SUR1-mutant iPS cell-derived islets recapitulate the pathophysiology of congenital hyperinsulinism.

AIMS/HYPOTHESIS: Congenital hyperinsulinism caused by mutations in the KATP-channel-encoding genes (KATPHI) is a potentially life-threatening disorder of the pancreatic beta cells. No optimal medical treatment is available for patients with diazoxide-unresponsive diffuse KATPHI. Therefore, we aimed to create a model of KATPHI using patient induced pluripotent stem cell (iPSC)-derived islets. METHODS: We derived iPSCs from a patient carrying a homozygous ABCC8V187D mutation, which inactivates the sulfonylurea receptor 1 (SUR1) subunit of the KATP-channel. CRISPR-Cas9 mutation-corrected iPSCs were used as controls. Both were differentiated to stem cell-derived islet-like clusters (SC-islets) and implanted into NOD-SCID gamma mice. RESULTS: SUR1-mutant and -corrected iPSC lines both differentiated towards the endocrine lineage, but SUR1-mutant stem cells generated 32% more beta-like cells (SC-beta cells) (64.6% vs 49.0%, p = 0.02) and 26% fewer alpha-like cells (16.1% vs 21.8% p = 0.01). SUR1-mutant SC-beta cells were 61% more proliferative (1.23% vs 0.76%, p = 0.006), and this phenotype could be induced in SUR1-corrected cells with pharmacological KATP-channel inactivation. The SUR1-mutant SC-islets secreted 3.2-fold more insulin in low glucose conditions (0.0174% vs 0.0054%/min, p = 0.0021) and did not respond to KATP-channel-acting drugs in vitro. Mice carrying grafts of SUR1-mutant SC-islets presented with 38% lower fasting blood glucose (4.8 vs 7.7 mmol/l, p = 0.009) and their grafts failed to efficiently shut down insulin secretion during induced hypoglycaemia. Explanted SUR1-mutant grafts displayed an increase in SC-beta cell proportion and SC-beta cell nucleomegaly, which was independent of proliferation. CONCLUSIONS/INTERPRETATION: We have created a model recapitulating the known pathophysiology of KATPHI both in vitro and in vivo. We have also identified a novel role for KATP-channel activity during human islet development. This model will enable further studies for the improved understanding and clinical management of KATPHI without the need for primary patient tissue.

Neonatal cardiac hypertrophy: the role of hyperinsulinism-a review of literature.

Hypertrophic cardiomyopathy (HCM) in neonates is a rare and heterogeneous disorder which is characterized by hypertrophy of heart with histological and functional disruption of the myocardial structure/composition. The prognosis of HCM depends on the underlying diagnosis. In this review, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM, as hyperinsulinism is widely associated with cardiac hypertrophy (CH) which cannot be distinguished from HCM on echocardiographic examination. We supply an overview of the incidence and treatment strategies of neonatal CH in a broad spectrum of hyperinsulinemic diseases. Reviewing the literature, we found that CH is reported in 13 to 44% of infants of diabetic mothers, in approximately 40% of infants with congenital hyperinsulinism, in 61% of infants with leprechaunism and in 48 to 61% of the patients with congenital generalized lipodystrophy. The correct diagnosis is of importance since there is a large variation in prognoses and there are various strategies to treat CH in hyperinsulinemic diseases.Conclusion: The relationship between CH and hyperinsulism has implications for clinical practice as it might help to establish the correct diagnosis in neonates with cardiac hypertrophy which has both prognostic and therapeutic consequences. In addition, CH should be recognized as a potential comorbidity which might necessitate treatment in all neonates with known hyperinsulinism.What is Known:• Hyperinsulinism is currently not acknowledged as a cause of hypertrophic cardiomyopathy (HCM) in textbooks and recent Pediatric Cardiomyopathy Registry publications.What is New:• This article presents an overview of the literature of hyperinsulinism in neonates and infants showing that hyperinsulinism is associated with cardiac hypertrophy (CH) in a broad range of hyperinsulinemic diseases.• As CH cannot be distinguished from HCM on echocardiographic examination, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM/CH as establishing the correct diagnosis has both prognostic and therapeutic consequences.

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.

Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals.

PURPOSE: Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI. METHODS: We documented the clinical features and molecular diagnoses of 9 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes. RESULTS: Molecular diagnoses of KS were established by identification of pathogenic variants in KMT2D (n = 5) and KDM6A (n = 4). Among the 100 infants with HI of unknown genetic etiology, a KS diagnosis was uncovered in one patient. CONCLUSIONS: The incidence of HI among patients with KS may be higher than previously reported, and KS may account for as much as 1% of patients diagnosed with HI. As the recognition of dysmorphic features associated with KS is challenging in the neonatal period, we propose KS should be considered in the differential diagnosis of HI. Since HI in patients with KS is well managed medically, a timely recognition of hyperinsulinemic episodes will improve outcomes, and prevent aggravation of the preexisting mild to moderate intellectual disability in KS.

