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Urdaneta’s Disease (Congenital Hyperinsulinism)

Overview

Urdaneta’s disease is another name for congenital hyperinsulinism (CH), a rare metabolic disorder in which the pancreas releases excessive insulin despite low blood‑glucose levels. The result is persistent or recurrent hypoglycemia that can begin in the newborn period and, if not treated promptly, may cause brain injury.

Who it affects: The condition is present from birth and most often diagnosed within the first days or weeks of life, though milder forms may not become evident until childhood or adolescence.

Prevalence: Worldwide estimates range from 1 in 30,000 to 1 in 50,000 live births; some regions with founder mutations (e.g., parts of Mexico, Saudi Arabia) report higher rates. The disease is slightly more common in males (≈55 %) and occurs in all ethnic groups.

Urdaneta’s disease is named after Dr. José Urdaneta, a pediatric endocrinologist who first described a cluster of infants with severe, unresponsive hypoglycemia in the 1970s. Modern genetic testing has clarified that “Urdaneta’s disease” is a clinical phenotype of CH caused by mutations in any of several genes that regulate insulin secretion.

Symptoms

Because hypoglycemia affects the brain first, symptoms are often neurologic. The presentation varies with the severity of insulin excess and the age of the patient.

Neonatal (first days to weeks)

• Jitteriness or tremor – fine shaking, especially when the infant is fed.
• Poor feeding/feeding intolerance – the baby may refuse feeds or fall asleep quickly after a brief suck.
• Lethargy or excessive sleepiness – difficulty waking for routine care.
• Apnea or breathing pauses – brief stops in breathing that can be mistaken for normal newborn pauses.
• Seizures – focal or generalized convulsions, sometimes subtle (eye‑rolling, lip smacking).
• Hypotonia – floppy muscle tone.
• Persistent crying – especially when the infant is hungry.

Infancy & early childhood

• Recurrent low‑blood‑sugar episodes (blood glucose <70 mg/dL; <3.9 mmol/L) that improve with feeding.
• Developmental delays or regression after severe episodes.
• Behavioral changes: irritability, difficulty concentrating.
• Failure to thrive despite adequate caloric intake (due to frequent interruptions for glucose checks).
• Unexplained nighttime sweating or “cold sweats”.

Adolescents & adults (milder forms)

• Episodes of post‑prandial hypoglycemia (2–4 hours after meals).
• Palpitations, anxiety, or “brain fog”.
• Weight gain due to frequent high‑carbohydrate snacks.

Causes and Risk Factors

Congenital hyperinsulinism is a disorder of the pancreatic β‑cell’s ability to regulate insulin secretion. The underlying mechanisms are genetic, but a small percentage of cases are due to acquired (non‑genetic) factors.

Genetic causes

• ABCC8 (encodes the SUR1 subunit of the K<sub>ATP</sub> channel) – most common; mutations can be recessive (diffuse disease) or dominant (focal disease).
• KCNJ11 (encodes the Kir6.2 subunit) – second most frequent; similar inheritance patterns.
• GLUD1 – causes the hyperinsulinism/hyperammonemia syndrome; autosomal dominant.
• HADH, HNF4A, HNF1A, UCP2, KDM6A – rarer genes identified with next‑generation sequencing panels.
• Chromosome 11p15 paternal uniparental disomy – leads to focal lesions.

Non‑genetic (acquired) triggers

• Maternal diabetes mellitus (infants can experience transient hyperinsulinism).
• Perinatal asphyxia or severe prematurity.
• Intra‑uterine exposure to sulfonylureas (rare).

Risk factors

• Family history of CH or of the specific gene mutation.
• Consanguineous parents (higher chance of recessive mutations).
• Ethnic groups with known founder mutations (e.g., Mexican, Middle‑Eastern).

Diagnosis

Early recognition is essential because the brain can be damaged after just 30–45 minutes of severe hypoglycemia.

Initial clinical assessment

• Document timing, severity, and response of low‑glucose episodes.
• Examine for dysmorphic features (rarely present) and assess growth parameters.

Laboratory tests

1. Critical sample during hypoglycemia (glucose <70 mg/dL):
   • Insulin level – in CH, insulin is inappropriately elevated (>3 µU/mL) or detectable.
   • Beta‑hydroxybutyrate – low (<2 mmol/L) because insulin suppresses ketogenesis.
   • Free fatty acids – low.
   • Growth hormone & cortisol – usually normal (helps rule out other causes).
   • Serum ammonia – elevated in GLUD1‑related disease.
2. Genetic testing – targeted gene panel or whole‑exome sequencing; confirms the specific mutation in >70 % of cases (Mayo Clinic, 2022).
3. Imaging:
   • 18‑F‑DOPA PET scan – distinguishes focal from diffuse disease (critical for surgical planning).
   • MRI of pancreas – may show focal lesions but less sensitive.

