Persistent Hypoglycemia and Macrosomia in a Newborn

A 5200-g girl was born to a gravida 3 para 1 mother at 37 weeks and 2 days gestation via urgent Cesarean delivery for macrosomia, polyhydramnios, and maternal hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Maternal medical history was notable for spontaneous abortion of unknown cause and obesity with body mass index of 38.4 (calculated as weight in kilograms divided by height in meters squared). Maternal serologies were unremarkable except for a positive result for herpes simplex virus 1, immunoglobulin G. Glucose tolerance test at 30 weeks’ gestation was normal at 1 hour and 3 hours. The only medication taken by the mother during pregnancy was prenatal vitamins, and there was no history of tobacco, alcohol, or drug use. There was no family history of metabolic disease, congenital anomalies, or inherited genetic or chromosomal disorders. Delivery was uncomplicated with Apgar scores of 8 at 1 minute and 9 at 5 minutes of life. A blood glucose level obtained at 30 minutes of life was 16 mg/dL and a repeat 13 minutes later was 19 mg/dL. An intravenous (IV) dextrose bolus of 200 mg/kg was given. She was transferred to an outside hospital neonatal intensive care unit (NICU) at 12 hours of life and started on IV dextrose-containing fluid infusion. Blood glucose levels were initially checked every 30 minutes until greater than 50 mg/dL. She had persistent hypoglycemia despite parenteral glucose at 10 mg/kg/min and frequent feedings of high-protein formula at 24 kilocalories per ounce. She was otherwise asymptomatic. Basic metabolic panel (BMP) and complete blood count (CBC) sent at 24 hours of life were within normal range, including no evidence of polycythemia (Table 1). Blood culture was also sent at 24 hours of life to rule out sepsis and results remained negative through the final reading at 5 days. To maintain normoglycemia, the glucose infusion rate (GIR) was escalated to 17 mg/kg/min. A critical sample was obtained with an insulin level of 34 μU/mL and a cortisol level of more than 22 μg/dL, with a blood glucose of 34 mg/dL (Table 2). The elevated insulin level in the presence of hypoglycemia suggested hyperinsulinism. Therefore, IV diazoxide was initiated at 10 mg/kg/d at 6 days of age as the first-line therapy for hyperinsulinemic hypoglycemia. An echocardiogram to monitor for side effects of diazoxide is generally recommended prior to starting therapy but was not done.1 She developed acute respiratory distress at 15 days of age with a chest radiograph showing pulmonary edema. Diazoxide was held, and she was initiated on high-flow nasal cannula and then transferred to our NICU for further management on the same day.On arrival in our NICU, vital signs were notable for tachycardia at 183 beats/min, normal blood pressure at 87/47 mm Hg, normal respiratory rate at 33 breaths/min, and mild hypoxemia with an oxygen saturation of 92% on high-flow nasal cannula at 6 L/min with FiO2 0.21. On physical examination, she was large for gestational age at 6190 g (>99th percentile, Z=5.0) with mild facial edema. She was not dysmorphic, but body hair growth was present. Lung sounds were clear bilaterally without increased work of breathing. Cardiac examination revealed tachycardia with normal heart sounds without murmur, rub, or gallop. Abdomen was soft to palpation, nondistended, and without hepatosplenomegaly. The remainder of the examination findings were normal. BMP, CBC, and C-reactive protein (CRP) on admission were normal. Repeat blood culture results on admission were negative through the final reading at 5 days. Newborn screen was normal. An echocardiogram demonstrated mildly increased right ventricular pressure likely due to diazoxide therapy in a neonate but was otherwise normal.Pediatric endocrinology was consulted and recommended an IV 50% dextrose infusion with a GIR of 17 mg/kg/min, later increased to 18 mg/kg/min, to maintain normoglycemia, in addition to frequent feedings of high-protein formula. IV diazoxide at 10 mg/kg/day was restarted in conjunction with chlorothiazide at 2 mg/kg twice a day at 17 days of age and later increased to 15 mg/kg/day. She was weaned off high-flow nasal cannula at 18 days of age. At 19 days of age, critical samples were obtained with a blood glucose level of 42 mg/dL. The evaluation revealed an inappropriately elevated insulin level of 34.6 μU/mL (normally <1.0 μU/mL), undetectable beta-hydroxybutyrate, cortisol level of less than 1.0 μg/dL (stimulated >22 μg/dL), growth hormone