68  Adrenal Gland Disorders

68.1 Introduction

The adrenal glands are essential endocrine organs responsible for the production of glucocorticoids, mineralocorticoids, and androgens. They play a central role in maintaining metabolism, electrolyte balance, and the stress response.
In children, adrenal gland disorders are particularly important because they can interfere with growth, puberty, and survival during physiological stress.

This lecture provides an overview of the anatomy and physiology of the adrenal glands, followed by a discussion of common paediatric adrenal disorders including adrenal insufficiency, congenital adrenal hyperplasia, Cushing syndrome, adrenal tumours, and disorders of adrenal medulla.

68.2 Anatomy and Physiology

Each adrenal gland is composed of two distinct regions:

1. Adrenal cortex — makes up about 90% of the gland.
   It has three zones:
   • Zona glomerulosa → secretes aldosterone (mineralocorticoid)
     
   • Zona fasciculata → secretes cortisol (glucocorticoid)
     
   • Zona reticularis → secretes androgens (DHEA and androstenedione)
2. Adrenal medulla — produces catecholamines (epinephrine and norepinephrine) under sympathetic nervous control.

Regulation:

• ACTH (adrenocorticotropic hormone) from the anterior pituitary regulates cortisol and androgen synthesis.

• Renin-angiotensin-aldosterone system (RAAS) primarily controls aldosterone secretion.

68.3 Major Adrenal Hormones and Their Actions

Hormone	Site of secretion	Major effects
Cortisol	Zona fasciculata	Gluconeogenesis, anti-inflammatory effect, stress response
Aldosterone	Zona glomerulosa	Sodium retention, potassium excretion, water balance
Androgens (DHEA)	Zona reticularis	Pubic/axillary hair development
Catecholamines	Medulla	“Fight or flight” response

68.4 Classification of Adrenal Disorders in Children

Adrenal disorders can be broadly classified into:

Category	Examples
Hypofunction (Adrenal insufficiency)	Primary (Addison’s disease), Secondary (ACTH deficiency), Congenital adrenal hyperplasia
Hyperfunction	Cushing syndrome, Hyperaldosteronism, Adrenogenital syndromes
Adrenal masses/tumours	Neuroblastoma, Adrenocortical carcinoma, Adenoma
Disorders of medulla	Pheochromocytoma

68.5 Adrenal Insufficiency

68.5.1 Definition

A condition in which the adrenal glands do not produce sufficient quantities of corticosteroids (cortisol ± aldosterone).

68.5.2 Classification

1. Primary adrenal insufficiency (Addison’s disease):
   • Destruction or dysfunction of the adrenal cortex.
   • Cortisol and aldosterone deficiency.
2. Secondary adrenal insufficiency:
   • Due to decreased ACTH secretion from the pituitary.
   • Cortisol deficiency only.
3. Tertiary adrenal insufficiency:
   • Resulting from hypothalamic dysfunction or prolonged exogenous steroid therapy.

68.5.3 Aetiology in Children

• Autoimmune adrenalitis (most common in developed settings).
  
• Congenital adrenal hyperplasia (CAH).
  
• Adrenal haemorrhage or infarction (e.g., Waterhouse–Friderichsen syndrome).
  
• Infections: Tuberculosis, CMV, fungal infections.
  
• Infiltrative diseases: Adrenoleukodystrophy, metastatic neuroblastoma.
  
• Surgical or drug-induced (ketoconazole, etomidate).

68.5.4 Clinical Features

• Failure to thrive and weight loss
  
• Fatigue, weakness, lethargy
  
• Hyperpigmentation (in primary cases)
  
• Hypotension, dehydration, salt craving
  
• Hypoglycaemia and hyponatremia
  
• Nausea, vomiting, abdominal pain

In neonates: prolonged jaundice, shock, or ambiguous genitalia (in CAH).

68.5.5 Investigations

• Serum cortisol: low morning level (< 100 nmol/L is suggestive).
  
• Plasma ACTH: elevated in primary, low in secondary.
  
• Electrolytes: hyponatremia, hyperkalemia, hypoglycemia.
  
• ACTH stimulation test (Synacthen test):
  • Failure of cortisol to rise confirms adrenal insufficiency.
    
• Adrenal autoantibodies for autoimmune cause.
  
• Imaging: CT or MRI of the adrenal glands when a structural cause issuspected.

68.5.6 Management

68.5.6.1 Acute Adrenal Crisis (Emergency)

Presentation: Shock, vomiting, dehydration, hypoglycaemia.

