Continuous glucose monitoring in a neonate with hyperinsulinemic hypoglycemia and ABCC8 gene mutation

Background

Hypoglycemia is one of the most common metabolic disorders, affecting approximately 5–15% of newborns and is associated with an increased risk of morbidity in the newborn population. There is still no consensus on the lowest cutoff point for hypoglycemia that averts neurological complications in that population (1, 2). Nonetheless, persistent or recurrent hypoglycemia, which is unresponsive to treatment, is known to be associated with adverse neurological outcomes in newborns.

Glucose is the primary energy substrate for a fetus and is transported through maternal–fetal circulation. Consequently, the fetus achieves 66% of the mother’s glucose concentration. After birth and cord clamping, newborns must provide endogenous glucose from glycogenolysis, gluconeogenesis, and feeding. This leads to lower glycemia in the first 4 h postnatally and is a risk factor for neonatal hypoglycemia (2).

There are a few risk factors for neonatal hypoglycemia, including being born to a diabetic mother and preterm birth. Hypoglycemia is usually transient, with a good response to pharmacological treatment. First-line treatment includes feeding and oral dextrose, which can be switched to intravenous glucose administration in more severe cases. For infants unresponsive to intravenous glucose, glucagon is recommended. Persistent neonatal hypoglycemia should prompt further investigation and differential diagnosis of the underlying condition in newborns (3).

The most common etiology of neonatal hypoglycemia is hyperinsulinemic hypoglycemia (HH). There are two forms of HH: transient and permanent. Transient HH is more common and can occur in newborns of diabetic mothers, newborns small for gestational age or large for gestational age (LGA), those with perinatal asphyxia, and those born preterm.

Congenital hyperinsulinemia (CHI) is a rare disorder characterized by persistent and refractory hypoglycemia, with an incidence of 1 in 30,000–50,000 newborns worldwide. Mutations in CHI genes involved in insulin secretion from pancreatic beta cells – including ABCC8, KCNJ11, HNF1A, HNF4A, GCK, HK1, and KCNQ1 – lead to persistent hypoglycemia (4). The most common mutations, ABCC8 and KCNJ11, are inactivating KATP channel mutations, accounting for 30–40% of all CHI cases.

Monitoring the glucose concentration and diagnosing all hypoglycemic events closely is essential to avoid neurological complications. However, the currently recommended method, self-monitoring of blood glucose (SMBG), is an intermittent method of glycemia assessment. Furthermore, it demands invasive procedures, such as heel-pricking. Continuous glucose monitoring (CGM), widely used in patients with diabetes mellitus, offers advantages over SMBG through continuous glycemic control. Consequently, CGM enables the detection of all hypoglycemic events, which may be essential in neonates to avoid long-term complications.

This case describes challenges in the proper diagnosis of HH with a genetic background. Our case presents a newborn born to a normoglycemic mother, with macrosomia diagnosed prenatally and an ABCC8 mutation identified postpartum.

Case presentation

We report a female infant born at 37 weeks and 3 days of gestation to a 34-year-old primiparous woman. The woman had been diagnosed with Hashimoto’s thyroiditis before pregnancy and was under medical supervision throughout the entire pregnancy. Routine first- and second-trimester ultrasound scans were reported as usual, with no maternal complications until 37 weeks of gestation. The pregnancy was complicated by fetal macrosomia.

At 37 3/7 Hbd, the mother was admitted to the hospital due to prelabor rupture of membranes and received antibiotic prophylaxis. The child was delivered by cesarean section due to suspected fetal macrosomia (estimated fetal weight >4,500 grams). The female newborn weighed 4,690 grams (+3SD and 100 percentiles based on Intergrowth 21st chart), with a head circumference of 37.0 cm (+3SD). The Apgar score was 8-8-9-9 points at 1-3-5-10 min, respectively, and umbilical cord blood gas values were as follows: pH 7.24, lactate 3.9 mmol/L, and BE −1.2 mmol/L, and glucose concentration was 10 mg/dL. Complete blood count from the umbilical artery was within the reference range.