level of 2.3 ng/mL (stimulated >7 ng/mL), and free fatty acid of 0.12 mmol/L (normally <0.73 mmol/L) (Table 2). Genetics was consulted and recommended genetic testing for Beckwith-Wiedemann syndrome (BWS). Alpha-fetoprotein was 1951 ng/mL (normal range 300–60 000 ng/dL). Free and total carnitine, acylcarnitine profile, and urine organic acids levels were within normal limits.The differential diagnosis of neonatal hypoglycemia includes infection, prematurity, infant of mother with diabetes, hyperinsulinism, inborn errors of metabolism, endocrine abnormalities, and polycythemia. Neonatal sepsis should be initially ruled out as a cause of neonatal hypoglycemia. In this case, infectious etiologies were felt to be unlikely given the absence of other symptoms of sepsis, normal CBC and CRP, and negative blood culture results.Persistent hypoglycemia is defined as low plasma glucose concentrations or the requirement of IV dextrose infusion to treat hypoglycemia beyond 48 hours after birth.2 Diagnosis of hyperinsulinism is supported by clinical presentation and laboratory testing referred to as “critical samples,” characterized by low plasma glucose, detectable or elevated insulin, inappropriately low plasma free fatty acids, and the absence of ketonuria. In this case, persistent hypoglycemia despite a high GIR and the inappropriately elevated insulin level is highly suggestive of hyperinsulinism. Newborns with hyperinsulinism may present with macrosomia, as this infant did, because of the anabolic effects of insulin in utero.Although hyperinsulinism may be transient, as with infants of mother with diabetes, hypoxic-ischemic injury, in utero growth restriction, or exposure to hypoglycemic agents, the persistence of hypoglycemia with hyperinsulinemia suggests a diagnosis of congenital hyperinsulinism (CHI). CHI is the most common cause of persistent hypoglycemia in newborns and is characterized by inappropriate or excess insulin secretion from pancreatic β cells. The most common and severe forms of CHI are secondary to autosomal recessive inactivating mutations in ABCC8 and KCNJ11 and often do not respond to diazoxide therapy.3Additionally, syndromes associated with hyperinsulinism include BWS and Kabuki syndrome. Approximately 50% of infants with BWS present with hyperinsulinism.4 BWS is caused by a constitutional epigenetic or genetic change resulting in an abnormal methylation pattern in the 11p15.5 region. BWS is highly suspected in infants with macroglossia, omphalocele, embryonal tumor, hemihyperplasia, macrosomia, hyperinsulinemic hypoglycemia, or cytomegaly of the adrenal cortex (tier 1 findings).5 This infant had 2 tier 1 findings, macrosomia and hyperinsulinemic hypoglycemia, associated with BWS but lacked other characteristic findings of BWS. Kabuki syndrome is a rare genetic condition characterized by distinctive facial features with long palpebral fissures, arched and broad eyebrows, long eyelashes, and short columella with depressed nasal tip. Hyperinsulinism occurrs in about 70% of the affected infants.6 Kabuki syndrome was felt to be unlikely in the absence of dysmorphic features.The normal newborn screen for this infant makes fatty acid oxidation disorders, galactosemia, and glycogen storage disorders unlikely. In particular, there is no evidence of long-chain 3-hydroxylacyl-coenzyme A dehydrogenase (LCHAD) deficiency on the newborn screen, which should be considered in infants born to mothers with HELLP syndrome.7 Hypopituitarism is also unlikely given her appropriate cortisol and growth hormone levels.This infant’s persistent requirement for a GIR up to 18 mg/kg/min to maintain euglycemia, and lack of response to diazoxide at 15 mg/kg/day raised the suspicion for CHI due to a genetic mutation. Her CHI gene panel obtained at 19 days revealed she was homozygous for a pathologic variant in the ABCC8 gene (c.2509C>T:p.Arg837*), confirming the diagnosis of CHI. Genetic analysis of the infant’s mother and father indicated both parents were heterozygous for the same c.2509C>T variant. DNA methylation and copy number analysis for chromosome 11p15 were negative, making BWS unlikely.Infants with CHI secrete inappropriate or excessive amounts of insulin from pancreatic β cells because of causative gene mutations. Responsible genes include ABCC8, KCNJ11, KCNQ1, SLC16A1, CACNA1D, GLUD1, GCK, HADH, UCP2, HK1, PGM1, PMM2, HNF4A, HNF1A, and FOXA2.8,9 To couple blood glucose levels to insulin secretion, ATP-sensitive KATP channels on the β-cell membrane regulate opening of