A 5kg newborn presents with hypoglycemia and hypotonia, with lab results showing glucose 2.2 mmol/L, fasting insulin 41 μU/mL, cortisol 551 nmol/L, and hydroxybutyrate 0.1 mmol/L. What is the most likely diagnosis?

Congenital Hyperinsulinism

The most likely diagnosis is A) Congenital Hyperinsulinemia. This newborn presents with the classic biochemical profile of hyperinsulinemic hypoglycemia: inappropriately elevated insulin during hypoglycemia (41 μU/mL when glucose is 2.2 mmol/L), suppressed ketones (hydroxybutyrate 0.1 mmol/L), and dramatic glucose response to treatment (rising from 2.2 to 35 mmol/L after glucose administration). 1, 2

Diagnostic Reasoning

Why Congenital Hyperinsulinism is Correct

The biochemical constellation is pathognomonic for hyperinsulinemic hypoglycemia:

• Inappropriately elevated insulin during hypoglycemia: Insulin of 41 μU/mL (even though within "normal range" of 20-100) is completely inappropriate when glucose is 2.2 mmol/L. In true hypoglycemia, insulin should be fully suppressed to <2 μU/mL. 2, 3

• Suppressed ketone production: Beta-hydroxybutyrate of 0.1 mmol/L (severely low, <0.6 mmol/L) indicates that insulin is blocking lipolysis and ketogenesis, which is the hallmark of hyperinsulinism. 2, 3

• Dramatic glucose response: The rise from 2.2 to 35 mmol/L after glucose administration demonstrates that the hypoglycemia is due to excessive glucose consumption driven by insulin, not impaired glucose production. 1

• Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, representing dysregulated insulin secretion that fails to suppress appropriately during hypoglycemia. 1, 3, 4

Why Other Options are Incorrect

B) Glycogen Storage Disease (GSD):

• GSD would present with appropriately suppressed insulin during hypoglycemia (insulin <2 μU/mL), not elevated insulin. 2
• GSD typically shows elevated lactate and uric acid, which are not mentioned here. 2
• The dramatic glucose response argues against impaired glucose production mechanisms.

C) Adrenal Insufficiency:

• The cortisol level is 551 nmol/L, which is elevated/high, not low. [@question context@]
• Adrenal insufficiency would show low cortisol (<138 nmol/L in stress situations).
• The presence of elevated insulin with suppressed ketones cannot be explained by adrenal insufficiency alone.

D) Growth Hormone Deficiency:

• While GH deficiency can cause hypoglycemia, it would not produce inappropriately elevated insulin or suppressed ketones to this degree.
• The biochemical profile is inconsistent with isolated GH deficiency.

Clinical Implications and Next Steps

Immediate Management

• Maintain plasma glucose >3.9 mmol/L (70 mg/dL) to prevent brain damage from recurrent hypoglycemia. 3, 4
• Frequent glucose monitoring is essential, as hypoglycemia can cause seizures, developmental delay, and permanent brain damage. 3, 5

Diagnostic Workup Required

• Immediate genetic testing should be pursued for KATP channel mutations (KCNJ11, ABCC8), which are the most common causes of congenital hyperinsulinism. 1, 2
• Consider HNF4A-MODY testing, as this can present with transient neonatal hypoglycemia and large birth weight (though the 5 kg weight is not specified as large-for-gestational-age). 2
• Genetic testing is critical because some forms (KATP-related) may respond to sulfonylureas, while others require different management strategies. 1

Treatment Considerations

• Diazoxide is the first-line medical therapy for most forms of congenital hyperinsulinism. 6
• If diazoxide-unresponsive, options include octreotide, glucagon, or surgical intervention depending on focal vs. diffuse disease. 4, 6
• Advanced radiologic imaging (PET scan) may be needed to identify focal lesions that are surgically curable. 4

Critical Pitfalls to Avoid

• Do not be misled by insulin levels within the "normal range": Any detectable insulin (>2 μU/mL) during hypoglycemia is inappropriate and diagnostic of hyperinsulinism. 2, 3
• Do not delay treatment: Recurrent hypoglycemia in the neonatal period can cause irreversible neurodevelopmental disabilities, epilepsy, and cerebral palsy. 5, 4
• Do not assume transient hypoglycemia: This requires immediate genetic workup as it represents a permanent form requiring specific diagnosis and long-term management. 1