Diazoxide-induced pulmonary hypertension in hyperinsulinaemic hypoglycaemia: Recommendations from a multicentre study in the United Kingdom.

OBJECTIVE: Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the incidence and risk factors of diazoxide-induced PH in a large HH cohort to provide recommendations for anticipating and preventing PH in diazoxide-treated patients with HH. DESIGN AND PATIENTS: Retrospective cohort study involving four UK regional HH centres; review of case notes of HH patients on diazoxide. MEASUREMENTS: The diagnosis of PH was based on clinical and echocardiography evidence. Patient and treatment-related risk factors were analysed for association. RESULTS: Thirteen (6 men) of 177 HH diazoxide-treated patients developed PH, an incidence of 7%. In the PH group, HH was diagnosed at median (range) of 9 (1,180) days, with diazoxide commenced 4 (0,76) days from diagnosis and reaching a maximum dose of 7 (2.5,20) mg/kg/d. The majority (8 of 13 patients) developed PH within 2 weeks of diazoxide. Complete diazoxide withdrawal, but not dose reduction, led to PH resolution at 41 (3,959) days. In three patients, PH continued beyond 12 months. Risk factors for the development of PH included the presence of congenital heart disease (CHD) (P = .008), and total fluid volume exceeding 130 mL/kg/d in the immediate 24 hours preceding diazoxide (P = .019). CONCLUSION: Pulmonary hypertension can occur in 7% of diazoxide-treated HH patients. Risk factors include the presence of congenital heart disease and fluid overload. Recommendations include echocardiography and fluid restriction to 130 mL/kg/d prior to diazoxide treatment and immediate discontinuation of diazoxide if PH develops.

Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia.

Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic ß cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the KATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.

Hyperinsulinaemic hypoglycaemia-an overview of a complex clinical condition.

Hyperinsulinaemic hypoglycaemia (HH) is a major cause of hypoglycaemia in the neonatal period, infancy and childhood. It is caused by unsuppressed insulin secretion in the setting of hypoglycaemia and carries a high risk of significant neurological sequelae, such as cognitive impairment. Genetic mutations have been implicated in the pathogenesis of the condition. Other causes include intra-uterine growth retardation, perinatal asphyxia, maternal diabetes mellitus and syndromes, such as Beckwith-Wiedemann. Based on the aetiology, the clinical presentation can range from absence of symptoms to the typical adrenergic symptoms and coma and even death. The diagnosis is based on biochemical findings and the gold-standard imaging technique is 18F-DOPA PET/CT scanning. Treatment options involve medications, such as diazoxide, nifedipine, glucagon and octreotide, as well as surgery. Novel treatment, such as long-acting octreotide, lanreotide and sirolimus, may be used as an alternative to pancreatectomy. Potential future medical treatments include exendin, a GLP-1 receptor antagonist, and glucagon infusion via a pump.Conclusion: Advances in the fields of genetic testing, imaging techniques and medical treatment are beginning to provide novel insights into earlier detection, less invasive treatment approaches and fewer complications associated with the complex entity of hyperinsulinaemic hypoglycaemia. What is Known: • HH is caused by dysregulated insulin release from the ß cell due to genetic mutations and carries a risk for complications, such as neurocognitive impairment. 18F-DOPA PET/CT scanning is presented as the gold-standard imaging technique currently in children with hyperinsulinaemic hypoglycaemia. • Clinical presentation is heterogeneous and treatment options include medical therapy and pancreatectomy. What is New: • 18F-DOPA PET/CT is indicated in suspected focal CHI due to paternal transmitted mutations in ABCC8 or KCNJ11. • Novel treatment options have been introduced, such as long-acting octreotide, lanreotide, sirolimus and selective nonpeptide somatostatin receptor subtype 5 (SSTR5) agonists. Future medical treatments include exendin, a GLP-1 antagonist, and glucagon infusion via a pump. However, all these options are off-label at present.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia.

