Diagnosis and treatment of a newborn with congenital hyperinsulinemia:Case report and literature review

doi:10.21203/rs.3.rs-3575891/v1

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Case Report

Diagnosis and treatment of a newborn with congenital hyperinsulinemia:Case report and literature review

https://doi.org/10.21203/rs.3.rs-3575891/v1

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Background: Congenital hyperinsulinemia (CHI) is a condition characterized by abnormal insulin secretion, primarily responsible for persistent hypoglycemia in infants. This study aims to analyze the diagnosis, treatment, and genetic variations in a newborn affected by congenital hyperinsulinemia (CHI), with the goal of enhancing comprehension and diagnostic accuracy of this condition.

Case summary: We gathered clinical data from a child diagnosed with CHI and conducted whole exome gene sequencing on the child's peripheral blood as well as that of the parents. Genetic tests revealed that the child carried a complex heterozygous mutation in the ABCC8 gene, specifically c.2153G > A (p.Gly718Asp) and c.946G > A (p.Gly316Arg). Both parents were carriers of these two heterozygous mutations. Notably, the c.2153G > A (p. Gly718Asp) mutation had not been previously reported. Initial treatment with diazoxide proved ineffective; however, stable blood glucose control was achieved after combining octreotide with nifedipine.

Conclusion: Hypoglycemia resulting from the complex heterozygous mutations in the ABCC8 gene, specifically c.2153G>A (p.Gly718Asp) and c.946G>A (p.Gly316Arg), can be effectively managed through a combination of octreotide and nifedipine. Genetic testing plays a crucial role in the early diagnosis and treatment of CHI, facilitating prompt and targeted intervention.

Congenital hyperinsulinemia

Hypoglycemia

ABCC8 gene

Diazoxide

Octreotide

Congenital hyperinsulinemia (CHI) stands as the leading cause of persistent hypoglycemia in infants and children. Numerous gene mutations are linked to CHI, with ABCC8 and KCNJ11 mutations being the primary culprits (1). Mutations in other pivotal genes involved in regulating insulin secretion from pancreatic β-cells (GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, and PMM2) are believed to contribute to the molecular mechanisms underlying CHI. This condition is marked by uncontrolled insulin secretion from pancreatic β-cells, leading to sustained and severe hypoglycemia. Affected children might display reduced appetite, diminished crying, drowsiness, and poor responsiveness. In severe cases, neurological symptoms can emerge, potentially resulting in irreversible brain damage. Hence, prompt diagnosis and treatment are crucial to prevent neurological complications. CHI treatment options encompass diazoxide, growth inhibitor analogs, calcium channel blockers, and surgical interventions, all of which can enhance the prognosis for CHI patients (2). In this study, we present a case of CHI featuring a complex heterozygous ABCC8 mutation. Our findings demonstrate the effectiveness of octreotide in combination with nifedipine for CHI treatment, offering a novel approach to managing this condition.

We enrolled a newborn admitted to the Neonatal Intensive Care Unit (NICU) of Lianyungang Hospital, Nanjing Medical University, on November 7, 2021, as the subject of our study. Here are the child's basic details: She is a female, born at 40 + 1 weeks' gestation, and was admitted to our department due to severe hypoglycemia, with glucose levels as low as 0.9 mmol/L after delivery. At birth, she had an Apgar score of 8 at 1 minute and 9 at 5 minutes, weighing 4100g (> 97th percentile). The child's mother underwent a cesarean section in our hospital due to pregnancy-related obesity (BMI: 35 kg/m^2), premature rupture of membranes for 12 hours, and inadequate fetal heart monitoring. Neither parent had a family history of diabetes, and there were no known diabetic relatives.

During the physical examination, the child's body temperature was 36.5℃, pulse rate was 128 beats per minute, and respiration rate was 45 breaths per minute. She weighed 4100g and appeared well-developed. The child exhibited appropriate responses, stable breathing, and had a healthy complexion. Her skin and mouth appeared rosy, the fontanel was flat and soft, the neck was supple, and there were no chest deformities. Her abdomen was soft, the umbilical cord was dry and clean. Normal anatomical features were observed in the anus and genitals, and the muscle strength in her limbs was normal. Physiological reflexes were elicitable.

