How do acromegaly and gigantism differ in pathophysiology, clinical presentation, and management?

Acromegaly vs Gigantism: Key Differences

The fundamental distinction between acromegaly and gigantism is timing: both result from identical GH excess pathophysiology, but gigantism occurs when GH hypersecretion begins before epiphyseal fusion, causing excessive linear growth, while acromegaly manifests after epiphyseal closure with soft tissue and bone overgrowth instead of height increase. 1

Pathophysiology

Both conditions share the same underlying cause:

• GH-secreting pituitary adenoma (somatotrophinoma) arising from somatotroph cells is the most common etiology in both conditions 1
• Rare causes include somatotroph hyperplasia from McCune-Albright syndrome, Carney complex, X-linked acrogigantism, or GH-releasing hormone-secreting tumors (particularly with MEN1 syndrome) 1
• Genetic basis identified in approximately 50% of gigantism cases, making genetic testing particularly important in children and young people 1

The critical pathophysiologic difference is epiphyseal plate status:

• Before epiphyseal fusion → Gigantism with accelerated linear growth 1
• After epiphyseal fusion → Acromegaly with acral and soft tissue enlargement 2, 3

Clinical Presentation

Gigantism (Pre-Epiphyseal Fusion)

Primary manifestation:

• Increased growth velocity is the most prominent feature, with height >2 standard deviation scores (SDS) above age-adjusted and sex-adjusted norms or >2 SDS above mid-parental height 1, 4
• Persistently elevated growth velocity (>2 SDS) 1, 4
• Delayed bone age despite excessive height 1

Associated features:

• Pubertal delay or arrested puberty (due to gonadotrophin inhibition from prolactin co-secretion or mass effects) 1
• Acral enlargement, headache, visual field defects, joint pain 1
• Acromegalic features develop concurrently: coarsened facial features, prognathism, dental malocclusion, teeth separation, frontal bossing 1, 4

Epidemiology:

• Annual incidence: 3-8 cases per million person-years in children aged 0-17 years 1
• More girls (62%) diagnosed in pediatric age group, though more males overall 1

Acromegaly (Post-Epiphyseal Fusion)

Primary manifestations:

• Coarsening of facial features: furrowing of forehead, pronounced brow protrusion, enlargement of nose and ears, thickening of lips, skin wrinkles, nasolabial folds 2
• Mandibular prognathism with dental malocclusion and increased interdental spacing 2
• Excessive growth of hands and feet (predominantly soft tissue swelling) present in vast majority 2

Systemic complications:

• Cardiovascular: left ventricular hypertrophy, diastolic dysfunction, hypertension 1, 4
• Metabolic: insulin resistance, glucose intolerance, secondary diabetes mellitus 1, 4
• Respiratory: sleep apnea, sleep disturbance 1
• Musculoskeletal: carpal tunnel syndrome, kyphosis, joint hypermobility 1

Epidemiology:

• Average age at diagnosis: 40-50 years 2
• Diagnostic delay: typically 5-10 years after onset due to insidious progression 2
• Equal gender distribution 2

Diagnostic Approach

Biochemical Testing (Identical for Both Conditions)

Initial screening:

• Elevated serum IGF-1 (age-adjusted, sex-adjusted, and Tanner stage-matched) is the most reliable marker 1, 4
• Failure of GH suppression below 1 μg/L after oral glucose load (though complete suppression difficult in normal adolescence) 1, 4

Important caveats:

• IGF-1 may be falsely normal/low with severe hypothyroidism, malnutrition, or severe infection 1
• IGF-1 may be falsely elevated in poorly controlled diabetes, hepatic/renal failure 1
• Oral estrogens reduce IGF-1 generation by liver 1
• In adolescents, GH nadir after glucose load is sex and pubertal stage-specific, with highest levels in mid-puberty (Tanner stage 2-3), particularly in girls 1

Additional testing:

• Dynamic pituitary assessment for hypofunction and hyperfunction of other anterior pituitary hormones 1
• Hyperprolactinemia present in 65% of pediatric acromegaly cases and 34-36% of gigantism cases 1, 4
• TSH co-secretion less frequent than prolactin 1

Clinical Triggers for Testing

In children/adolescents (gigantism):

• Excess height (>2 SDS) OR consistently elevated height velocity AND acromegalic features 1, 4
• With or without delayed/arrested puberty or family history of pituitary adenoma 1, 4

In adults (acromegaly):

• Less than 15% actively seek attention for appearance changes 2
• More commonly present with systemic comorbidities or local tumor effects 2

Imaging and Genetic Evaluation

• Contrast-enhanced pituitary MRI to detect adenoma 1
• Clinical evaluation for syndromic causes in all cases 1
• Biochemical screening for pituitary hormone excess in all patients with Carney complex, McCune-Albright syndrome, MEN1, or MEN1-like disease 1

Management Considerations

Key principle: Both conditions require identical treatment approaches targeting GH excess, but gigantism has additional urgency:

• Gigantism requires more aggressive intervention to prevent irreversible excessive height before epiphyseal closure 1
• Delayed puberty in gigantism paradoxically worsens outcome by extending the window for longitudinal growth 1
• Both require assessment and treatment of complications: glucose intolerance, hypertension, cardiovascular disease 1, 4

Monitoring:

• Both GH and IGF-1 should be monitored at baseline and during follow-up (GH levels predict surgical outcome and monitor adenoma activity) 1
• Baseline GH levels correlate linearly with IGF-1 only up to 4 μg/L, then plateau at approximately 10 μg/L 1

Critical Pitfalls to Avoid

• Do not dismiss tall stature in adolescents without evaluating for acromegalic features and growth velocity 1
• Do not rely solely on GH suppression testing in adolescents, as approximately 30% of children with tall stature fail to suppress GH below 1 μg/L 1
• Do not overlook genetic testing in pediatric cases, as nearly 50% have identifiable genetic causes 1
• Do not miss hyperprolactinemia evaluation, present in majority of cases and contributing to pubertal delay in gigantism 1, 4
• Serial heights and photographs are essential for timing disease onset 1