Maria Guemes

The Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia.

Insulin secretion from pancreatic β-cells is tightly regulated to keep fasting blood glucose concentrations within the normal range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is a heterozygous condition in which insulin secretion becomes unregulated and its production persists despite low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. The most severe and permanent forms are due to congenital hyperinsulinism (CHI). Recent advances in genetics have linked CHI to mutations in 9 genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A and HNF1A). Histologically, CHI can be divided into 3 types; diffuse, focal and atypical. Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage. Therefore, it is essential to diagnose and treat HH promptly. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children. This review provides an overview of the genetic and molecular mechanisms leading to development of HH in children. The article summarizes the current diagnostic methods and management strategies for the different types of CHI.

Hepatocyte Nuclear Factor-4 Alfa Mutation Associated with Hyperinsulinaemic Hypoglycaemia and Atypical Renal Fanconi Syndrome: Expanding the Clinical Phenotype.

Background: The p.R63W mutation in the hepatocyte nuclear factor-4 alpha (HNF4A) results in macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia (HI). We describe 2 infants carrying this mutation, presenting with additional features. Cases Series: Patient 1, a male born with a birth weight of 1.7 SDS, was diagnosed with HI on day 2 of life. He responded to 3-10 mg/kg/day of diazoxide. Raised serum creatinine led to the investigation of renal tubular function, showing leaking of electrolytes and protein. The patient also had conjugated hyperbilirubinaemia with liver steatosis. Patient 2 was a male born with a weight of 0.36 SDS. His mother had renal Fanconi syndrome. He received parenteral nutrition and presented with HI at 1 month of age, while establishing enteral feeds. Biochemistry workup showed renal tubular leaking of calcium, sodium, and phosphate. A hypoglycaemia screen documented HI, and the patient was commenced on 2 mg/kg/day of diazoxide. Continuous glucose monitoring was performed in his mother, revealing overnight hypoglycaemia. Conclusion: Renal Fanconi syndrome represents the only HNF4A feature showing complete penetrance. Our cases suggest that the p.R63W HNF4A mutation must be considered in subjects with a normal birth weight and postulate the possibility of liver involvement as a part of this condition.

Assessment of Nifedipine therapy in Hyperinsulinemic Hypoglycemia due to mutations in the ABCC8 gene.

Context Previous case reports have documented the effectiveness of l-type calcium channel blockers (such as nifedipine and verapamil) for treating different forms of hyperinsulinemic hypoglycemia (HH). Objective To systematically assess the glycemic response to nifedipine therapy in 11 patients with HH due to mutations in the ABCC8 gene. Design Dose escalation of nifedipine therapy. Settings and Patients Eleven children who were inpatients at a tertiary hospital and had diazoxide unresponsive HH due to mutations in the ABCC8 gene. Intervention(s) Nifedipine was administered orally at an escalating dose up to a maximum of 2.5 mg/kg/d. Main Outcome Measures Improvement in glycemic control, avoidance of hypoglycemic episodes, reduction of intravenous glucose infusion, and reduction in the requirements of other medical therapies. Results The median age of the patients was 0.44 years (range 0.14 to 3.77). The ABCC8 gene mutations were homozygous in 3 cases, paternally inherited heterozygous in 4, and compound heterozygous in 4. 18F-DOPA PET/CT scan demonstrated a focal lesion in 2 cases and the rest were diffuse HH disease. One subject had nifedipine as monotherapy, whereas the rest had it in combination with octreotide/glucagon/diazoxide or cornstarch. After a median of 6.5 (3 to 23) days of maximal (2.5 mg/kg/d) dose of nifedipine therapy, none of the patients showed any improvement in glycemic control and patients continued to have hypoglycemic episodes. Conclusions HH due to mutations in the ABCC8 gene does not respond to nifedipine therapy. Mutations in the KATP channel genes might render the l-type calcium channel ineffective to therapy with nifedipine.

Severe Hyperinsulinaemic Hypoglycaemia in Beckwith-Wiedemann Syndrome due to Paternal Uniparental Disomy of 11p15.5 Managed with Sirolimus Therapy.

Background: Almost half of the children with Beckwith-Wiedemann syndrome (BWS) will develop hyperinsulinaemic hypoglycaemia (HH). In the majority of BWS cases, HH will be transient; however, approximately in 5% of them, HH will be severe and often medically-unresponsive. Children with BWS due to paternal uniparental disomy (UPD) of chromosome 11p15 belong to this severe category and have traditionally required near-total pancreatectomy. The use of mTOR inhibitors had not been reported yet in this type of patients. Case: A 1-month-old female with genetically confirmed BWS due to UPD of chromosome 11p15 was admitted for management of severe HH. Blood glucose concentrations were stabilised with high intravenous dextrose concentration, glucagon and octreotide infusions as she was proven to be diazoxide unresponsive. To avoid a subtotal pancreatectomy, an mTOR inhibitor - sirolimus - was introduced. The dose of sirolimus was optimised progressively and she was able to come off intravenous fluids and glucagon therapy. She has not presented any side effects and her growth is normal after 19 months of therapy. Conclusion: This is the first case reported of BWS due to UPD of chromosome 11p15 where sirolimus treatment has been effective in stabilising the blood glucose concentrations and avoiding a near-total pancreatectomy without major side effects detected.

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

CONTEXT Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. OBJECTIVE The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. DESIGN A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. RESULTS Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology. CONCLUSIONS Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.

Idiopathic postprandial hyperinsulinaemic hypoglycaemia.