Table 1

Laboratory tests of the child
Laboratory inspection items		Results	Normal results
Blood glucose	Rapid blood glucose (peripheral blood)	0.9 mmol/L	3.9–6.1 mmol/L
Blood routine examination(the first day after birth)	Leukocyte	24.68x10^9/L	10–20x10^9/L
	Neutrophil ratio	63.3%	40%-75%
	Lymphocyte ratio	25.2%	20%-55%
	Hematocrit	61.9%	35%-45%
	Hemoglobin	189 g/L	170–200 g/L
	Platelet	228x10^9/L	125-350x10^9/L
	Hypersensitive C-reactive protein	0.05 mg/L	0–4 mg/L
Liver function:	Total protein	45.8 g/L	60–83 g/L
	Albumin	30.02 g/L	28–44 g/L
	Total bilirubin	7.5 umol/L	3.4–17.1 umol/L
Insulin assay	Random insulin (three days after birth)	18µIU/ml	10–20 µIU/ml
	Fasting insulin (one month after birth)	6.89 µIU/ml	5–20 µIU/ml
C-peptide		1.66 ng/ml	0.5–2.5 ng/ml
β -hydroxybutyric acid		0.08mmol/L	0.24–2.28 mmol/L
Cortisol		337.8 nmol/L	160–660 nmol/L
Free fatty acid		206 umol/L	300-900umol/L
Thyroid function:	FT3	5.81	3.67–10.43 pmol/L
	FT4	12.84 pmol/L	11.2–20.1 pmol/L
	TSH	15.06 mIU/L	0.56–5.91 mIU/L
	T3	2.3 mmol/L	1.34–2.73 mmol/L
	T4	133.44 mmol/L	78.4-157.4 mmol/L

The laboratory test results are summarized in Table 1. Regarding the imaging examinations: the whole chest radiograph revealed no abnormalities; abdominal ultrasound indicated a slightly enlarged liver with poor texture, and no distinct focal spaces were observed in the spleen, pancreas, kidneys, or adrenal area. 18F-DOPA-PET/CT scans showed increased FDOPA uptake in the pancreas, especially in the head of the pancreas. Abdominal MRI enhancement of the pancreas showed no evident irregularities, along with a small amount of ascites present. Head MRI demonstrated no apparent interruption or displacement of white matter fibers in skull diffusion tensor imaging. Pituitary MR enhancement exhibited no obvious abnormalities, while the extracerebral space appeared widened, and the lateral ventricles were full. Moreover, MRCP of the liver and gallbladder did not reveal any significant abnormalities.

Upon admission to the hospital, the child received formula milk, a 10% glucose infusion, and intravenous glucose infusion to stabilize blood glucose levels (the glucose rate was escalated from 4mg/kg/min to 11mg/kg/min). Despite these interventions, the patient experienced recurrent episodes of hypoglycemia, with blood sugar levels ranging between 1.6 mmol/L and 3 mmol/L. Based on the child's clinical symptoms and auxiliary examinations, we strongly suspected congenital hyperinsulinemia. Consequently, we started oral diazoxide therapy, initially at a dose of 5mg/kg. Depending on the child's blood glucose control, we titrated the dosage up to 15mg/kg, gradually discontinuing hormonal support. Unfortunately, the child's hypoglycemia persisted, necessitating continued intravenous glucose supplementation and more frequent feedings to maintain stable blood sugar levels.

During diazoxide treatment, the patient developed bilateral lower limb edema and abdominal fluid accumulation. Subsequently, we transitioned to octreotide therapy, adjusting the glucose infusion rate based on blood glucose values and increasing the subcutaneous octreotide dose to 0.032 mg q6h. Despite octreotide treatment, glucose infusion was still required to maintain blood glucose levels. We attempted combination therapy with octreotide and nifedipine (2.5mg q8h), which proved effective. The child responded positively to this regimen, and her blood glucose gradually stabilized between 4 and 5 mmol/L.

We conducted fasting diagnostic and glucagon tests before her discharge from the hospital (3, 4). The fasting test was initiated immediately after a meal, with the glucose infusion rate reduced by 1 mg/kg/min per hour. Blood glucose levels were monitored hourly initially and half-hourly when glucose dropped below 3.8 mmol/L. The child's lowest blood glucose level was 2.6 mmol/L. We promptly collected a blood specimen and measured insulin (6.89 µIU/ml), β-hydroxybutyric acid (0.08 mmol/L), and free fatty acid (206 µmol/L). Subsequently, she received a glucagon injection of 30–100 µg/kg (up to 1 mg) over 40 minutes, raising her blood glucose level to 4.9 mmol/L (> 1.7 mmol/L). These results confirmed the diagnosis of congenital hyperinsulinemia.

