What is the clinical presentation of Congenital Hyperinsulinism (CHI) in pediatric endocrinology?

Clinical Presentation of Congenital Hyperinsulinism (CHI) in Children

Congenital hyperinsulinism presents most commonly in the neonatal period (65% of cases) with severe, recurrent hypoglycemia characterized by inappropriately elevated insulin levels despite low blood glucose, creating a hypoketotic, hypofattyacidemic biochemical profile that distinguishes it from other causes of neonatal hypoglycemia. 1, 2, 3, 4

Age at Presentation

CHI manifests across three distinct age groups with different clinical implications:

• Neonatal onset (65% of cases): Symptoms appear within the first 28 days of life, often within hours to days after birth 3, 4
• Infancy onset (28% of cases): Presentation occurs between 1 month and 1 year of age 4
• Childhood onset (7% of cases): Rare late presentations beyond infancy 4

The timing of presentation carries prognostic significance, with infancy-onset patients showing higher rates of unfavorable neurodevelopmental outcomes compared to neonatal-onset cases 4

Cardinal Clinical Features

Hypoglycemic Episodes

The hallmark presentation involves recurrent, severe hypoglycemia with specific characteristics:

• Hypoketotic hypoglycemia: Absence of ketone bodies despite low glucose levels 2
• Hypofattyacidemic profile: Inappropriately low free fatty acids during hypoglycemia 2
• Inappropriately elevated insulin: Detectable insulin levels when glucose is low (normally insulin should be suppressed) 2, 5

Clinical Manifestations of Hypoglycemia

Infants may present with:

• Seizures (a common presenting symptom) 3, 4
• Lethargy or altered consciousness 3
• Poor feeding 3
• Jitteriness or tremors 3
• Apnea or cyanotic episodes 3

Early symptom onset occurs in 80% of cases, emphasizing the urgency of recognition and intervention 3

Associated Physical Findings

Birth Weight Abnormalities

A subset of neonatal-onset CHI patients demonstrates significant macrosomia:

• 27% of neonatal-onset patients have markedly increased birth weight (>2.0 standard deviation scores) 4
• Mean birth weight in this subgroup reaches 3.2 standard deviation scores above normal 4
• This reflects chronic fetal hyperinsulinemia causing increased intrauterine growth 4

Syndromic Associations

CHI occurs in isolation but can also present as part of syndromic conditions 1:

• Overgrowth syndromes: Beckwith-Wiedemann syndrome, Sotos syndrome 1
• Chromosomal syndromes with growth failure: Turner syndrome, Kabuki syndrome, Costello syndrome 1
• Congenital disorders of glycosylation 1
• Syndromic channelopathies: Timothy syndrome 1

When CHI presents with congenital anomalies or additional medical issues, consider syndromic forms requiring broader genetic workup 1

Biochemical Diagnostic Profile

The characteristic laboratory pattern during a hypoglycemic episode includes:

• Low blood glucose (typically <50 mg/dL) with detectable insulin 2
• Suppressed ketones (β-hydroxybutyrate <1.5 mmol/L) 2
• Low free fatty acids 2
• Inappropriate glycemic response to glucagon (rise >30 mg/dL indicates insulin excess) 2

This hypoketotic, hypofattyacidemic pattern is pathognomonic for hyperinsulinemic hypoglycemia and distinguishes CHI from ketotic hypoglycemia, fatty acid oxidation defects, and other metabolic causes 2

Clinical Heterogeneity

CHI demonstrates marked heterogeneity in presentation:

• Histologic variants: Diffuse versus focal pancreatic disease (focal forms are surgically curable) 5
• Genetic heterogeneity: Multiple gene mutations affecting the insulin secretion pathway 1, 5
• Treatment responsiveness: Variable response to diazoxide (29% of neonatal-onset versus 69% of infancy/childhood-onset patients respond) 4

Critical Complications and Outcomes

Neurological Sequelae

The most devastating consequence of CHI is permanent brain damage from recurrent hypoglycemia, occurring in 44% of patients with psychomotor or mental retardation 3, 4:

• Mental retardation or developmental delay: 22-44% of cases 3, 4
• Epilepsy: 13-25% of cases 3, 4
• Infancy-onset manifestation correlates with worse neurodevelopmental outcomes 4

Treatment-Related Complications

Surgical management carries significant risks:

• Persistent hypoglycemia after pancreatectomy: 40% of operated patients 4
• Insulin-dependent diabetes mellitus: 27% of surgically treated patients develop diabetes either immediately post-surgery or years later 4
• Pancreatectomy rates: 70% in neonatal-onset versus 28% in infancy/childhood-onset groups 4

Key Clinical Pitfalls

• Delayed recognition leads to irreversible brain damage: The high rate of neurological sequelae (44%) emphasizes the critical need for immediate recognition and aggressive treatment 3, 4
• Transient versus persistent forms: In syndromic CHI, the metabolic disturbance may be transient, but neonatal hypoglycemia still requires immediate intervention 1
• Misattribution to other causes: The hypoketotic, hypofattyacidemic profile must be recognized to avoid misdiagnosis as sepsis, other metabolic disorders, or transient neonatal hypoglycemia 2