A case of familial nesidioblastosis: prenatal diagnosis of foetal hyperinsulinism

Persistent neonatal hyperinsulinaemic hypoglycaemia due to nesidioblastosis is a rare condition probably transmitted by an autosomal recessive inheritance. Recurrent hypoglycaemic episodes become evident after birth and cause severe neurological damage without intensive treatment. The intrauterine detection of hypoglycaemia and hyperinsulinism in newborns subsequently diagnosed as affected by nesidioblastosis has not yet been reported. We describe a case of familial nesidioblastosis in which an intrauterine diagnosis could be suggested by high levels of insulin and C-peptide and low values of glucose in the amniotic fluid.     

Somatostatin analogue SMS 201-995 in the short-term management of neonatal hyperinsulinism due to nesidioblastosis

Abstract A neonate with persistent hyperinsulinaemic hypoglycaemia is presented in whom the use of intravenous somatostatin SMS 201-995 allowed good glycaemic control over 10 days. A 95% pancreatectomy was then performed.     

Near-Total Pancreatectomy for Hyperinsulinism: Spontaneous Remission of Resultant Diabetes

ABSTRACT. Persistent hyperinsulinism in the newborn may warrant surgical intervention to prevent neurologic sequelae. Subtotal pancreatectomy may not be adequate, necessitating near-total pancreatectomy with subsequent development of diabetes mellitus. We report an infant with hyperinsulinemic hypoglycemia who underwent near-total pancreatectomy. The postoperative period was characterized by insulin-dependency and extreme insulin sensitivity. Clinical follow-up and C-peptide determinations showed a return of insulin secretory capacity permitting the discontinuation of insulin therapy after five months. This experience reaffirms the potential for a favorable outcome after near-total pancreatectomy in the newborn period for severe hyperinsulinism.     

A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase

Activating mutations in the GLUD1 gene, which encodes glutamate dehydrogenase (GDH), result in the hyperinsulinism‐hyperammonemia syndrome. GDH is an allosterically regulated enzyme responsible for amino acid‐mediated insulin secretion via the oxidative deamination of glutamate to 2‐oxoglutarate, leading to ATP production and insulin release. This study characterizes a novel combination of mutations in GLUD1 found in a neonate who presented on the first day of life with severe hypoglycemia, hyperammonemia, and seizures. Mutation analysis revealed a novel frameshift mutation (c.37delC) inherited from the asymptomatic mother that results in a truncated protein and a de novo activating mutation (p.S445L) close to the GTP binding site that has previously been reported. GTP inhibition of GDH enzyme activity in 293T cells expressing the p.S445L or wild‐type GDH showed that the half‐maximal inhibitory concentration (IC₅₀) for GTP was approximately 800 times higher for p.S445L compared to wild type. GTP inhibition of GDH activity in lymphoblasts from the patient, from a heterozygote for the p.S445L mutation, and in wild‐type lymphoblasts showed that the IC₅₀ for GTP of the patient was approximately 200 times that of wild type and 7 times that of heterozygote. However, while the patient had a loss of GTP inhibition of GDH that was more severe than that of heterozygotes, the patient's clinical phenotype is similar to typical heterozygous mutations of GDH. This is the first time we have observed a functionally homozygous activating mutation of GDH in a human.     