Management steps:

1. Immediate IV access.
   
2. Hydrocortisone: 50 mg/m² IV stat, then 50–100 mg/m²/day divided q6h.
   
3. IV fluids: 0.9% saline with 5% dextrose for rehydration and glucose correction.
   
4. Correct electrolytes.
   
5. Identify and treat precipitating cause (infection, steroid withdrawal, stress).

68.5.6.2 Chronic Replacement Therapy

• Glucocorticoid: Hydrocortisone 8–10 mg/m²/day orally (divided 3 doses).
  
• Mineralocorticoid: Fludrocortisone 0.05–0.2 mg daily.
  
• Education: “Sick day” rule—double or triple steroid dose during illness or surgery.
  
• Monitoring: Growth, weight, blood pressure, electrolytes.

68.6 Congenital Adrenal Hyperplasia (CAH)

68.6.1 Definition

A group of autosomal recessive enzyme defects in cortisol biosynthesis, leading to cortisol deficiency, variable aldosterone deficiency, and androgen excess.

68.6.2 Most Common Type

• 21-hydroxylase deficiency (≈90–95%)

68.6.3 Pathophysiology

• Block in cortisol synthesis → increased ACTH → adrenal hyperplasia.
  
• Excess precursors diverted to androgen pathway → virilisation.
  
• In salt-wasting forms → aldosterone deficiency causes hyponatremia and hyperkalemia.

68.6.4 Classification

Type	Features
Classical (Severe)	Salt-wasting or simple virilising
Non-classical (Mild)	Partial enzyme deficiency, late onset virilisation

68.6.5 Clinical Features

68.6.5.1 Salt-wasting type

• Neonatal onset (first 2 weeks).
  
• Vomiting, dehydration, weight loss, shock.
  
• Hyponatremia, hyperkalemia, hypoglycemia.
  
• Female: ambiguous genitalia (virilisation).
  
• Male: normal genitalia but presents with adrenal crisis.

68.6.5.2 Simple virilising type

• Ambiguous genitalia in females at birth.
  
• Precocious puberty, accelerated bone age.
  
• No salt wasting.

68.6.5.3 Non-classical type

• Later onset (childhood/adolescence).
  
• Hirsutism, acne, irregular menses in girls.
  
• Early pubarche in boys.

68.6.6 Diagnosis

• 17-hydroxyprogesterone (17-OHP): elevated (>30 nmol/L basal or post-ACTH).
  
• Electrolytes: hyponatremia, hyperkalemia.
  
• Genetic testing: CYP21A2 mutations.
  
• Ultrasound: assess internal genitalia in virilised females.

68.6.7 Management

68.6.7.1 Hormone Replacement

• Hydrocortisone: 10–15 mg/m²/day (3 divided doses).
  
• Fludrocortisone: 0.05–0.2 mg/day in salt-wasting forms.
  
• Sodium supplementation: especially in neonates.

68.6.7.2 Surgical Correction

• Genitoplasty for virilised females (timing individualized).

68.6.7.3 Long-Term Care

• Growth monitoring (avoid overtreatment leading to growth suppression).
  
• Periodic bone age assessment.
  
• Psychological and genetic counselling.
  
• Lifelong follow-up in endocrinology clinic.

68.7 Cushing Syndrome

68.7.1 Definition

A state of chronic glucocorticoid excess, either due to endogenous overproduction or exogenous steroid use.

68.7.2 Aetiology

Type	Cause
Exogenous	Prolonged corticosteroid therapy (most common in children)
Endogenous	ACTH-secreting pituitary adenoma (Cushing disease), adrenal adenoma or carcinoma, ectopic ACTH secretion (rare)

68.7.3 Clinical Features

• Growth failure and weight gain
  
• Moon facies, truncal obesity, buffalo hump
  
• Striae (purple), acne, hirsutism
  
• Hypertension, glucose intolerance
  
• Mood changes (depression, irritability)
  
• Osteopenia or fractures
  
• Delayed puberty or amenorrhea

68.7.4 Investigations

1. Screening tests
   • 24-hour urinary free cortisol: elevated.
   • Late-night salivary cortisol: loss of diurnal variation.
   • Low-dose dexamethasone suppression test: failure to suppress cortisol.
2. Differentiation tests
   • Plasma ACTH:
     • Low → adrenal cause
       
     • Normal/high → ACTH-dependent cause.
3. Imaging
   • MRI pituitary (Cushing disease).
     
   • CT or MRI adrenals for adenoma/carcinoma.

68.7.5 Management

• Exogenous: Gradual tapering of steroid dose.
  
• Pituitary adenoma: Trans-sphenoidal surgery.
  
• Adrenal tumour: Surgical excision ± radiotherapy.
  