Upon stabilization, she was discharged 52 days after birth and continued oral nifedipine (2.5 mg tid) and subcutaneous octreotide (0.032 mg q6h). The patient was followed up in the outpatient department until 9 months. Her blood sugar levels remained normal, and she continued to thrive, displaying growth patterns typical for a child her age.

Outcome

We collected 2ml of peripheral blood samples from the child and her parents for genetic testing. The DNA library was prepared using the xGen® whole exome panel, and genetic diseases' whole exome genes were analyzed using Illumina second-generation sequencers. The sequencing data were processed through bioinformatics databases like KMTD/KMED, Human Gene Mutation Database (HMD), ClinVar, ESP6500, Thousand Genomes, and dbSNP.

The results of whole-exome sequencing revealed two heterozygous variants in the child's ABCC8 gene. The first variant, c.2153G > A (p.Gly718Asp), located in exon 16, resulted in an amino acid change from glycine (Gly) to asparagine (Asp) and was classified as a missense mutation. The child's mother (see Fig. 1) was also found to be heterozygous for this mutation. Notably, this variant was not present in HGMD, ESP6500, 1000 Genomes, or dbSNP147 databases. The second mutation, c.946G > A (p.Gly316Arg), located in exon 6, caused an amino acid change from glycine (Gly) to arginine (Arg) and was identified as a missense mutation. The child's father (see Fig. 2) was heterozygous for this mutation. This variant has previously been reported in patients with congenital hyperinsulinemia and type 2 diabetes [PMID: 26545620/33046911], and it is included in the dbSNP147 database (rs1201126343); however, it was not found in ESP6500 and 1000 Genomes databases (see Table 2). The family pedigree is illustrated in Fig. 3.

Arrows indicate the mutation site.

The proband exhibits a mutated sequence in the ABCC8 gene at position c.2153G > A. The mutation site is marked by arrows.

Table 2

Analysis of Genetic Variations and Pathogenicity
Gene	Chromosome position	Position	Reference transcription sample: cDNA level (protein level)	Status	Variation type	The child’s father	The child’s mother
ABCC8	Chr11:17448665	Exon16	NM000352.6:c.2153G > A(p.Gly718Asp)	Heterozygosis	Missensevariation	Not detected	Heterozygosis
ABCC8	Chr11:17482100	Exon6	NM000352.6:c.946G > A(p.Gly316Arg)	Heterozygosis	Missensevariation	Heterozygosis	Not detected

Congenital Hyperinsulinemia (CHI) constitutes a group of syndromes characterized by persistent and profound hypoglycemia, displaying diverse histological, genetic, and clinical features. Onset typically occurs within the first two years of life, with approximately one-third of cases manifesting within 28 days after birth, varying in severity (5, 6). Neonates with CHI exhibit varying clinical symptoms related to hypoglycemia, and severe cases can result in irreversible damage to the nervous system or even cerebral palsy due to inadequate glucose supply to the brain (7, 8). Early CHI diagnosis is crucial to prevent hypoglycemic brain injuries. Current diagnostic criteria encompass: (1) intravenous plasma glucose levels < 2.8mmol/L accompanied by abnormal insulin secretion (serum insulin > 1–2µIU/ml; C-peptide > 0.2mmol/L) (2) hypoketonemia (β-hydroxybutyric acid < 1.8mmol/L) (3) Low free fatty acid levels < 1.7mmol/L (4) Positive response to glucagon stimulation test (1mg intramuscular or intravenous glucagon injection, 0.5mg for newborns, with blood glucose rise ≥ 1.7mmol/L).

The neonate reported in this study was diagnosed during the neonatal period, exhibiting multiple episodes of hypoglycemia immediately after birth. Fasting diagnostic tests revealed insulin levels at 6.89 µIU/ml, β-hydroxybutyric acid at 0.08mmol/L, and free fatty acids at 206µmol/L. Following glucagon injection, the child's blood sugar increased by more than 1.7mmol/L, and blood ammonia, cortisol, and growth hormone levels were normal. The final diagnosis was confirmed by integrating genetic test results. The child received prompt treatment in the neonatal unit after birth, and subsequently, standard diagnosis and treatment were administered, preventing any clinical manifestations of neurological damage. Head MRI showed no significant brain injuries. Nine months of follow-up indicated the child's normal growth and development, underscoring the importance of timely diagnosis and treatment.