voltage-gated calcium channels, which control Ca2+ influx into the β-cell and subsequent insulin exocytosis. The KATP channels are composed of sulfonylurea receptor 1 (SUR1) and inward-rectifying potassium channel (Kir6.2) subunits, which are coded by ABCC8 and KCNJ11 genes, respectively.10 Inactivating mutations in ABCC8 and KCNJ11 are the most common and severe cause of CHI, accounting for approximately 50% of the cases.11–13 Pathologic variants in these genes result in inactivation and persistent closure of KATP channels, leading to persistent closure and constant influx of Ca2+ and inappropriate insulin secretion.Management of CHI aims to optimize blood glucose levels through a multidisciplinary approach that includes high-calorie feeding, IV glucose infusion, pharmacologic therapy, and surgery.14 Diazoxide is the first-line medical treatment for hyperinsulinemic hypoglycemia. It acts on the SUR1 subunit of the KATP channel to keep the channel open, hence downregulating the calcium inflow channel and subsequently reducing insulin secretion. Adverse effects of diazoxide include pulmonary edema, pulmonary hypertension, and hypertrichosis.15 Chlorothiazide is often used with diazoxide to reduce fluid retention. Octreotide is second-line therapy that inhibits insulin secretion by activating somatostatin receptor 5. Glucagon can also be a treatment option if glycogen storage is appropriate. However, glucagon should be used with caution because it can cause paradoxical insulin secretion.16If hyperinsulinemic hypoglycemia fails to respond to medical treatments, pancreatic surgery should be considered to avoid long-term hypoglycemic brain injury. Partial pancreatectomy can be performed for a focal lesion, although subtotal pancreatectomy may be needed for a diffuse lesion. It is important to determine the subtype of CHI (focal vs diffuse) prior to surgery and avoid an unnecessary subtotal pancreatectomy with the potential postoperative complication of persistent hyperglycemia due to loss of insulin-secreting β cells, as well as pancreatic exocrine insufficiency. As a preoperative diagnosis, 18F-dihydroxyphenylalanine positron emission tomography should be obtained to differentiate focal from diffuse CHI.17Infants with recessive inactivating mutations in ABCC8 or KCNJ11 fail to respond to medical therapy in up to 90% of cases and may require pancreatectomy. Infants with CHI due to compound heterozygous mutations or dominant activating mutations in these genes, as well as mutations in GLUD1, GCK, HNF4A, or HADH, are more likely to be diazoxide responders.1,18The infant was started on IV glucagon infusion at 6.6 μg/kg/h at 22 days of age to stabilize blood glucose levels while receiving a GIR up to 18 mg/kg/min and high-calorie feeding. Diazoxide was discontinued because of inefficacy despite the maximum dosing, as is common with ABCC8 mutation-associated CHI. Glucose levels were stably maintained with a glucagon infusion, high-calorie formula feeding, and IV dextrose infusion. She was transferred to another hospital at 54 days of age for evaluation for pancreatectomy. Before proceeding to pancreatectomy, a trial of octreotide was started and, although transiently effective, was stopped when hypoglycemia returned despite escalation of the octreotide dose to 15 mg/kg/d. At that time, the decision was made to proceed with a near total (∼98%) pancreatectomy. Following pancreatectomy, she was advanced to full enteral feedings but also required a continuous 20% dextrose infusion via gastrostomy tube at a GIR of 2 mg/kg/min to maintain her blood glucose levels at greater than 70 mg/dL. She was discharged home on feedings of 20 kilocalories per ounce every 3 hours, as well as a continuous 20% dextrose infusion at a GIR of 2 mg/kg/min through her gastrostomy tube, without the need for total parenteral nutrition.Hyperinsulinism is the most common cause of persistent hypoglycemia in newborns, especially in the setting of macrosomia and hypoglycemia persisting despite a high GIR and frequent high-calorie feedings.Diazoxide is the first-line therapy for hyperinsulinemic hypoglycemia, and monitoring for pulmonary hypertension is recommended.ABCC8 and KCNJ11 mutations are the most common genetic cause of hyperinsulinism and result in severe CHI not responsive to diazoxide therapy in about 90% of patients.If medical management fails, pancreatectomy can be considered while weighing risks of potential postoperative complications, such as persistent hyperglycemia and pancreatic exocrine insufficiency.