Ten years' experience of persistent hyperinsulinaemic hypoglycaemia of infancy

OBJECTIVE: To review the presentation, management and outcome of persistent hyperinsulinaemic hypoglycaemia of infancy seen at the Royal Alexandra Hospital for Children over a 10 year period. METHODOLOGY: A retrospective review of 20 subjects was performed. As well as laboratory data, data were collected on clinical presentation, medical and surgical management and developmental outcome. RESULTS: Twenty subjects (11 male) were identified with presentation at a median age of 1.5 months (range 0-10 months), with 10 (50%) presenting in the first week of life. Only 20% of patients were large for gestational age. Diagnosis was made on the basis of high glucose requirements and inappropriately high insulin levels at the time of hypoglycaemia. Eight (40%) responded well to diazoxide treatment alone, seven (35%) received diazoxide in combination with other short-term medical therapy initially and five (25%) required pancreatectomy (repeat surgery in three). Those who required surgery had a higher mean birth weight. Infants presenting in the first week of life were less likely to respond to diazoxide. At the time of last review, eight (40%) of those treated medically had ceased all treatment. Two of the five cases requiring pancreatectomy now require insulin treatment. Neurodevelopmental assessment was normal in 11 (55%), mild delay was found in six (30%) and moderate or severe delay was found in three (15%). CONCLUSIONS: Persistent hyperinsulinaemic hypoglycaemia of infancy remains a major diagnostic and management challenge. Early suspicion and recognition is critical with definitive investigation and medical therapy to avoid hypoglycaemia, with pancreatectomy in medically unresponsive cases. Normal neurodevelopmental outcome was found in only 55% of cases.     

Prospective study of nesidioblastosis in newborns and infants: Hypoglycemic seizures,epileptogenesis and the significance of the C-peptide suppression test in pancreatectomy

The long-term follow-up of chronic hyperinsulinemic seizures, epileptogenesis and other neurological complications in five patients who were treated with conservative therapy followed by pancreatectomy during the neonatal period and infancy, who were confirmed to have diffuse nesidioblastosis are described. The reaction pattern of the C-peptide (CPR) suppression test and its relation to the final extent of pancreatectomy was examined in four patients. The chronological change in electro-encephalography (EEG) and its epileptogenesis was also examined in each patient during hyperinsulinemic hypoglycemia, and during normoglycemia in a long-term post-pancreatectomy follow-up. All patients demonstrated several types of hypoglycemic seizures, ranging from apnea, erratic seizures, partial seizures evolving to generalized/unilateral tonic-clonic or tonic seizures, myoclonic seizures and EEG abnormalities. Four of five patients still suffered from epilepsy at the age of 4–22 years. The reaction pattern of the CPR suppression test showed dichotomy, with a hyper-reactive pattern in two patients who required total pancreatectomy to control hypoglycemia, and a suppression pattern in two other patients treated with 90–95% pancreatectomy. Neonatal onset and subsequent myoclonic seizures were ominous signs of epileptogenesis to various types of intractable epilepsy and other neurological sequelae. A prompt diagnosis and pancreatectomy of a sufficient extent at the first operation are essential. The CPR suppression test may be useful for a prompt diagnosis and selection of the extent of pancreatectomy.     

Neonatal case of novel KMT2D mutation in Kabuki syndrome with severe hypoglycemia

A newborn Japanese girl with Kabuki syndrome had neonatal persistent hyperinsulinemic hypoglycemia, which seemed to be a rare complication of Kabuki syndrome. On sequence analysis she was found to have a novel heterozygous KMT2D mutation. Diazoxide therapy was effective for the hypoglycemia. Hypoglycemia should be considered when Kabuki syndrome patients have convulsion or other non‐specific symptoms. Diazoxide may help to improve hypoglycemia in patients with Kabuki syndrome complicated with hyperinsulinemic hypoglycemia.     

A Case of Persistent Hyperinsulinemic Hypoglycemia of Infancy Successfully Managed with Subcutaneous Octreotide Injection and Nocturnal Intravenous Glucose Supply

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is often resistant to medical therapy and is normally treated by subtotal pancreatectomy to avoid neurological complications. However, many problems after surgery, such as recurrence of hypoglycemia and diabetes mellitus, remain to be solved. This report concerns a case of PHHI that was resistant to octreotide or diazoxide alone but was successfully controlled with subcutaneous injection of octreotide in combination with nocturnal glucose infusion through central venous catheter. The patient exhibited natural remission of hyperinsulinism with age, and all treatment was ceased at the age of 4 yr. Growth and neurological development of the patient have been normal. This combined therapy can be a therapeutic option as a substitute for surgical solutions.     

