REGISTRO DOI: 10.69849/revistaft/ch10202512061219
João Lucas Miranda Fontelles1*†; Wallace Acioli Freire de Gois1,2; Rodrigo Pinheiro de Abreu Miranda2; Ana Paula Amaral Souza1,2; Adriana Domingues Graziano2; , Elisa de Carvalho2 & Acimar Gonçalves da Cunha Junior1,2
Abstract
Congenital hyperinsulinism (CHI) is the leading cause of persistent hypoglycemia in neonates. We describe a male newborn with macrosomia who developed severe, recurrent hypoglycemia within the first hours of life. Laboratory evaluation confirmed hyperinsulinemia with suppressed ketone bodies and free fatty acids, and PET-CT with 6Ga-DOTATOC revealed no focal lesion. Whole-exome sequencing (WES) did not identify pathogenic variants in the canonical CHI genes, placing this patient within the subset of genetically unresolved cases of severe, diazoxide-unresponsive disease. A heterozygous variant in AUTS2 (c.3419C>A; p.Arg1140Gln) was detected as part of the broader analysis, but it has no known relationship to insulin secretion. Despite therapy with diazoxide, octreotide, and glucocorticoids, hypoglycemia remained refractory, and subtotal pancreatectomy (95%) was performed at 18 months of age. The patient subsequently achieved sustained euglycemia without medication. At two years of age, he exhibited normal growth, preserved exocrine pancreatic function, and exclusive oral feeding. Neurological follow-up identified autism spectrum disorder, compatible with the known spectrum of AUTS2-related neurodevelopmental findings. This case underscores the clinical and diagnostic challenges of diffuse, diazoxide-unresponsive CHI without identifiable pathogenic variants, highlighting the limitations of WES and the importance of expanded genomic evaluation in unresolved cases.
Keywords: Neonatal hypoglicemia, Congenital hyperinsulinism, Genetic mutations, Pancreatectomy
Introduction
Congenital hyperinsulinism (CHI) is a rare endocrine–metabolic disorder characterized by inappropriate insulin secretion by pancreatic β-cells, regardless of glycemia. This dysregulated insulin production results in persistent hypoglycemia, particularly during the neonatal period, and represents the most frequent cause of recurrent hypoglycemia in this age group, surpassing pituitary disorders, adrenal insufficiency, and inborn errors of metabolism 1,2.
The global incidence of CHI is estimated at 1:25,000 to 1:50,000 live births, but it may be up to 20 times higher in populations with high rates of consanguinity or founder mutations 3. Genetic heterogeneity is a hallmark of the disease, most commonly associated with mutations in ABCC8 and KCNJ11, which encode subunits of the ATP-sensitive potassium (KATP) channel. Recessive variants in these genes typically result in diffuse forms of CHI, whereas focal disease arises from a paternal heterozygous mutation combined with soma tic loss of the maternal allele in pancreatictissue 4,5.
Additional molecular mechanisms have been described, including activating mutations in GCK, aberrant HK1 expression in β-cells, and defects in mitochondrial transporters such as SLC25A36, expanding the known genetic spectrum of CHI 6,7. Nevertheless, a subset of patients remains without a defined molecular diagnosis, underscoring the relevance of next-generation sequencing (NGS) and whole-exome sequencing (WES) as diagnostic tools 5 .
The prognosis of CHI is closely linked to early diagnosis and timely treatment. Up to 50% of patients with poorly controlled hypoglycemia may develop neurological sequelae, including global developmental delay, epilepsy, and hypoxic-ischemic encephalopathy 8 . Initial treatment includes clinical measures such as continuous glucose infusion and pharmacological agents like diazoxide and octreotide, but refractory cases often require surgical intervention, most commonly subtotal pancreatectomy. Although effective for immediate metabolic control, surgery carries longterm complications, such as insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency 9,10 .
In this context, we report a case of severe diffuse CHI unresponsive to medical therapy and without identifiable pathogenic variants in the canonical CHI genes, illustrating the diagnostic and therapeutic challenges encountered in genetically unresolved forms of the disease.
Case Presentation
A male newborn, born to a 32-year-old mother in her fourth pregnancy, was delivered at 38 weeks of gestation by vaginal delivery after a prolonged second stage. At birth, he presented with macrosomia (weight: 4,785 g; length: 56 cm; head circumference: 36 cm). Apgar scores were 2 and 7 at the first and fifth minutes, respectively, and transient ventilatory support was required.
During the first hours of life, the patient developed hypoglycemia associated with hypotonia, refractory to intravenous glucose bolus. To maintain normoglycemia, continuous glucose infusion at high rates (up to 17 mg/kg/min) was necessary. Laboratory tests collected during episodes of severe hypoglycemia revealed hyperinsulinemia, characterized by elevated C-peptide levels, suppression of β-hydroxybutyrate and free fatty acids, absence of ketonuria, and an acylcarnitine profile within the reference range. Evaluation of counter-regulatory hormones, including growth hormone, ACTH, and cortisol, showed no abnormalities, nor did infectious disease screening. Because of persistent hyperinsulinism, PET-CT scan with 68Ga-DOTATOC was performed to investigate insulinoma, with no evidence of abnormal tracer uptake.
In addition to hyperinsulinemia, the patient exhibited feeding intolerance, which worsened hypoglycemia. From the second month of life, he developed recurrent vomiting, which intensified at five months. At seven months, a gastrostomy was performed due to feeding failure. Because emesis persisted, esophageal pH monitoring was conducted, confirming acid gastroesophageal reflux. At the same age, he underwent fundoplication combined with pyloromyotomy.