OBJECTIVES: To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays. SUBJECTS: A total of 298 patients with CHI and 58 control patients with non-hyperinsulinemic hypoglycemia, who were diagnosed after 2007. METHODS: The levels of biochemical markers (glucose, insulin, ß-hydroxybutyrate [BHB], free fatty acids [FFA], lactate, ammonia) at the time of hypoglycemia were analyzed along with the maximal glucose infusion rate (GIR) to maintain euglycemia and clinical outcomes. RESULTS: Median levels of blood glucose in patients with CHI and in controls were 30 and 46 mg/dL, while insulin levels were 9.90 and undetectable (<.5) µU/mL, respectively. Similarly, median levels of BHB were 17.5 and 3745 µmol/L, and those of FFA were 270.5 and 2660 µmol/L, respectively. For patients after 5 months, cutoffs of insulin >1.25 µU/mL, BHB < 2000 µmol/L, and FFA < 1248 µmol/L predicted CHI with sensitivities of 97.5, 96.2, and 95.2% and specificities of 84.2, 89.3, and 92.3%, respectively. Maximal GIR in the CHI groups tended to decrease with age. In addition, decreased gestational age, low birth weight, and elevated lactate at hypoglycemia were significantly more common in patients who were off treatment within 100 days without pancreatectomy. CONCLUSIONS: After introduction of high-sensitive assays, the diagnostic value of insulin was improved, allowing for more efficient cutoffs to be set for diagnosis of CHI. Premature birth, low birth weight and elevated lactate might be helpful in predicting early remission of hypoglycemia.

Molecular and clinical features of KATP -channel neonatal diabetes mellitus in Japan.

BACKGROUND: There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). OBJECTIVES: To elucidate the characteristics of Japanese patients with KATP-NDM. METHODS: By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts. RESULTS: Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea. CONCLUSION: Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

A case with neonatal hyperinsulinemic hypoglycemia: It is a characteristic complication of Sotos syndrome.

Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis.

HNF4A mutation: switch from hyperinsulinaemic hypoglycaemia to maturity-onset diabetes of the young, and incretin response.

BACKGROUND: Hepatocyte nuclear factor 4α (HNF4A) is a member of the nuclear receptor family of ligand-activated transcription factors. HNF4A mutations cause hyperinsulinaemic hypoglycaemia in early life and maturity-onset diabetes of the young. Regular screening of HNF4A mutation carriers using the oral glucose tolerance test has been recommended to diagnose diabetes mellitus at an early stage. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are incretin hormones, responsible for up to 70% of the secreted insulin after a meal in healthy individuals. We describe, for the first time, gradual alteration of glucose homeostasis in a patient with HNF4A mutation after resolution of hyperinsulinaemic hypoglycaemia, on serial oral glucose tolerance testing. We also measured the incretin response to a mixed meal in our patient. CASE REPORT: Our patient was born with macrosomia and developed hyperinsulinaemic hypoglycaemia in the neonatal period. Molecular genetic analysis confirmed HNF4A mutation (p.M116I, c.317G>A) as an underlying cause of hyperinsulinaemic hypoglycaemia. Serial oral glucose tolerance testing, after the resolution of hyperinsulinaemic hypoglycaemia, confirmed the diagnosis of maturity-onset diabetes of the young at the age of 10 years. Interestingly, the intravenous glucose tolerance test revealed normal glucose disappearance rate and first-phase insulin secretion. Incretin hormones showed a suboptimal rise in response to the mixed meal, potentially explaining the discrepancy between the oral glucose tolerance test and the intravenous glucose tolerance test. CONCLUSIONS: Maturity-onset diabetes of the young can develop as early as the first decade of life in persons with an HNF4A mutation. Impaired incretin response might be contributory in the early stages of HNF4A maturity-onset diabetes of the young.

Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome.

Sotos syndrome (OMIM #117550) is a congenital syndrome characterized by overgrowth with advanced bone age, macrocephaly, and learning difficulties. Endocrine complications of this syndrome have not yet been fully described in previous reports. We here investigated the clinical manifestations of Sotos syndrome in Japanese patients who presented with hyperinsulinemic hypoglycemia of infancy. We recruited patients diagnosed as having Sotos syndrome who presented with the complication of hyperinsulinemia during the neonatal period using a survey of the abstracts of Pediatric Meetings in domestic areas of Japan from 2007 to 2011. As a result, five patients (four females and one male) were recruited to evaluate the clinical presentation of Sotos syndrome by reference to the clinical record of each patient. A 5q35 deletion including the NSD1 gene was detected in all patients. Major anomalies in the central nervous, cardiovascular, and genito-urinary systems were frequently found. Hypoglycemia occurred between 0.5 and 3 hr after birth and high levels of insulin were initially found within 3 days of birth. The patients were treated with intravenous glucose infusion at a maximum rate of 4.6-11.0 mg/kg/min for 12-49 days. Three of the five patients required nasal tube feeding. One patient received medical treatment with diazoxide. This study shows that patients with Sotos syndrome may present with transient hyperinsulinemic hypoglycemia in the neonatal period.