Histopathology of Congenital Hyperinsulinism: Retrospective Study with Genotype Correlations

The majority of the most severe cases of congenital hyperinsulinism (HI) are caused by defects in the -cell adenosine triphosphate (ATP)-sensitive potassium channel and usually require pancreatectomy to control blood sugar levels. In contrast to the recent advances in understanding the pathophysiology and genetic bases of HI, the histologic classification of this condition remains controversial. A recent proposal to classify the HI pancreata into diffuse and focal forms has drawn much interest because of its relative simplicity and its good correlation with the genetic abnormalities. We undertook a retrospective study to determine whether this classification scheme could be applied to 38 pancreata resected for HI at our institution. We also obtained leukocyte genomic DNA from 29 cases and screened the exons of ABCC8 and KCNJ11 genes for the presence of mutations. Nineteen cases (50.0%) were histologically classified as diffuse HI and 14 cases (36.8%) were categorized as focal form. The mutational analysis revealed that 14 of the 16 diffuse cases analyzed had either homozygous or compound heterozygous mutations of ABCC8 or KCNJ11 and 7 of 10 focal cases had only the paternally inherited mutations, consistent with the previous observations. Two patients (5.3%) had normal pancreatic histology but had persistent hypoglycemia postoperatively, leaving the possibility of residual focal lesion. Three of 38 cases (7.9%) did not fit well into either diffuse or focal category. Two cases differed from the described pattern for the diffuse form in that the nuclear enlargement was confined to a single area of the pancreas. The other case had a focal lesion but -cell nuclear enlargement was present in nonadjacent areas. Mutations for typical diffuse or focal HI were not identified in two of these three equivocal cases. We conclude from this study that nearly 90% of HI cases can be classified into either a diffuse or a focal form. However, a small percentage of cases represented a diagnostic challenge.     

�����������Ը��ȵ���Ѫ֢15���ٴ�����

??Abstract?? Objective??To study the diagnosis and treatment of neonatal Congenital Hyperinsulinism Hypoglycemia??CHI??. Methods??The clinical data of 15 newborn babies with CHI??who were diagnosed in Beijing Children’s Hospital between 2000 and 2010??were retrospectively reviewed. Results??Sex ratio of boys to girls was 10??4. Time variation in disease onset?? from less than 1 hour after labor to 25 days. ten of 15 patients were large for gestational age?? 8 of them were macrosonias. Convulsion??cyanosis??lethargy??refusing milk sucking??irritability and sweating were common symptoms. The laboratory findings displayed persistent hypoglycemia and hyperinsulinism in all of the 15 newborn babies. There were no urine and blood ketones elevating in all of the 15 newborn babies. Nine infants were treated with oral diazoxide??but only 2 of them showed effectiveness to the therapy. One patient was given subtotal pancreatectomy and the blood glucose level was restored to normal after operation. Two newborn babies died within 2 weeks. Of the other 13 newborn babies??only 3 who were effectively treated had normal intelligence. Nine of them presented mental retardation in a 5-year follow-up. Conclusion??The measurement of blood glucose??blood insulin and urinary ketones is helpful in the diagnosis of persistent hyperinsulinemic hypoglycemia of infancy. Most patients have no response to diazoxide therapy. Whenever drug treatment is comfirmed unresponsive??operation should be considered.     

Congenital Hypoglycemia Disorders: New Aspects of Etiology,Diagnosis, Treatment and Outcomes

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 (HI) is the most common and severe cause of persistent hypoglycemia in neonates and children. Recent discoveries of the genetic causes of HI 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 summary of a recent international symposium on congenital hypoglycemia disorders with emphasis on novel molecular mechanisms resulting in HI, genetic diagnosis, overall approach to management, novel therapies under development, and current outcomes.     