Abstract Background: Idiopathic postprandial hyperinsulinaemic hypoglycaemia (PPHH) has rarely been reported in the paediatric age. The objective of this study was to describe the clinical characteristics, diagnosis and management in a group of children with PPHH. Methods: Six children (three females) with a mean follow-up of 3.5±3.0 years at a single tertiary paediatric hospital. All had 24-h blood glucose monitoring, diagnostic fast and prolonged oral glucose tolerance test (OGTT). Follow-up included: 24-h blood glucose monitoring or continuous glucose monitoring system, prolonged OGTT and/or mixed meal (MM) test. Results: Age at diagnosis ranged from 5.4 to 15.7 years and auxology parameters were within normal range in all subjects. All the children had a normal fasting tolerance for age. Prolonged OGTT demonstrated symptomatic hypoglycaemia after 120 min in all the patients with simultaneous detectable serum insulin concentration. Acarbose was tried in three patients, having a positive effect on glycaemic and symptom control, but due to side effects, only two patients continued acarbose in the long run. Diazoxide proved to be beneficial in one patient. The rest of the patients were managed with frequent feeds but despite this, prolonged OGTT/MM demonstrated on-going PPHH. Conclusions: Prolonged OGTT is necessary to diagnose PPHH in children. Acarbose is beneficial in children with PPHH, although not well tolerated. Patients managed exclusively on frequent feeds demonstrated persistent hypoglycaemia on OGTT. The underlying cause of the PPHH in these patients remains unknown.

Enteroinsular hormones in two siblings with Donohue syndrome and complete leptin deficiency

The main biochemical hallmark of the rare and lethal condition of Donohue syndrome (DS) is hyperinsulinemia. The roles of the gut and other pancreatic hormones involved in glucose metabolism, satiety and energy expenditure have not been previously reported in DS. Two siblings with genetically confirmed DS and extremely low weight underwent a mixed meal (MM) test where pancreatic hormones insulin, C‐peptide, glucagon, active amylin, pancreatic polypeptide (PP) as well as gut hormones active glucagon‐like peptide 1 (GLP‐1), glucose‐dependent insulinotropic peptide (GIP), ghrelin, peptide YY (PYY) and leptin were analyzed using a Multiplex assay. Results were compared to those of 2 pediatric controls. As expected, concentrations of insulin, C‐peptide and amylin were very high in DS cases. The serum glucagon concentration was undetectable at the time of hypoglycemia. GIPs concentrations were lower in the DS, however, this was not mimicked by the other incretin, GLP‐1. Ghrelin concentrations were mainly undetectable (<13.7 pg/mL) in all participants. DS cases had higher PYY and dampened PP concentrations. Leptin levels remained completely undetectable (<137.0 pg/mL). Patients with DS have extremely high amylin levels, completely undetectable serum glucagon and leptin levels with abnormal satiety regulating hormone PP with a relatively normal ghrelin response during a MM test. The low serum GIP might be acting as physiological brake on insulin secretion. The undetectable serum leptin levels suggest the potential of using leptin analogues as therapy for DS patients.

Post-Prandial Hyperinsulinaemic Hypoglycaemia after Oesophageal Surgery in Children

Introduction: Post-prandial hyperinsulinaemic hypoglycaemia (PPHH) is a recognized complication of various gastric surgeries in children, but rarely reported after oesophageal atresia repair. We report 2 children diagnosed with PPHH after oesophageal surgery and the challenges of their management. Case 1: A 2-year-old boy diagnosed with oesophageal atresia at birth was surgically repaired requiring 6 oesophageal dilatations in the first year of life. At 11 months of age, he manifested hypoglycaemic seizures and investigations confirmed PPHH. Acarbose and diazoxide trials failed. He was managed with 17-h continuous gastrostomy feeds. Currently, he is 28 months old with euglycaemia on daytime bolus gastrostomy feeds and overnight 12-h continuous gastrostomy feeds. Case 2: A 6-month-old girl diagnosed with Wolf-Hirschhorn syndrome and tracheo-oesophageal fistula was surgically repaired, requiring monthly oesophageal dilatations. At 5 months of age, she was reported to have hypoglycaemia and PPHH was confirmed. She responded to diazoxide and continuous nasogastric tube feeds, but developed pulmonary hypertension possibly diazoxide-induced. Subsequently, diazoxide was stopped and normoglycaemia was secured via 20-h continuous gastrostomy feeds. Conclusion: PPHH may be an underdiagnosed complication in children undergoing surgery for oesophageal atresia. These children must be monitored closely for symptoms of hypoglycaemia and if there are concerns must be screened for possible PPHH. Our cases demonstrate that continuous feeding regimens might be the only therapeutic option, until PPHH gradually lessens in intensity over time.

The Use of a Long-Acting Somatostatin Analogue (Lanreotide) in Three Children with Focal Forms of Congenital Hyperinsulinaemic Hypoglycaemia

Background: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. Conclusion: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.

Sirolimus precipitating diabetes mellitus in a patient with congenital hyperinsulinaemic hypoglycaemia due to autosomal dominant ABCC8 mutation.

Abstract Background: Sirolimus (mTOR inhibitor) is proven to be effective in children with congenital hyperinsulinism (CHI). Studies in animals suggest that sirolimus may have diabetogenic actions. However, its role in precipitating diabetes mellitus (DM) in children with CHI has not been reported. Case presentation: A 16-year-old female with CHI due to a dominant ABCC8 gene mutation was switched from diazoxide therapy to sirolimus, due to the hypertrichosis side effect of diazoxide. She developed facial cellulitis that was treated with clarithromycin and a month later, once the infection was resolved, she was found to have persistent hyperglycaemia, and was diagnosed with DM. She was unresponsive to oral sulfonylurea therapy and is currently managed with metformin. Her mother, who had the same ABCC8 mutation, developed DM at her 30s. Conclusions: Patients with dominant ABCC8 gene mutations are prone to DM in adulthood, but Sirolimus therapy might increase the risk of developing diabetes at an early age, as this case illustrates.