Congenital Hyperinsulinemia (CHI) is categorized into two types based on distinct mutated genes: (1) Genes linked to ion channels include ABCC8 and KCNJ11, encoding the sulfonylurea receptor 1 (SUR1) protein and the inward rectifier potassium channel (Kir6.2), respectively. These genes are responsible for the ATP-sensitive potassium channels (KATPs) present in pancreatic β-cell membranes. (2) Genes associated with metabolic diseases encompass GCK, SCHAD, GLUD1, SLC16A1, HNF1A, HNF4A, and UCP2 (8, 9). Histologically, CHI is further divided into three subgroups: diffuse, focal, and atypical forms (10). Currently, the most common and severe mutations in CHI are inactivating mutations in ABCC8 and KCNJ11 (11). The β-cell ATP-sensitive potassium channel encoded by these genes is a crucial component of the glucose-stimulated insulin secretion pathway (12). Mutations in these genes disrupt insulin secretion, leading to congenital hyperinsulinemia. The inheritance patterns of ABCC8 and KCNJ11 genes are predominantly autosomal recessive, although there are instances of autosomal dominant inheritance and de novo mutations. Autosomal recessive mutations in ABCC8 and KCNJ11 genes cause persistent hypoglycemia due to structural and functional abnormalities of KATP. This results in continuous depolarization of the pancreatic β-cell membrane, activation of voltage-gated calcium channels, and influx of calcium ions into pancreatic β-cells, triggering insulin release. This type of inheritance is characterized by early onset and severe symptoms. Typically, autosomal recessive inheritance exhibits diffuse and focal disease histological types. Autosomal dominant inheritance of these genes usually leads to focal histological changes in the pancreatic islets, manifesting with late onset and milder symptoms (13, 14).

KATP-HI resulting from mutations in the ABCC8 gene is commonly inherited as either a recessive or dominant trait, with fewer documented cases involving compound heterozygous mutations. In a prior study (15), a case of CHI with compound heterozygous mutations in ABCC8 was reported. The child, born macrosomic, experienced hypoglycemia after birth and received treatment with glucose, hydrocortisone, and diazoxide. Despite the interventions, their blood sugar levels remained between 2.4 and 2.7 mmol/L. Subsequently, the condition progressed to diabetes following subtotal pancreatectomy surgery. Another case, as reported by Kumaran et al. (16), involved a newborn with a complex heterozygous mutation in ABCC8 (mutation sites C.502cC > T and C.1817G > C). This macrosomic child was admitted to the hospital due to hypoglycemia just 2 hours after birth, experiencing seizures the following day. The 18F-DOPA-PET/CT scan indicated diffuse CHI. While the patient responded poorly to diazoxide, their blood glucose stabilized after transitioning to octreotide and glucagon. Additionally, Al Balwi et al. (17) described a novel compound heterozygous mutation in the ABCC8 gene. The patient exhibited a poor response to diazoxide but positively responded to octreotide.

These literature findings indicate that patients with CHI harboring compound heterozygous mutations in the ABCC8 gene tend to experience neonatal onset and are frequently macrosomic. Most cases with biallelic ABCC8 gene mutations present as diffuse histotypes (18). In the cases described in this study, CHI onset occurred within 24 hours after birth, manifesting as severe and refractory hypoglycemia. An 18F-DOPA-PET/CT scan revealed diffuse CHI and poor responsiveness to diazoxide treatment. Genetic analysis identified two heterozygous mutations in the ABCC8 gene (c.946G > A and c.2153G > A), both predicted to be pathogenic based on bioinformatics software analysis. The former mutation, inherited from the father, was previously reported by WU et al. (19). Interestingly, their study indicated that CHI patients with the c.946G > A mutation showed a positive response to diazoxide treatment, with the drug gradually discontinued by the age of 2. The latter mutation is novel, inherited from the mother, and has not been documented in existing literature. We consider this mutation (c.2153G > A) to be pathogenic, acting synergistically with the former mutation (c.946G > A) on KATP channels, leading to clinical heterogeneity. Notably, the clinical manifestations of CHI are influenced not only by the type of mutation but also by the specific mutant gene locus. The identification of this new ABCC8 gene locus offers a valuable theoretical basis for our diagnosis and treatment of CHI.

The treatment of congenital hyperinsulinemia encompasses both medication and surgical options. Diazoxide stands as the primary medication of choice (20). Functioning as a KATP channel opener, it binds to the SUR1 subunit of KATP-sensitive potassium channels, hindering β-cell depolarization and reducing insulin secretion (21). Common side effects of this drug include cardiac failure, fluid retention, pulmonary edema, hypertension, and neutropenia. Notably, CHI patients with functional KATP channels in the β-cell membrane respond better to diazoxide therapy. However, most cases of KATP-HI resulting from ABCC8 or KCNJ11 mutations do not respond effectively to diazoxide treatment. As alternatives to diazoxide, growth inhibitor analogues, nifedipine, GLP1 receptor antagonists, and sirolimus are considered (22).