Genetic investigation by WES, an NGS-based method targeting coding regions and canonical splice sites, identified a heterozygous pathogenic variant in the AUTS2 gene: c.3419C>A; p.(Arg1140Gln). Parental genetic testing could not be performed due to financial limitations; however, both parents are clinically healthy and have no history or symptoms compatible with congenital hyperinsulinism.
At 18 months of age, given the refractoriness of hypoglycemia to medical management, including diazoxide, octreotide, and glucocorticoids, the case was classified as diazoxide-unresponsive congenital hyperinsulinism. Subtotal pancreatectomy (95% resection of the pancreas) with duodenal preservation was performed. In the immediate postoperative period, diazoxide and octreotide were gradually discontinued, and the patient received total parenteral nutrition during the first week. Only mild transient hypoglycemia was observed, with no recurrence after progressive reintroduction of enteral feeding.
At two-year outpatient follow-up, the patient remained clinically stable, on exclusive oral feeding, without the need for medication, and with no further episodes of hypoglycemia since hospital discharge. Laboratory evaluation showed normal fecal elastase levels, and anthropometric parameters were within the appropriate percentiles for age. Neurologically, global developmental delay, stereotypies, and mild impairment in social interaction were observed. Under specialized neurological follow-up, a diagnosis of autism spectrum disorder (ASD) was established, a condition frequently associated with pathogenic AUTS2 variants.
Discussion
The clinical and biochemical findings in this case — including severe hypoglycemia requiring high glucose infusion rates, suppressed ketogenesis, and detectable C-peptide — are characteristic of congenital hyperinsulinism (CHI). These alterations reflect inappropriate insulin secretion, impaired mobilization of alternative substrates, and an increased risk of neuroglycopenic injury, consistent with established diagnostic criteria 1,2.
The patient was classified as presenting with diazoxide-unresponsive CHI, a clinical condition strongly correlated with KATP channel mutations. In fact, up to 90% of such cases are linked to pathogenic variants in ABCC8 or KCNJ11 10. Diffuse CHI, as observed in this case, is usually associated with recessive variants, while focal CHI arises from a unique genetic mechanism combining a paternal heterozygous mutation and somatic maternal allele loss in pancreatic tissue. Focal forms are potentially curable by localized surgical resection, whereas diffuse disease frequently requires near-total pancreatectomy, with lifelong implications 10.
Whole-exome sequencing did not identify pathogenic variants in ABCC8, KCNJ11, GCK, HK1, GLUD1, or other genes known to cause CHI. The heterozygous variant in AUTS2 (c.3419C>A; p.Arg1140Gln) must therefore be interpreted as incidental, as AUTS2 has no established relationship with CHI according to ClinGen or current literature. Although AUTS2 variants are recognized causes of autism spectrum disorder and neurodevelopmental delay 11, there is no clinical, mechanistic, or experimental evidence supporting any role for this gene in pancreatic β-cell physiology.
Advanced sequencing methods such as WES are essential in atypical CHI cases, as they enable detection of rare coding variants and some splice-site intronic alterations that may be missed by conventional sequencing. However, deep intronic or regulatory variants usually require wholegenome sequencing (WGS) or functional studies for accurate identification 12. These limitations are particularly relevant in diazoxide-unresponsive CHI, in which 10–15% of patients remain without a molecular diagnosis despite modern sequencing techniques. In this case, parental testing was not performed due to financial constraints, and broader genomic approaches such as wholegenome sequencing were unavailable, leaving the etiology unresolved. This scenario exemplifies the diagnostic gap still present in CHI and underscores the importance of comprehensive molecular strategies in selected cases 5,12.
Subtotal pancreatectomy remains the established treatment for diffuse CHI that fails to respond to medical therapy. Although effective in achieving immediate euglycemia, long-term metabolic complications are common: nearly half of patients develop diabetes mellitus within seven years of surgery, and more than 70% develop exocrine pancreatic insufficiency 9. In the present case, the patient remained euglycemic with preserved exocrine function at two years of follow-up; however, this relatively short interval is insufficient to predict long-term outcomes, and careful surveillance remains essential. The neurodevelopmental findings observed are most consistent with the identified AUTS2 variant rather than with hypoglycemia or CHI itself.
Conclusion
This case expands the existing body of knowledge on severe, diazoxide-unresponsive diffuse CHI, particularly among patients who do not exhibit pathogenic variants in the canonical CHI genes. By documenting the clinical course, therapeutic response, and postoperative evolution of a genetically unresolved case, this report highlights the practical limitations of WES and underscores the importance of correctly interpreting incidental findings such as AUTS2. It provides real-world postoperative data in a patient without molecular diagnosis and reinforces the need for prolonged surveillance following subtotal pancreatectomy. Importantly, this case emphasizes a critical gap in current understanding: even with advanced molecular testing, a proportion of CHI cases remains without a definitive genetic explanation, demonstrating the need for broader genomic and functional investigations in this population.
Data Availability Statement
Data are contained within the article.
Conflicts of Interest
The author declares that there is no conflict of interest regarding the publication of this article.
Funding Statement
This research received no external funding.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Hospital Materno Infantil de Brasília (protocol code 89645525.1.0000.5553, approval date 30 June 2025).
Informed Consent
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and accompanying clinical information.
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1Hospital Materno Infantil de Brasília, Brasília, 70203-900, Distrito Federal, Brazil;
2Hospital da Criança de Brasília José Alencar, Brasília, 70684831, Distrito Federal, Brazil;
*†Corresponding author;
†E-mail: joao-fontelles@fepecs.edu.br