Subtotal pancreatectomy for hypoglycemia due to congenital hyperinsulinism: long-term follow-up of neurodevelopmental and pancreatic function

Abstract: Objective: To evaluate neurodevelopmental status as well as endocrine and exocrine pancreatic function in children who have undergone subtotal pancreatectomy for hypoglycemia due to congenital hyperinsulinism. Patients and methods: Out of 15 identified patients, eight children (mean age 12.7 ± 0.8 yr) participated in detailed psychometric testing and studies assessing glucose homeostasis, secretion of proinsulin, insulin, glucagon and C‐peptide during a test meal. Additionally, a 24‐h fast, glucagon challenge test, 72‐h stool collection, and ultrasonography of the pancreatic remnant were performed. Results: Five of the 15 initially identified children had seizure disorders, including two with mental retardation. Diabetes developed in two of 15 children. All eight children investigated in the present study had evidence for attentional control impairment and 50% had subnormal intellectual functioning. Two had symptomatic hypoglycemia during the 24‐h fast, while one had an elevated fasting glucose concentration. Four children, including the latter patient, had proinsulin/insulin ratios resembling patients with type 2 diabetes. Exocrine pancreatic function was normal in all eight children. No correlation was found between pancreatic endocrine function and pancreatic remnant size, nor between multiple pre‐ and postoperative factors (i.e., age at diagnosis and surgery) and neurodevelopmental outcome. Conclusion: While severe mental retardation or diabetes occurred infrequently in our patient population compared with previous reports, all of the studied children had subtle anomalies in their cognitive performance tests and the majority had endocrine test results indicative of abnormal insulin secretion and stressed pancreatic β cells. Although partial pancreatectomy remains the treatment of choice after medical therapy fails, improved therapeutic means are necessary to achieve better clinical outcome.     

Severe fasting hypoglycemia in a child after total pancreatectomy with islet autotransplantation

TPIAT is an increasingly utilized treatment option for select children with CP. Post‐TPIAT fasting hypoglycemia, unrelated to exogenous insulin, is a complication recently reported in adults. This phenomenon has not been described in children. We review a case of severe fasting hypoglycemia in an adolescent female occurring 10 months post‐TPIAT. A 12‐year‐old girl underwent TPIAT for CP. Ten months postoperatively she developed recurrent hypoglycemia on a total daily insulin dose of 0.03 units/kg. Consequently, insulin therapy was discontinued. Approximately 20 hours after her last rapid‐acting insulin exposure, she had an episode of fasting hypoglycemia (33 mg/dL on glucometer). Her CGM documented two separate, precipitous drops in glucose overnight. The family was instructed to revise her diet, and there were no subsequent episodes of severe, fasting hypoglycemia. This is the first report of fasting hypoglycemia occurring post‐TPIAT in a pediatric patient. Use of a CGM allowed for documentation of glucose trends and alarm notification of hypoglycemic events. Dietary changes appeared to help mitigate hypoglycemia recurrence. This report demonstrates that fasting hypoglycemia is a potential complication that should be recognized and safeguarded against in post‐TPIAT pediatric patients.     

Portosystemic shunt as a cause of congenital hyperinsulinemic hypoglycemia

Congenital hyperinsulinemic hypoglycemia (CHH) is characterized by the inappropriate secretion of insulin from pancreatic beta cells in the presence of hypoglycemia. We herein describe the case of a 5‐month‐old boy with CHH due to congenital portosystemic shunt (CPSS). Insulin secreted from pancreatic beta cells flows into the portal vein and is first metabolized in the liver. First‐pass elimination of insulin in the liver leads to great decrease in insulin concentration by approximately 40–80% in humans. CPSS accounts for a large quantity of insulin delivery into the systemic circulation due to the lack of hepatic first‐pass elimination. Hypoglycemia can result from consistently high levels of insulin after reaching normal glucose level. CPSS therefore should be considered as a rare cause of CHH, especially in the case of post‐prandial hyperinsulinemic hypoglycemia.     

