Zollinger‑Ellison Syndrome in Children

Overview

Zollinger‑Ellison syndrome (ZES) is a rare disorder characterized by the development of one or more gastrin‑producing tumors (gastrinomas) in the pancreas or duodenum. The excess gastrin stimulates the stomach to secrete large amounts of gastric acid, leading to recurrent peptic ulcers, diarrhea, and malabsorption.

Who it affects: While ZES most often presents in adults (average age 40–50 years), approximately 5–10 % of cases occur in children and adolescents. Both boys and girls are affected, with a slight male predominance reported in pediatric series.

Prevalence: Gastrinomas are the second most common functional pancreatic neuroendocrine tumor, with an estimated overall incidence of 0.5–2 cases per million per year. In children, the incidence is < 0.1 per million per year, making ZES an exceedingly rare condition.

Most pediatric cases are associated with the hereditary syndrome Multiple Endocrine Neoplasia type 1 (MEN‑1). Sporadic (non‑hereditary) gastrinomas can also occur.

Symptoms

Symptoms result from hyperacidic gastric secretions and the local effects of the tumor. Children may present with variable severity, and some symptoms overlap with common pediatric conditions, which can delay diagnosis.

Gastro‑intestinal (GI) symptoms

• Recurrent abdominal pain: Often epigastric, worsens after meals.
• Peptic ulcer disease: Multiple ulcers in the duodenum or jejunum; may be refractory to standard therapy.
• Severe or chronic diarrhea: 3–10 + watery stools per day; can lead to dehydration.
• Steatorrhea (fatty stools): Resulting from malabsorption of fats due to acid‑induced inactivation of pancreatic enzymes.
• Nausea & vomiting: May accompany ulcer disease or obstruction.
• Weight loss or failure to thrive: Due to malabsorption and poor appetite.

Systemic symptoms

• Fatigue & weakness: Secondary to anemia, electrolyte loss, or nutrient deficiency.
• Iron‑deficiency anemia: Chronic GI bleeding from ulcers.
• Osteoporosis or bone pain: Long‑standing malabsorption of calcium and vitamin D.

Signs of MEN‑1 (if present)

• Parathyroid hyperplasia → hypercalcemia (muscle aches, polyuria)
• Pituitary adenomas → headaches, visual changes, growth hormone excess

Causes and Risk Factors

Pathophysiology

Gastrinomas arise from neuroendocrine cells in the pancreas (≈60 %) or duodenum (≈30 %). The tumor secretes gastrin, a hormone that stimulates parietal cells to produce hydrochloric acid. Excess acid overwhelms the protective mucus barrier, leading to ulcer formation and inactivation of pancreatic enzymes.

Risk factors

• Genetic predisposition – MEN‑1: Autosomal‑dominant mutation in the MEN1 tumor suppressor gene. Up to 30 % of children with ZES have MEN‑1.
• Family history of gastrinomas or other endocrine tumors.
• Radiation exposure: Very rare, but high‑dose abdominal radiation has been linked to neuroendocrine tumors.
• Chronic H. pylori infection: Not a direct cause but may mask ulcer symptoms, delaying diagnosis.

Diagnosis

Because symptoms mimic common GI disorders, a high index of suspicion is essential, especially in children with refractory ulcers or unexplained diarrhea.

Step‑wise diagnostic approach

1. Clinical assessment: Detailed history (ulcer recurrence, family history of MEN‑1) and physical exam.
2. Laboratory tests:
   • Fasting serum gastrin level – markedly elevated (> 1000 pg/mL) in > 80 % of cases.
   • Secretin stimulation test – gastrin rises > 120 pg/mL after IV secretin (highly specific).
   • Basic metabolic panel – assess electrolytes, calcium, and renal function.
   • Complete blood count – look for anemia.
3. Imaging to locate the tumor:
   • Endoscopic ultrasound (EUS): Sensitive for small (< 1 cm) duodenal lesions.
   • Multiphasic contrast CT or MRI of the abdomen: Detects larger gastrinomas and metastases.
   • Somatostatin receptor scintigraphy (Octreoscan) or ^68Ga-DOTATATE PET/CT: Gold standard for neuroendocrine tumor localization.
4. Genetic testing: Targeted sequencing of the MEN1 gene when MEN‑1 is suspected.
5. Endoscopy: Upper GI endoscopy to document ulcer disease and obtain biopsies if indicated.

Diagnosis is confirmed when (1) fasting gastrin is markedly elevated, (2) secretin test is positive, and (3) a gastrinoma is identified on imaging.