Within 60 min after birth, the newborn was admitted to the special care baby unit (SCBU) due to glycemia less than 25 mg/dL and qualified for intravenous glucose administration. At the fifth hour after birth, she was transferred to the neonatal intensive care unit (NICU) and observed for recurrent episodes of dysglycemic events. She was given two boluses of glucose intravenously with no effect, and treatment was switched to continuous intravenous infusion of glucose.

Investigation and treatment

For the next 48 h, she experienced severe hypoglycemic episodes despite 30% intravenous glucose infusion. Therefore, a pediatric metabolic medicine consultant was consulted, and the neonate was given octreotide (5 μg/kg/24 h) administered intravenously in four doses, after which normoglycemia was achieved.

In subsequent days, while in the NICU, the octreotide dosage was increased to 6.4 μg/kg/24 h with good therapeutic effect, followed by incremental increases every 3 days by 5 ug/kg/dose. Consequently, the route of octreotide administration was switched to subcutaneous as it provides slower absorption and longer therapeutic effects. Due to persistent hypoglycemic episodes, the newborn patient was given diazoxide on the 20th day after birth, administered orally at a dosage of 5.2 mg/kg/24 h divided into three doses. This treatment adjustment enabled a gradual reduction in intravenous glucose infusion. The maximal whole glucose supply throughout hospitalization was 30 mg/kg/min.

Initially, glucose concentration was assessed via an Optimum Xido glucose meter (Abbott Diabetes Care, USA). In severe hypoglycemia, arterial blood gas (ABG; ABL90 Flex Plus) was collected to qualify for dysglycemia treatment properly. However, this approach necessitated 110 invasive procedures solely for glycemia assessment. Therefore, CGM (Dexcom G6, USA) was introduced on the 10th day after birth. From that point, glycemia was assessed with a Dexcom sensor to reduce the number of invasive procedures. We decided to insert the sensor on the lower extremities in the femoral region (Fig. 1).

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Newborn with Dexcom G6 sensor inserted in the right thigh.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 2; 10.1530/EDM-25-0002

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In addition, several tests, including adrenal, thyroid, and pancreas function tests, C-peptide, insulin growth factor-1 (IGF-1), glucagon stimulation test, screening for congenital adrenal hypoplasia, amino acids and acylcarnitine profile (MS/MS analysis), organic acids GC-MS analysis, and the Beutler test, were performed. Brain magnetic resonance imaging (brain-MRI) was performed, which was reported to be normal. High insulin levels (between 1,277 and 1,296 mIU/L) were detected during hypoglycemic events, and further investigation for congenital hyperinsulinemia was undertaken.

Outcome and follow-up

Whole exome sequencing (WES) identified a heterozygotic splicing variant (1467+1G>T; Nm_00352.6; hg38) of the ABCC8 gene mutation, classified as likely pathogenic according to ACMG guidelines and as such reported in ClinVar. Parental screening revealed paternal inheritance of the mutation. However, reduced penetrance cannot be excluded in this case based on available data (5). The genetic result indicated positron emission tomography using ¹⁸F-fluoro-L-dihydroxyphenylalanine (¹⁸F-DOPA PET) to make diffuse/local HH differential diagnoses. The patient was referred to a hospital specializing in PET in pediatric patients. The diffuse form of HH was diagnosed based on imaging. As indicated, a full pancreatectomy was performed. The family, including the patient, is under genetic supervision.

Discussion and conclusion

Congenital hyperinsulinism is the leading cause of persistent hypoglycemia in neonates and is associated with 12 gene mutations (6). The most severe form is correlated with ABCC8 and KCNJ11 mutations, which lead to dysfunction of the adenosine triphosphate-sensitive potassium channel (K_ATP). The potassium ATP channel is responsible for insulin secretion, and a mutation triggers inappropriate insulin secretion, causing hypoglycemia.

The most severe is a diffuse form that leads to abnormal function of all beta cells. There is no prenatal noninvasive screening for congenital HH, but it might be detected, if suspected, with invasive genetic testing such as amniocentesis. It is suggested in cases with a family history of congenital HH and with fetal manifestation of macrosomia. In our patient, fetal macrosomia was diagnosed but there was no family history of congenital hyperinsulinemia. It could also be beneficial in cases such as the one described above, but it is an expensive method that is currently not reimbursed in our country. However, the International Guidelines for the Diagnosis and Management of Hyperinsulinism published in 2023 state that rapid testing of ABCC8 is crucial for managing children with HH. In our case, performing these tests simultaneously with screening for monogenic mutations could have been beneficial to avoid delayed diagnosis and decrease the risk of permanent neurodevelopmental complications.