• Medical therapy: Ketoconazole, metyrapone, or mitotane when surgery is contraindicated.

68.7.6 Prognosis

• Normal growth may resume post-treatment, but final height may be compromised if prolonged disease.
  
• Requires careful perioperative steroid coverage to prevent adrenal insufficiency.

68.8 Adrenal Tumours

68.8.1 Overview

Adrenal tumours in children may be benign (adenoma) or malignant (carcinoma), and may secrete hormones or be non-functioning.

68.8.1.1 Adrenocortical Tumours

• Adenomas: often hormonally active (Cushing, virilisation).
  
• Carcinomas: aggressive, may secrete multiple hormones.

Clinical features:

• Rapid virilisation in girls.
  
• Cushingoid features.
  
• Precocious puberty in boys.
  
• Abdominal mass or pain.

Diagnosis:

• Elevated serum and urinary steroid precursors.
  
• Imaging (CT/MRI): large irregular mass.
  
• Histopathology confirms diagnosis.

Treatment:

• Surgical excision is mainstay.
  
• Chemotherapy for carcinoma (mitotane, cisplatin-based regimens).
  
• Lifelong hormonal follow-up.

68.8.1.2 Neuroblastoma

A malignant tumour arising from neural crest cells of the adrenal medulla.

Clinical features:

• Abdominal mass, weight loss, hypertension.
  
• Opsoclonus–myoclonus syndrome (rare paraneoplastic sign).

Investigations:

• Elevated urinary catecholamine metabolites (VMA, HVA).
  
• Imaging: calcified adrenal mass.
  
• Bone marrow or MIBG scan for metastases.

Treatment:

• Surgery, chemotherapy, and radiotherapy as appropriate.
  
• Prognosis depends on stage and age (better in <1 year).

68.9 Disorders of the Adrenal Medulla

68.9.1 Pheochromocytoma

A rare catecholamine-secreting tumour of chromaffin cells.

68.9.1.1 Clinical Features

• Paroxysmal or sustained hypertension.
  
• Headache, palpitations, sweating.
  
• Pallor, tremor, anxiety.
  
• May be part of MEN2A/2B syndromes.

68.9.1.2 Investigations

• 24-hour urinary metanephrines and catecholamines (diagnostic).
  
• Plasma free metanephrines.
  
• MRI or MIBG scan to localize tumour.

68.9.1.3 Management

1. Preoperative preparation:

   • Alpha-blockade (phenoxybenzamine) for 1–2 weeks.
     
   • Then beta-blocker (propranolol) if tachycardia.

2. Definitive surgery: Adrenalectomy.
   

3. Postoperative monitoring for hypotension or recurrence.

68.10 Investigation Summary Table

Disorder	Key Test	Diagnostic Findings
Adrenal insufficiency	ACTH stimulation	Low cortisol response
CAH	17-hydroxyprogesterone	Elevated
Cushing syndrome	Dexamethasone suppression	Failure to suppress cortisol
Adrenocortical tumour	Urinary steroids, imaging	Elevated androgens/cortisol
Pheochromocytoma	Urinary metanephrines	Elevated catecholamines

68.11 Long-Term Management Considerations

• Hormone replacement therapy requires frequent adjustment as the child grows.
  
• Stress dosing of steroids during illness or surgery is lifesaving.
  
• Growth monitoring is crucial to avoid overtreatment or under-replacement.
  
• Psychological support is vital for children with virilisation or chronic illness.
  
• Family education on emergency management (e.g., injectable hydrocortisone) is essential.

68.12 Summary Points

• Adrenal gland disorders in children range from life-threatening adrenal insufficiency to hormone-secreting tumours.
  
• Congenital adrenal hyperplasia is the most frequent inherited adrenal disorder.
  
• Adrenal crisis is a paediatric emergency; treat promptly with IV fluids and hydrocortisone.
  
• Cushing syndrome in children commonly results from exogenous steroids.
  
• Pheochromocytoma, though rare, should be suspected in children with unexplained hypertension.
  
• Lifelong follow-up and interdisciplinary care (paediatric endocrinology, surgery, psychology) improve outcomes.

68.13 Suggested Reading

1. Nelson Textbook of Pediatrics, 22nd Edition.
   
2. Brook’s Clinical Pediatric Endocrinology, 7th Edition.
   
3. Speiser PW, et al. ESPE/LWPES Consensus on CAH Management, J Clin Endocrinol Metab 2018.
   
4. Husebye ES et al. Diagnosis and management of primary adrenal insufficiency in children, Lancet Diabetes Endocrinol, 2021.
   
5. WHO. Paediatric Endocrine Disorders: A Practical Guide for Clinicians, 2023.