Recurrent spontaneous hypoglycaemia causes loss of neurogenic and neuroglycopaenic signs in infants with congenital hyperinsulinism.

OBJECTIVE: Hypoglycaemia-associated autonomic failure (HAAF) with impaired neurogenic and neuroglycopaenic responses occurs in adults following recent, repeated hypoglycaemia. We aimed to evaluate whether HAAF also occurs in patients with infant-onset congenital hyperinsulinism (CHI). DESIGN, PATIENTS: A controlled fast was performed in (i) seven CHI infants with initial symptomatic hypoglycaemia and three recent episodes of spontaneous recurrent hypoglycaemia each lasting <5 min and in (ii) seven infants with idiopathic ketotic hypoglycaemia for control. MEASUREMENTS: At the time of hypoglycaemia (blood glucose <3 mmol/l or clinical signs), blood was drawn for serum insulin, cortisol, glucagon, adrenalin and nor-adrenalin. Signs of hypoglycaemia were documented. In CHI patients, the ABCC8 and KCNJ11 genes were analysed by denaturing high performance liquid chromatography (DHPLC) and/or direct bidirectional sequencing. RESULTS: Two CHI patients had a paternal ABCC8 mutation, five had no mutations. When repeated hypoglycaemia was provoked, all CHI patients exhibited a complete loss of clinical signs of hypoglycaemia, along with a global blunting of the counter-regulatory hormones cortisol, glucagon, growth hormone, adrenalin and nor-adrenalin responses (median values 256 nmol/l, 23 pmol/l, 5·6 mU/l, 390 pmol/l and 2·9 nmol/l, respectively), irrespective of mutational status. In the controls, hypoglycaemia was always clinically overt with normal counter-regulatory cortisol, glucagon, adrenalin and nor-adrenalin responses (530 nmol/l, 60, 920 pmol/l and 4·0 nmol/l, respectively). CONCLUSION: Recurrent hyperinsulinaemic hypoglycaemia even of short duration blunts the autonomic, neuroglycopaenic and glucose counter-regulatory hormonal responses in patients with infant-onset CHI resulting in clinically silent hypoglycaemia. Tight, or continuous, glucose monitoring is therefore recommended, especially in conservatively treated patients.

ATP-Sensitive Potassium Channels in Hyperinsulinism and Type 2 Diabetes: Inconvenient Paradox or New Paradigm?

Secretion of insulin from pancreatic ß-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of ß-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.

Clinical characteristics of recessive and dominant congenital hyperinsulinism due to mutation(s) in the ABCC8/KCNJ11 genes encoding the ATP-sensitive potasium channel in the pancreatic beta cell.

BACKGROUND: Recessive mutations in ABCC8/KCNJ11 of beta-cell K(ATP) channel generally cause severe medically unresponsive hyperinsulinemic hypoglycemia (HH). Rarer dominant mutations in these genes have been described that mostly cause milder, medically responsive congenital hyperinsulinism. Rarer dominant mutations in these genes have been described that mostly cause milder, medically responsive congenital hyperinsulinism. To date the phenotype of patients with dominant mutations seems to be different from those with recessive mutations as the majority of patients are responsive to diazoxide therapy. Controversy exists on whether these dominant ABCC8 or KCNJ11 genes mutations predispose to diabetes mellitus in adulthood or not. SUBJECTS: We report the clinical and genetic characteristics of five patients with neonatal HH, three had recessively inherited K(ATP) channel mutations and two with a dominantly acting mutation. As a result of failure to medical therapy, patients with recessive K(ATP) channel mutations underwent a near total pancreatectomy. Two siblings with a novel dominant mutation showed good response to medical treatment. Although the HH remitted in early infancy, they became diabetic at the prepubertal age. Their mother, maternal aunt and maternal grandfather had the same mutation without any medical history of neonatal HH. CONCLUSION: The clinical presentation of our two patients with a dominant ABCC8 mutation was milder than that of patients with the resessive form of the disease as they responded well to medical management.

Persistent hyperinsulinemic hypoglycemia with left ventricular hypertrophy and dysrhythmia: a case report.