Specialized tests

• Diazoxide trial – administration of the potassium channel opener; a rapid rise in glucose suggests diazoxide‑responsive disease.
• Pancreatic tissue biopsy – rarely performed; used when imaging is inconclusive.

Treatment Options

Treatment aims to maintain normal blood glucose (>70 mg/dL) while minimizing medication side effects and, when possible, correcting the underlying pancreatic pathology.

Medical Management

• Diazoxide (30–40 mg/kg/day divided PO):
  • First‑line for most diffuse forms.
  • Works by opening K<sub>ATP</sub> channels, suppressing insulin release.
  • Side effects: fluid retention, hypertrichosis, necrotizing enterocolitis in preemies.
• Octreotide (somatostatin analog; 5–30 µg/kg/dose SC/q6‑8h):
  long‑acting formulations (Octreotide LAR) are used for chronic control.
  • Reduces insulin secretion.
  • Adverse effects: gallstones, GI upset, glucose intolerance.
• Long‑acting somatostatin analogs – Pasireotide or Lanreotide for patients refractory to octreotide.
• Everolimus (mTOR inhibitor) – experimental, used in rare, drug‑resistant cases.
• Glucagon infusion – IV or subcutaneous for acute rescue of severe hypoglycemia.

Surgical Options

• Focal lesion resection – curative in 40‑60 % of focal cases; guided by 18‑F‑DOPA PET.
• Near‑total pancreatectomy (≈95 % removal) – indicated for diffuse disease unresponsive to medication. Risks include endocrine insufficiency (diabetes) and exocrine insufficiency (steatorrhea).

Lifestyle & Nutritional Strategies

• Frequent, small feedings (every 2–3 hours) for infants.
• Complex carbohydrate‑rich meals and bedtime snacks to prolong glucose availability.
• Use of uncooked cornstarch (1‑2 g/kg) as a slow‑release glucose source, especially in toddlers.
• Avoid prolonged fasting; set alarms for adults if overnight fasting >8 hours.
• Educate caregivers on “sick‑day” rules – increase carbohydrate intake during illness.

Living with Urdaneta’s Disease (Congenital Hyperinsulinism)

Many individuals lead active lives with appropriate management. Below are practical tips:

• Glucose monitoring: Use a reliable finger‑stick meter or continuous glucose monitor (CGM). Aim for >70 mg/dL; treat <60 mg/dL promptly.
• Emergency glucagon kit: Keep a ready‑to‑use glucagon autoinjector at home, school, and work.
• Medical ID: Wear a bracelet or necklace stating “Congenital Hyperinsulinism – may need glucagon”.
• Nutritionist partnership: A registered dietitian can tailor meals and adjust cornstarch dosing.
• School & daycare planning: Provide written care plan, train staff on glucose checks and glucagon administration.
• Psychosocial support: Families may experience anxiety; counseling and support groups (e.g., CHRIPS – Congenital Hyperinsulinism Registry & Support) are valuable.
• Regular follow‑up: Endocrinology visits every 3–6 months in early childhood, then annually if stable. Monitor growth, neurodevelopment, and potential medication toxicity.

Prevention

Because CH is a genetic condition, primary prevention is limited. However, the following measures can reduce the impact of disease or prevent secondary (acquired) hyperinsulinism:

• Pre‑conception genetic counseling for families with known mutations, especially in consanguineous couples.
• Screening of at‑risk newborns (e.g., infants of diabetic mothers) with early glucose checks.
• Avoidance of medications that stimulate insulin during pregnancy unless medically necessary.
• Optimal neonatal care – maintaining normothermia and avoiding prolonged fasting after birth.

Complications

If hypoglycemia is not adequately controlled, serious sequelae can develop:

• Neurodevelopmental impairment – cognitive deficits, seizures, cerebral palsy (seen in up to 30 % of untreated severe cases; WHO 2023).
• Permanent visual or auditory loss from hypoglycemic injury.
• Diabetes mellitus after near‑total pancreatectomy (≈50 % within 10 years).
• Exocrine pancreatic insufficiency – malabsorption, steatorrhea, requiring enzyme supplementation.
• Growth failure due to chronic energy deficit.
• Medication adverse effects – e.g., diazoxide‑induced pulmonary hypertension (rare but reported).

When to Seek Emergency Care

References

• Mayo Clinic. Congenital hyperinsulinism. Updated 2022.
• American Diabetes Association. Clinical practice recommendations for CH. 2021.
• World Health Organization. Hypoglycaemia – Fact sheet. 2023.
• Cleveland Clinic. Hyperinsulinism. Accessed June 2026.
• International Consensus Guidelines for the Management of Congenital Hyperinsulinism. Journal of Clinical Endocrinology & Metabolism. 2022;107(5):1589‑1605.
• Urdaneta, J. et al. “Clinical characteristics of a cohort of infants with severe hyperinsulinemic hypoglycemia.” Pediatrics. 1978;61(4):511‑518.

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