If conservative treatment fails, an 18F-DOPA PET/CT scan can help assess the need for surgical intervention. Nifedipine, a calcium channel blocker, impacts insulin release by interacting with calcium channels on the β-cell membrane of pancreatic islets. Potential side effects of calcium channel blockers include dizziness, headache, and hypotension, among others (23). The use of nifedipine in CHI treatment has been sparingly reported both domestically and internationally. A previous study (24) documented a case of persistent hypoglycemia in CHI children unresponsive to diazoxide treatment after near-total pancreatic resection. This patient was successfully managed with octreotide and nifedipine post-surgery. Similarly, Khawash et al. (25) published a case study involving a child with a complex heterozygous mutation in the ABCC8 gene. Following subtotal pancreatectomy, the child was treated with octreotide and nifedipine, maintaining normal blood glucose levels monitored through a continuous glucose monitoring system (CGMS).

The mentioned reports indicate that blood glucose control can be achieved with nifedipine, often in combination with another drug, as described here. We speculate that nifedipine and octreotide might have a synergistic effect. However, a separate study investigating the long-term use of nifedipine in 11 CHI patients with ABCC8 mutations found no improvement in patients' hypoglycemia(26). The response to nifedipine could depend on an underlying heritable defect. While there remains some controversy surrounding nifedipine treatment, our experience corroborates its usefulness in congenital hyperinsulinemic hypoglycemia, offering additional therapeutic options for CHI. Mechanistic insights in this area are limited, and further experimental studies are necessary to validate these findings.

The simultaneous occurrence of genetic mutations at two distinct sites, inherited from both parents, likely accounts for the child's inadequate response to diazoxide treatment, as demonstrated in this study. Consequently, the complex heterozygous mutation in the ABCC8 gene presents multifaceted clinical characteristics. The structural and functional alterations in the protein encoded by the child's ABCC8 gene disrupt the normal expression of KATP channel subunits on the cell surface. Additionally, this research identified a novel mutation in the ABCC8 gene locus and confirmed the effectiveness of octreotide combined with nifedipine in treating CHI patients. This finding provides a practical approach for CHI medication therapy.

In conclusion, there exists a close association between genetic mutations and congenital hyperinsulinemia. Newborns with congenital hyperinsulinemia should be carefully monitored for recurring hypoglycemic episodes. Swift genetic testing for both parents and infants is essential to ensure accurate diagnoses. Prompt pharmacological intervention is crucial to prevent neurological system damage. It is noteworthy that the efficacy of drugs varies significantly depending on the specific type of CHI gene mutation. Therefore, genetic testing plays a pivotal role in the early diagnosis of children with CHI, guiding the development of diagnostic and therapeutic protocols, and determining prognosis.

Acknowledgments

We would like to thank the child and her family for their support.

Author Contributions

YY revise and supervised the article. QY and MZ collected the relevant clinical data and wrote the article. YW was responsible for analyzing the data, organized images and tables. All authors contributed to the article and agreed with the version submitted.YY revised and supervised the article. QY and MZ collected the pertinent clinical data and drafted the manuscript. YW was responsible for data analysis, organizing images, and tables. All authors contributed to the article and consented to the submitted version.

Funding

This subject was supported by the National Natural Science Foundation of China (81900772).

All data analyzed during this study are included in this published article. To obtain a copy of the data for this study, please contact the author, Meiyu Zhang(email: [email protected]).

Ethics approval and consent to participate

The research involving human participants was thoroughly reviewed and ethically approved by the Ethics Committee of the First People's Hospital of Lianyungang.

Consent for publication

Prior to participation, written informed consent was obtained from the legal guardians or immediate family members of the participants, ensuring their voluntary and informed involvement in the study.

Conflict of interest

The authors affirm that this study was conducted without any business or financial affiliations that could be perceived as potential conflicts of interest. For specific examples, please refer to the provided link.

Author details

¹Pediatric Endocrinology Department, Lianyungang Clinical Medical College of Nanjing Medical University, Lianyungang,China, ²Department of Pediatrics, The People's Hospital of Suzhou New District , Suzhou, China, ³Postgraduate Training Base of Lianyungang First People's Hospital of Jinzhou Medical University, Lianyungang, China

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No competing interests reported.

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Diagnosis and treatment of a newborn with congenital hyperinsulinemia:Case report and literature review

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