Treatment Options

Management aims to (a) control acid hypersecretion, (b) remove or reduce tumor burden, and (c) address associated endocrine abnormalities.

Medical therapy – acid control

• Proton pump inhibitors (PPIs): High‑dose omeprazole, esomeprazole, or pantoprazole are first‑line. Doses may be 2–4 × the adult dose in children, titrated to symptom control.
• H2‑receptor antagonists: Cimetidine or ranitidine can be added if PPIs alone are insufficient, though they are less potent.
• Goal: keep gastric pH > 4 continuously to allow ulcer healing.

Surgical options

• Enucleation: Removal of a solitary, well‑localized gastrinoma; preferred when the tumor is < 2 cm and no metastasis.
• Pancreaticoduodenectomy (Whipple procedure): Considered for larger or multiple duodenal tumors.
• Liver metastasectomy or ablative therapies: For isolated hepatic spread.
• Pre‑operative imaging is crucial to plan the extent of surgery.

Medical therapy – tumor control

• Somatostatin analogues (SSA): Octreotide or lanreotide bind somatostatin receptors, suppressing gastrin secretion and may shrink tumor size. Dosing is weight‑based in children.
• Targeted therapy: Everolimus (mTOR inhibitor) or sunitinib (tyrosine‑kinase inhibitor) can be used for unresectable or progressive disease, though data in pediatrics are limited.
• Chemotherapy: Generally reserved for high‑grade neuroendocrine carcinomas.

Lifestyle & supportive measures

• Small, frequent meals low in acidic foods.
• Avoid NSAIDs, aspirin, and alcohol, which aggravate ulcer formation.
• Supplementation with calcium, vitamin D, and iron as needed.
• Regular monitoring of growth parameters and bone density.

Living with Zollinger‑Ellison Syndrome in Children

Chronic conditions require a team approach—pediatric gastroenterologist, endocrinologist, surgeon, dietitian, and psychologist.

Daily management tips

• Medication adherence: Use a pill organizer, set alarms, and involve school nurses for mid‑day doses.
• Monitoring symptoms: Keep a simple diary of pain, stool frequency, and medication timing; share with the care team.
• Nutrition:
  • Incorporate high‑calorie, nutrient‑dense foods (smoothies, nut butter, fortified milk).
  • Consider a low‑fat diet if steatorrhea persists; medium‑chain triglyceride (MCT) oils are easier to absorb.
• School accommodations: Provide a medical note for bathroom breaks, medication administration, and a low‑stress environment during flare‑ups.
• Emotional health: Children may feel isolated; counseling or support groups (e.g., Children’s Cancer & Blood Disorders) can help.
• Regular follow‑up:
  • Every 3–6 months: gastrin level, PPI dose adjustment, growth chart.
  • Annually: imaging (CT/MRI) to detect recurrence.
  • If MEN‑1: screening for hyperparathyroidism (serum calcium) and pituitary disease (prolactin, IGF‑1).

Prevention

Because most gastrinomas are sporadic or genetically determined, primary prevention is limited. However, risk can be reduced by:

• Early genetic counseling: Families with known MEN‑1 mutations should undergo testing in childhood.
• Avoiding chronic gastric irritants: Limit long‑term NSAID use; treat H. pylori infection promptly.
• Routine health surveillance: Annual endoscopic evaluation for children with MEN‑1, even before symptoms appear.

Complications

If left untreated or poorly controlled, ZES can lead to serious complications:

• Perforated peptic ulcer: Sudden severe abdominal pain, peritonitis.
• Bleeding ulcer: Hematemesis or melena; may cause anemia.
• Gastro‑intestinal obstruction: From scarring or tumor mass effect.
• Severe malnutrition: Failure to thrive, growth retardation, and micronutrient deficiencies.
• Metastatic disease: Liver is the most common site; metastatic gastrinomas have a poorer prognosis.
• Bone disease: Osteopenia/osteoporosis secondary to chronic acid‑induced calcium loss.

When to Seek Emergency Care

Prompt treatment can prevent life‑threatening complications and improve long‑term outcomes.

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References: Mayo Clinic. Zollinger‑Ellison syndrome. https://www.mayoclinic.org; National Institutes of Health (NIH). Genetics Home Reference – MEN1. https://ghr.nlm.nih.gov; American Journal of Gastroenterology. “Pediatric Zollinger‑Ellison syndrome: a systematic review” 2021; World Health Organization (WHO). Neuroendocrine Tumors – classification 2022. Cleveland Clinic. Gastrinomas and treatment options. https://my.clevelandclinic.org.