoma, parathyroid adenoma). Since a congenital focal hyperinsulinism has a similar parent of origin effect this suggests a broader role for the imprinted locus, 11p15, in not just the pathogenesis of pediatric insulinomas but also in beta-cell replication. Citation Format: Arupa Ganguly, Tricia Bhatti, Karthik Ganapathy, Laura Conlin, Courtney MacMullen, Susan Becker, Eduardo Ruchelli, Charles Stanley. Molecular evidence for a parent of origin effect in pediatric insulinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2015-3293

Targeting the cell cycle inhibitor p57Kip2 promotes adult human β cell replication

Children with focal hyperinsulinism of infancy display a dramatic, non-neoplastic clonal expansion of β cells that have undergone mitotic recombination, resulting in paternal disomy of part of chromosome 11. This disomic region contains imprinted genes, including the gene encoding the cell cycle inhibitor p57Kip2 (CDKN1C), which is silenced as a consequence of the recombination event. We hypothesized that targeting p57Kip2 could stimulate adult human β cell replication. Indeed, when we suppressed CDKN1C expression in human islets obtained from deceased adult organ donors and transplanted them into hyperglycemic, immunodeficient mice, β cell replication increased more than 3-fold. The newly replicated cells retained properties of mature β cells, including the expression of β cell markers such as insulin, PDX1, and NKX6.1. Importantly, these newly replicated cells demonstrated normal glucose-induced calcium influx, further indicating β cell functionality. These findings provide a molecular explanation for the massive β cell replication that occurs in children with focal hyperinsulinism. These data also provided evidence that β cells from older humans, in which baseline replication is negligible, can be coaxed to re-enter and complete the cell cycle while maintaining mature β cell properties. Thus, controlled manipulation of this pathway holds promise for the expansion of β cells in patients with type 2 diabetes.

Subtotal Pancreatectomy for Congenital Hyperinsulinism: Our Experience and Review of Literature.

Congenital hyperinsulinism (HI) is characterized by profound hypoglycemia caused by inappropriate insulin secretion. HI is a heterogeneous disorder with at least two histologic lesions and several implicated genes. If HI is caused by a focal lesion, elective surgery is the treatment of choice because it leads to complete recovery without diabetes. On the contrary, near-total pancreatectomy though recommended for diffuse HI, long-term risks of endocrine and exocrine deficiencies are present. Between the years 2006-2011, three patients of HI were referred to and operated by a single surgeon. The preoperative diagnosis was confirmed by recurrent hypoglycemia, inappropriately high insulin levels, and augmented glucose requirements. The medical records of all three patients were reviewed to study their clinical features, medical and surgical treatment, and postoperative outcome (short- and long-term). There were three patients in this series (male/female ratio, 1:2), all presenting in the neonatal age. All patients failed medical treatment, and radiological imaging did not reveal any pancreatic lesion. All patients underwent subtotal (80%) pancreatectomy. Two patients had diffuse type of HI and one focal HI. One patient had transient hyperglycemia for 3months, which needed insulin supplementation. No patient has developed recurrent hypoglycemia, malabsorption syndrome, or any neurological sequelae until the last follow-up. Doing subtotal or near-total pancreatectomy in diffuse type of HI still remains controversial as one has a higher risk of recurrent hypoglycemia, while the other has a higher rate of insulin dependent diabetes mellitus. Subtotal (80%) pancreatectomy may be considered as the primary modality of surgical intervention in diffuse type of HI, especially when the diagnostic facilities are limited or diagnosis is not known after preliminary investigations. This minimizes the chances of postoperative diabetes mellitus, and redo surgery can always be considered if there is recurrent hypoglycemia.

Clinical Presentation and Management of Children With Diffuse and Focal Hyperinsulinism: A Review of 223 Cases

Congenital hyperinsulinism (HI) occurs in two distinct histologic forms: diffuse and focal. Distinguishing between them is essential because a pancreatectomy is curative for focal HI and palliative for diffuse HI. The purpose of this study was to compare the presentations, treatment, and outcomes of diffuse and focal HI. A retrospective chart review of children who underwent pancreatectomy for hyperinsulinism from December 2004 through September 2012 was conducted. Based on pancreatic histology, 223 children were classified into 3 groups: diffuse (n = 97, 44%), focal (n = 114, 51%), and other (n = 12, 5%). Children with diffuse vs focal HI had significantly different mean gestational ages (38 vs 39 weeks, P < .0005) and birth weights (3963 vs 3717 g P = .012). Children with focal HI presented at an older age (0.3 vs 0 months, P < .0005) and more frequently with seizures (50 vs 25%, P < .0005). Children with diffuse HI had higher insulin levels during hypoglycemia (31.8 vs 12 μU/mL, P < .0005) and required higher glucose infusion rates (19.2 vs 16.1 mg/kg/min, P = .002). Children with diffuse HI had a median percent pancreactectomy of 98%, and postoperatively 41% required treatment for continued hypoglycemia. Children with focal HI had a median percent pancreatectomy rate of 27%, and 94% required no treatment after surgery. Focal and diffuse HI present unique challenges, but the clinical differences between the 2 are subtle. Children with focal HI are at higher risk of delayed diagnosis and hypoglycemic seizures, but most are cured with surgery. In contrast, children with diffuse disease may be identified earlier, but face ongoing blood glucose abnormalities.

Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism

PurposeThe purpose of the study was to determine the sensitivity of the 18fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography scan (18F-PET/CT) in the diagnosis of focal congenital hyperinsulinism (HI). MethodsA retrospective review of children with HI who underwent a preoperative 18F-PET/CT scan was performed. ResultsBetween 1/2008 and 2/2012 we performed 105 consecutive 18F-PET/CT scans on infants with HI. Fifty-three patients had focal HI. Of those fifty-three patients, eight had a preoperative 18F-PET/CT scan read as “diffuse disease”. The sensitivity of the study in the diagnosis of focal HI was 85%. The location of the eight missed focal lesions was: head (3), body (2), and tail (3). The 18F-PET/CT of the missed head lesions showed homogeneous tracer uptake (n =2) or heterogeneous uptake throughout the pancreas (n=1). The 18F-PET/CT of the 2 missed body lesions and 1 missed tail lesion showed heterogeneous uptake throughout the pancreas. The 18F-PET/CT of the other 2 missed tail lesions showed lesions adjacent to and obscured by the signal of the upper renal pole, identified retrospectively by closer observation. Fifty-two of the 105 patients had diffuse HI. Two of them had 18F-PET/CT studies read as “focal disease”. Therefore, the specificity of the study was 96%. Of the forty-seven 18F-PET/CT studies read as “focal disease”, forty-five had true focal HI. Therefore, the positive predictive value of the study in the diagnosis of focal HI was 96%. ConclusionThe sensitivity and specificity of 18 F-PET/CT can be affected by certain anatomic features of the pancreas, by the location of the lesion, and by the reader's experience.

Genotype and Phenotype Correlations in 417 Children With Congenital Hyperinsulinism

Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes. Our objective was to correlate genotype with phenotype in 417 children with HI. Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1. Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxide-unresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity. Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI.

Next-Generation Sequencing Reveals Deep Intronic Cryptic ABCC8 and HADH Splicing Founder Mutations Causing Hyperinsulinism by Pseudoexon Activation

Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ~10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease.

Congenital Hyperinsulinism Associated With Beckwith Wiedemann Syndrome

J. D. is a 9-month-old Caucasian male with hyperinsulinism (HI). J. D. reportedly had hypoglycemia at birth (exact data unavailable). He was discharged day of life (DOL) 3, when blood glucose (BG) levels “stabilized.” On DOL 4, he had a seizure, was taken to the emergency room, and had a dangerously low BG level of 6 mg/dL (70–110). His medical evaluation was consistent with HI, but he failed medication therapy. He was discharged home on continuous feeds, but over the next several months had persistent hypoglycemia with BGs less than 50 mg/dL. Therefore, he was readmitted to his local hospital. Without additional treatment options, he was transferred to a hyperinsulinism center for further evaluation. J. D. was the product of a pregnancy complicated by maternal lupus. He was full term and weighed 4.6 kg (large for gestational age). HI was confirmed when laboratory values revealed a detectable insulin level, suppressed serum beta-hydroxybutyrate, and an inappropriate glycemic response to glucagon at the time of hypoglycemia. HI genetic testing was negative. An 18 F-DOPA PET scan of the pancreas suggested a possible focal lesion in the pancreatic head causing HI. During exploratory surgery, there was no evidence of focal or diffuse HI. The pathology of J. D.'s pancreatic biopsies indicated diffuse islet cell hyperplasia. J. D. had hemihypertrophy, raising the suspicion of Beckwith Wiedemann syndrome (BWS). Mosaic BWS was diagnosed, with a mutation on chromosome 11 (11p15.5p11.11). A gastrostomy tube was placed for continuous enteral administration of dextrose. J. D. maintained BGs greater than 70 mg/dL for 12 hours on a glucose infusion rate of 5 mg/kg per minute. He was discharged home on this regimen. BWS is frequently associated with HI. The clinical course and response to treatment have been variable, and medical therapy may not be successful. Further research is needed to analyze this association and treatment modalities. The genetic mutations in both HI and BWS are on chromosome 11, raising the question of a genetic link. Alternatively, because BWS is an overgrowth syndrome, perhaps the HI is simply an effect of islet cell hyperplasia.

Pancreatic head resection and Roux-en-Y pancreaticojejunostomy for the treatment of the focal form of congenital hyperinsulinism

Purpose To determine the outcome of patients who underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy to the remaining normal pancreatic body and tail for the treatment of a focal lesion in the pancreatic head causing congenital hyperinsulinism (HI). Methods One hundred thirty-eight patients underwent pancreatic resection for focal HI between 1998 and 2010. Twenty-three patients in the group underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy. Results There were 13 females and 10 males. Median age and weight at surgery were 8 weeks and 5.8 kg, respectively. Twenty-one patients had a near-total pancreatic head resection, and 2 patients had a pylorus-preserving Whipple procedure. The pancreaticojejunostomy anastomosis was performed with interrupted fine monofilament sutures such that the transected end of the pancreatic body was tucked within the end of the Roux-en-Y jejunal limb. Median hospital stay was 22 days. All patients were cured of HI. Conclusion We conclude that pancreatic head resection with Roux-en-Y pancreaticojejunostomy is a safe and effective procedure for the treatment of the HI patient with a large focal lesion in the pancreatic head that is not amenable to local resection alone.

Congenital hyperinsulinism: current trends in diagnosis and therapy

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.