Introduction to Addison Disease in Children

Addison disease, also known as primary adrenal insufficiency, is a rare endocrine disorder characterized by the inadequate production of adrenal hormones, primarily cortisol and aldosterone. In children, this condition can have significant impacts on growth, development, and overall health. The incidence of Addison disease in the pediatric population is estimated to be 0.5 cases per million children annually.

The adrenal glands, located atop the kidneys, play a crucial role in producing hormones essential for various bodily functions, including:

• Stress response
• Metabolism regulation
• Blood pressure control
• Electrolyte balance

In Addison disease, the destruction or dysfunction of the adrenal cortex leads to insufficient production of these vital hormones, resulting in a range of symptoms and potential life-threatening complications if left untreated.

Etiology of Addison Disease in Children

The causes of Addison disease in children can be categorized into several groups:

1. Autoimmune adrenalitis: The most common cause in developed countries, accounting for about 80% of cases. It may occur in isolation or as part of autoimmune polyglandular syndromes (APS).
2. Infectious causes:
   • Tuberculosis (more common in developing countries)
   • Fungal infections (e.g., histoplasmosis, coccidioidomycosis)
   • HIV-associated adrenalitis
3. Genetic disorders:
   • Congenital adrenal hyperplasia (CAH)
   • Adrenoleukodystrophy (ALD)
   • Familial glucocorticoid deficiency
4. Adrenal hemorrhage or infarction: Can occur in critically ill children or those with coagulation disorders.
5. Bilateral adrenalectomy: Surgical removal of both adrenal glands.
6. Medications: Rarely, certain drugs like ketoconazole or mitotane can cause adrenal insufficiency.

Understanding the underlying cause is crucial for proper management and identifying potential associated conditions, especially in cases of autoimmune or genetic etiology.

Clinical Presentation of Addison Disease in Children

The symptoms of Addison disease in children can be insidious and nonspecific, often leading to delayed diagnosis. Key clinical features include:

Chronic symptoms:

• Fatigue and weakness
• Weight loss or poor weight gain
• Anorexia and abdominal pain
• Nausea and vomiting
• Salt craving
• Hyperpigmentation of the skin and mucous membranes
• Orthostatic hypotension
• Vitiligo (in autoimmune cases)

Acute adrenal crisis:

This is a life-threatening emergency that can occur in undiagnosed cases or during periods of stress in known patients. Symptoms include:

• Severe hypotension or shock
• Severe abdominal pain, vomiting, and diarrhea
• Decreased consciousness or coma
• Hypoglycemia
• Hyponatremia and hyperkalemia
• Fever

Growth and Development:

Children with Addison disease may experience:

• Growth failure
• Delayed puberty
• Poor school performance due to fatigue and cognitive difficulties

It's important to note that the presentation can vary depending on the age of onset and the underlying cause. A high index of suspicion is necessary for timely diagnosis and management.

Diagnosis of Addison Disease in Children

Diagnosing Addison disease in children requires a combination of clinical suspicion, laboratory tests, and imaging studies:

1. Initial Laboratory Tests:

• Serum electrolytes: Hyponatremia, hyperkalemia
• Blood glucose: Hypoglycemia
• Complete blood count: Anemia, eosinophilia, lymphocytosis
• Renal function tests
• Thyroid function tests (to rule out associated thyroid disorders)

2. Hormonal Evaluation:

• Morning serum cortisol: Usually low (<3 μg/dL)
• Plasma ACTH: Elevated (>100 pg/mL)
• Serum aldosterone and plasma renin activity: Low aldosterone, high renin

3. Confirmatory Tests:

• ACTH stimulation test (gold standard):
  • Measure cortisol levels before and 30-60 minutes after administration of synthetic ACTH (Cosyntropin)
  • A peak cortisol level <18 μg/dL confirms adrenal insufficiency
• Insulin tolerance test (rarely used in children due to risks)

4. Etiological Evaluation:

• Adrenal antibodies: To confirm autoimmune etiology
• Very long-chain fatty acids: For adrenoleukodystrophy in boys
• Genetic testing: For suspected inherited disorders
• Tuberculin skin test or interferon-gamma release assay: If TB is suspected

5. Imaging Studies:

• Abdominal CT or MRI: To evaluate adrenal gland size and structure
• Chest X-ray: If tuberculosis is suspected

Early diagnosis is crucial to prevent life-threatening adrenal crises and ensure proper growth and development in children with Addison disease.

Treatment of Addison Disease in Children

The treatment of Addison disease in children focuses on hormone replacement therapy and management of acute crises:

1. Chronic Management:

Glucocorticoid Replacement:

• Hydrocortisone: 8-12 mg/m²/day divided into 3 doses
• Dose adjustments based on clinical response and growth
• Stress dosing during illness or surgery (usually 2-3 times the maintenance dose)

Mineralocorticoid Replacement:

• Fludrocortisone: 0.05-0.2 mg/day
• Dose adjusted based on blood pressure, electrolytes, and plasma renin activity

Salt Supplementation:

• Especially important in infants and young children
• Typically 1-3 g/day of sodium chloride

2. Acute Adrenal Crisis Management:

• Immediate administration of hydrocortisone:
  • 50-100 mg/m² IV bolus, followed by continuous infusion or divided doses
• Fluid resuscitation with normal saline
• Correction of hypoglycemia if present
• Gradual correction of electrolyte imbalances

3. Patient and Family Education:

• Recognition of symptoms of adrenal insufficiency
• Stress dosing protocols
• Use of emergency hydrocortisone injection
• Importance of medical alert identification

4. Management of Associated Conditions:

• Treatment of other endocrine deficiencies in APS
• Specific management for genetic causes (e.g., Lorenzo's oil for ALD)

Long-term follow-up is essential to ensure optimal growth, development, and quality of life for children with Addison disease.

Prognosis and Follow-up of Addison Disease in Children

With proper management, children with Addison disease can lead normal, healthy lives. However, ongoing medical care and vigilance are necessary:

Prognosis:

• Life expectancy is generally normal with adequate treatment
• Quality of life can be good, but adherence to medication is crucial
• Risk of adrenal crises remains a concern, especially during illness or stress

Follow-up Care:

1. Regular Clinic Visits:
   • Every 3-6 months, or more frequently in younger children
   • Assessment of growth, puberty, and overall health
   • Monitoring for symptoms of under- or over-replacement
2. Laboratory Monitoring:
   • Electrolytes and plasma renin activity
   • Annual bone age X-ray to assess growth
   • Periodic ACTH levels to monitor for development of associated conditions
3. Medication Adjustments:
   • Dose increases needed during periods of rapid growth
   • Transition to adult dosing regimens during late adolescence
4. Psychosocial Support:
   • Addressing the challenges of chronic disease management
   • School accommodations if needed
5. Transition to Adult Care:
   • Planned transition to adult endocrinology care
   • Education on self-management and long-term health implications

Long-term Considerations:

• Monitoring for other autoimmune conditions in cases of APS
• Bone health assessment due to long-term glucocorticoid use
• Cardiovascular risk assessment in adulthood
• Fertility counseling when appropriate

With comprehensive care and patient/family education, most children with Addison disease can achieve normal growth, development, and a high quality of life.