Persistent hyperinsulinemic hypoglycemia in neonatal period is characterized by insulin hypersecretion. The major feature is severe hypoglycemia, generally unresponsive to routine medical treatment. Subtotal or total pancreatectomy is performed in unresponsive cases. In this case report, we present a newborn with persistent hypoglycemia unresponsive to medical treatment with dysrhythmic left ventricular hypertrophy. The insulin/C-peptide ratio was 58 as a confirmation of diagnosis. Since hypoglycemia persisted after the initial medical treatment, a subtotal pancreatectomy was performed followed by near-total pancreatectomy. A histologic examination revealed diffuse insulin islets. At the 70th post-natal day, death occurred due to heart failure and ventricular dysrhythmia. To our knowledge, severe dysrhythmia and left ventricular hypertrophy in persistent hyperinsulinemic hypoglycemia (PPH) is identified in the patient.

Congenital hyperinsulinsim: case report and review of literature.

Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates and children. Prompt diagnosis and management of the underlying hypoglycemia disorder is critical for preventing brain damage and improving outcomes. Congenital hyperinsulinism (CHI) is the most common and severe cause of persistent hypoglycemia in neonates and children, it represents a group of clinically, genetically and morphologically heterogeneous disorders characterised by dysregulation of insulin secretion from pancreatic ß-cells. It is extremely important to recognize this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, CHI is divided mainly into two types focal and diffuse disease. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localized to a small region of the pancreas. Recent discoveries of the genetic causes of CHI have improved our understanding of the pathophysiology, but its management is complex and requires the integration of clinical, biochemical, molecular, and imaging findings to establish the appropriate treatment according to the subtype. Here we present a case of sever congenital hyperinsulinism in a girl admitted for lethargy, irritability and general seizures accompanied with profound hypoglycemia, in spite of aggressive medical treatment, she died because of sever congenital hyperinsulinism diazoxide unresponsive.

The role of 18F-DOPA PET/CT in the diagnosis of the congenital focal form of hyperinsulinism in children. / Papel de la PET/TC con 18F-DOPA en el diagnóstico de la forma congénita focal del hiperinsulinismo en niños.

BACKGROUND: Congenital hyperinsulinism (CHI) is a neuroendocrine disease with focal or diffuse abnormalities in pancreas. While drug-resistant diffuse forms require near-total pancreatectomy or prolonged pharmacotherapy, focal CHI may be treated by targeted surgical resection. We evaluated the usefulness of 18F-DOPA PET/CT to identify the focal pancreatic form. SUBJECTS AND METHODS: Nineteen children (11 boys, 8 girls, aged 2-54 months) with clinical signs of neonatal CHI and positive genetic examinations were enrolled in the study. After i.v. administration of 18F-DOPA, early PET and late PET/CT acquisition covering one-bed length over thoraco-abdominal region were performed. Both acquisitions were done in dynamic mode to allow exclusion of frames with motion artefacts. Standardized uptake values were adjusted to bodyweight (SUVbw). The finding was considered as focal when the ratio of SUVbwmax between the suspicious region and the rest of pancreas was greater than 1.2. RESULTS: Focal forms were recorded in 10/19 children and 4 of them underwent surgical resection with complete recovery. Focal uptake was significantly higher than the uptake in the normal pancreatic tissue (p=0.0059). Focal and diffuse forms of CHI did not differ significantly in normal pancreatic tissue uptake. We found no advantage in the measurement of SUVbwmean ratio compared to SUVbwmax ratio (p=0.50). CONCLUSION: 18F-DOPA PET/CT is a useful tool for the localization of focal CHI and planning of surgical treatment.

Hyperinsulinism in developmental syndromes.

Hyperinsulinism is a cause of recurrent and severe hypoglycaemia in the newborn and infancy period. Several developmental genetic syndromes are associated with hyperinsulinism. The underlying molecular mechanisms that lead to hyperinsulinaemic hypoglycaemia in most of these syndromes are unclear. Beckwith-Wiedemann syndrome (BWS) is the most common syndrome associated with hyperinsulinism. The incidence of hyperinsulinism in children with BWS is about 50%. The hyperinsulinaemic hypoglycaemia can be transient, which, in the majority of infants, will be asymptomatic and resolve within the first few days of life. Rarely patients with BWS may require a pancreatectomy. Other overgrowth syndromes such as Soto's syndrome may overlap with BWS and present with hyperinsulinism. Patients with other rare syndromes such as Costello, Timothy and Kabuki syndromes can present with hyperinsulinaemic hypoglycaemia but the genetic mechanism(s) that leads to dysregulated insulin secretion in these syndromes is(are) still unclear. The congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic syndromes with a wide symptomatology and severity. They all stem from deficient N-glycosylation of proteins. Hyper-insulinism has been described in congenital disorders of glycosylation, mostly in CDG-Ib but also as the leading symptom in a CDG-Ia patient. In summary, hyperinsulinism may be associated with a large number of developmental syndromes however the underlying molecular mechanisms that cause hyperinsulinism in these syndromes are still unknown.