Kate Morgan

Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation

Abstract Introduction: Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of severe diazoxide unresponsive HH involves near total pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. mTOR inhibitors are used in cancer patients and recently found to be effective in the treatment of insulinoma and HH patients. Case: A 36 weeks large for gestational age neonate presented with severe hypoglycaemia on day 1 of life. The hypoglycaemia screen confirmed HH and genetic testing revealed compound heterozygous ABCC8 mutation, confirming diffuse disease. He was unresponsive to the maximal dose of diazoxide (15 mg/kg/day), hence needed treatment with higher concentration of intravenous glucose (25 mg/kg/min), intravenous glucagon and subcutaneous octreotide (30 μg/kg/day) infusions to maintain normoglycaemia. Sirolimus, a mTOR inhibitor, was commenced at 9 weeks of age following which he showed a marked improvement in his glycaemic control. After 4 weeks of sirolimus therapy, he was discharged home on subcutaneous octreotide injection (20 μg/kg/day) and oral sirolimus, thereby avoiding the need for a near total pancreatectomy. Conclusion: We report the first case of compound heterozygous ABCC8 mutation causing severe diffuse HH that responded to therapy with a mTOR inhibitor.

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.

Use of Long-Acting Somatostatin Analogue (Lanreotide) in an Adolescent with Diazoxide-Responsive Congenital Hyperinsulinism and Its Psychological Impact

Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic β cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life.

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.

C1.1 Development and implementation of congenital hyperinsulinism transition clinic pathway

Background Congenital Hyperinsulinism (CHI) is caused by inappropriate secretion of insulin which leads to severe hypoglycaemia in infants and children causing hypoglycaemic brain injury if not managed promptly. There is no designated centre in the country providing highly specialised expert input in adults with Hyperinsulinism. It was recognised that some young people at GOSH were discharged to local adult endocrinologist/diabetologist with little or no CHI experience and no multidisciplinary team input and support. The aim of our project was to develop and implement CHI transition clinics and resources to support patients, parents/carers and healthcare professionals. Methods The patients that are older and imminently needed transitioning were seen in the clinic first. A joint multi-disciplinary CHI transition clinic takes place for 13–20 years old patients. The clinic takes place once a month at the Royal London Homeopathic Hospital on Friday afternoons. The clinic would have multi-disciplinary team this includes paediatric and adult endocrinologist, psychologist, clinical nurse specialists and dietitian. Information on pre and post clinic outcome and PedsQL were collected during the clinic appointment. Results Over 6 months, we held 6 transition clinics, with 25 patients seen. Qualitative and Quantitative data has been collected and patient feedback is very positive. Resources for patients and healthcare professionals have been created to support the transition process. Conclusion Transition from paediatric to adult care is a very import part of the patient journey. Transition needs to be planned and structured to meet the needs of individual patients and should include a multi-disciplinary team. Caring for the mental and social wellbeing of the patient is just as important as their clinical needs. Patients and parents have found the transition clinic to be very useful. We will use the qualitative data collected to continually improve the patient experience and build our resource toolkit.

G100(P) Hyperinsulinaemic Hypoglycaemia of Short Duration – Can It Be Associated with Severe Hypoglycaemic Brain Injury?

Background Neurological damage is a known risk associated with hyperinsulinaemic hypoglycaemia (HH). Insulin suppresses ketone body formation and hence no alternative fuels are available for the brain to use; however it is not yet known how long HH has to last to cause brain injury. We report that neurological damage can occur after a short time in term, normal weight infants with diazoxide responsive HH. Aim To describe the clinical course and neurological outcome of 3 term neonates with severe hypoglycaemic brain injury who were not diagnosed with HH for at least 72 hours. Methodology 3 patients who presented in the neonatal period with biochemically confirmed HH were recruited. Detailed clinical information was collected including MRI brain reports. Results All three term neonates were discharged home after 24–36 hours of birth. Birth weight range was 2730–3460 gms and each delivery was classified as normal vaginal births with no associated risk factors for HH. All infants presented to the Emergency department on day 3 to 4 of life with non-specific symptoms like poor feeding and lethargy. However all of them were noted to have jerky and seizure like movements. Biochemically, all had their true blood glucose levels less than 0.6 mmols/L with raised insulin and suppressed ketone body formation They all successfully responded to small doses (5mg/kg/day) of Diazoxide (two of them are off Diazoxide now and had transient hyperinsulinism). Each neonate had MRI brain due to clinical neurological concerns within the first few weeks of life that showed significant evidence of hypoglycaemic brain injury like gross white matter changes with parieto-occipital infarcts. Conclusion It is very important for early identification and prompt management of HH as untreated severe hypoglycaemia can result in severe brain injury and subsequent neurodevelopmental handicap. Term infants with no risk factors are often difficult to identify due to non-specific symptoms. Parental education to recognise early symptoms of hypoglycaemia would be recommended and prompt medical advice should be sought. Blood glucose levels should be of utmost priority for babies presenting to A&E with non specific symptoms such as poor feeding/lethargy etc.