Nesidiodysplasia and Nesidioblastosis of Infancy: Structural and Functional Correlations with the Syndrome of Hyperinsulinemic Hypoglycemia

Subtotal pancreatectomy specimens of seven infants with persistent hyperinsulinemic hypoglycemia were studied; all showed the characteristic light microscopic picture of nesidioblastosis. Specimens were studied by electron and conventional light microscopy and by light microscopic immunohistochemistry for insulin, glucagon, somatostatin, and HPP (human pancreatic polypeptide); double staining and quantitative methods were also used. Findings were compared with those in age-matched controls.

In the hyperinsulinemic hypoglycemic infants, an increase in total endocrine cell volume was found; however, the typical features of nesidioblastosis were also found in the controls. In both groups, immunohistochemistry and electron microscopy suggested that some endocrine cells are capable of producing synchronously more than one hormone. Amphicrine (”composite” or “intermediate”) cells with exocrine and endocrine differentiation were found in three hypoglycemic infants.

Observations are discussed in relation to current concepts of embryo genesis of the gastroenteropancreative endocrine system. We conclude that nesidioblastosis, as defined anatomically cannot be considered as the morphologic basis of hyperinsulinemic hypoglycemia. The term “nesidiodysplasia” is suggested and includes increased, maldistributed, and malregulated or malprogrammed endocrine and amphicrine cells when associated with endocrine abnormality.     

Focal or Diffuse Lesions in Persistent Hyperinsulinemic Hypoglycemia of Infancy: Concerns about Interpretation of Intraoperative Frozen Sections

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) results from defects of regulated insulin release from pancreatic β cells and is often refractory to medical treatment. Histological changes in the pancreas associated with PHHI may be focal or diffuse, and the intraoperative confirmation and siting of focal lesions would require frozen section diagnosis. The recognition of focal involvement and its distinction from diffuse disease by frozen section depends on the identification and distribution pattern of islet cells with large hyperchromatic nuclei. This study was designed to test the feasibility of using this parameter in PHHI to delineate focal from diffuse diseases prior to the introduction of frozen sections to guide intraoperative management in our institution. A total of 66 coded and randomized paraffin sections (from 18 PHHI and 4 postmortem pancreases) were scored by three independent observers into the following categories: a focal lesion (A), no large endocrine nuclei (B), few large endocrine nuclei (C), and frequent large endocrine nuclei (D). Interobserver concordance was complete in 88%, but there were minor discrepancies in the remaining 12%. When a focal lesion was present in one section no large endocrine nuclei were seen in sections from the rest of the pancreas. In four patients with diffuse PHHI, no or only very scanty large endocrine nuclei were seen. From this finding, and the observation that in other examples of diffuse disease, large endocrine nuclei were sparse even in large paraffin sections, we have reservations about using small frozen sections for reliable diagnosis. Received January 31, 2000; accepted May 2, 2000.     

Glycemic variability in preterm infants receiving intermittent gastric tube feeding: Report of three cases

Late‐onset hypoglycemia (day 12–16, blood glucose <50 mg/dL) was detected in three preterm infants (birthweight 998–1780 g; gestational age 27–30 weeks) by routine screening. All infants showed high serum insulin levels and extremely low ketone levels at the time of hypoglycemia. Continuous glucose monitoring was conducted at 31–34 weeks' postconceptual age when the infants were receiving intermittent gastric tube feeding with no intravenous glucose infusion. The continuous glucose monitoring results showed characteristic postprandial glucose increases and subsequent sharp deceases along with many hyper‐ and hypoglycemic events. This fluctuating pattern disappeared at 38–40 weeks' postconceptual age. These observations suggest that prolonged insulin oversecretion may be associated with early aggressive intravenous nutrition, and that large glycemic variability is a common feature of tube‐fed preterm infants that can be explained by immature glucose homeostasis.