Treatment of diffuse forms of CH requires high doses of concentrated intravenous glucose infusions. In our case, the newborn required maximal glucose intake of 30 mg/kg/min. Diazoxide is the drug of choice for treating HH, and its mechanism of action involves binding to the SUR1 subunit of the K_ATP channel. The ABCC8 mutation should not respond to diazoxide, but as previously described, not all KATP channels are affected in some cases, and these patients may benefit from that treatment, such as in our case. Diazoxide and octreotide allowed us to lower the dosages of glucose infusion.

HH demands close monitoring of the glucose concentration to detect all hypoglycemic events. There is an ongoing debate concerning how hypoglycemia affects the brain of neonates. Most neonates are diagnosed with transient hypoglycemia, which lasts up to 7 days postpartum and is easy to control. Transient hypoglycemia is considered not to cause severe neurological deficits. Our patient had glycemia controlled for 36 days, with recurrent episodes of severe hypoglycemia. Therefore, CGM was beneficial for identifying all asymptomatic hypoglycemia, allowing for faster reactions and treatment.

CGM may be considered the preferred method in cases of HH. Real-time glucose assessment facilitates personalized treatment and, in some situations, highlights significant glycemia fluctuations, thereby preventing unnecessary interventions. CGM is currently widely utilized among diabetic patients and pregnant women diagnosed with hyperglycemia during pregnancy. Research has shown that CGM improves glycemic control and reduces the risk of adverse outcomes for these patients. In addition, studies have evaluated the effectiveness of CGM in preterm neonates, demonstrating benefits for these patient groups. The system supports a longer duration within the normal glycemia range (2.6–10 mmol/L, 47–180 mg/dL). Furthermore, real-time glucose level assessment enables personalized adjustments of glucose infusion when necessary. CGM, in collaboration with diazoxide and octreotide, helped reduce the risk of hyperglycemia episodes, which could impact developmental and health complications during adolescence. The REACT trial also showed that CGM reduced exposure to both hyper- and hypoglycemia. On the other hand, Perri et al. analyzed CGM-guided glucose infusion in another high-risk group – very low birthweight infants, exhibiting fewer dysglycemic episodes with the use of CGM. This underlines that in special groups, such as HH patients, CGM may be beneficial for better short- and long-term outcomes due to improved glycemic control and treatment adjustments based on current glycemic trends observed on the sensor.

Another positive feature of CGM that should be emphasized is its ability to reduce the number of invasive procedures performed to check glucose concentration, thereby leading to reduced pain in newborns. Consequently, CGM is considered superior for effective glucose management in cases with severe fluctuations in neonates, such as in HH with ABCC8 mutation. In our case, before using CGM, our patient underwent 110 heel pricks for glucose assessment within 10 days. In these situations, the Dexcom device is an ideal solution to minimize painful procedures for these patients.

While CGM seems to be useful and beneficial for neonates, the device has not been approved for that patient population. There is still the need for calibration in line with lower glucose levels suitable for newborns and the placement of the device in the event of limited subcutaneous tissue. Further studies are needed to adjust the device and assess the usefulness of CGM in neonates.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent was obtained from the patient’s parents to publish this case report and any accompanying images.

Author contribution statement

All authors listed have coordinated the drafting and revision of the manuscript. All authors listed have read and approved the final version of the manuscript.

Data availability

The authors confirm that the data supporting the presented case report are available within the article and its supplementary materials. DNA sequencing data were submitted to the ClinVar database. ClinVar accession SCV005187333, submission SUB14654235.

Statement of ethics

The published case report complies with the guidelines for human studies and was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Ethics approval and consent to participate

Data for this case report were collected as routine data during hospitalization, and the patient’s parents gave consent to use medical data concerning their child for publication. Consent for WES analysis was obtained from parents, and the standard form accepted by the Institute of Mother and Child was used.