What is the appropriate diagnostic work‑up for a child or adolescent with excessive linear growth suggestive of gigantism?

Diagnosis and Assessment of Gigantism

When to Test for Gigantism

Offer testing for growth hormone excess to any child or adolescent with height exceeding 2 standard deviation scores (SDS) above age- and sex-adjusted norms OR consistently elevated growth velocity (>2 SDS), particularly when accompanied by acromegalic features, pubertal delay, or family history of pituitary adenoma. 1

Clinical Features That Should Trigger Evaluation

Primary Growth Abnormalities

• Height >2 SDS above ethnicity-adjusted, age-adjusted, and sex-adjusted normal values OR >2 SDS above mid-parental target height 1
• Persistently elevated growth velocity >2 SDS despite already being tall 1
• Delayed bone age despite excessive height – a critical distinguishing feature from constitutional tall stature 1, 2

Acromegalic Features in Children

• Acral enlargement (disproportionately large hands and feet) 1
• Coarsened facial features, prognathism, dental malocclusion, teeth separation, frontal bossing 1
• Joint pain and hypermobility 1
• Headache and visual field defects indicating mass effect 1

Endocrine Manifestations

• Pubertal delay or arrested puberty – occurs due to prolactin co-secretion (65% of pediatric cases), stalk compression, or gonadotropin deficiency from mass effect 1, 2
• Galactorrhea when hyperprolactinemia is present 2

Metabolic and Cardiovascular Complications

• Insulin resistance, glucose intolerance, or secondary diabetes mellitus 1
• Hypertension, left ventricular hypertrophy, diastolic dysfunction 1
• Sleep disturbance, sleep apnea, excessive sweating 1

Biochemical Diagnostic Work-Up

First-Line Screening Test

Measure serum IGF-1 adjusted for age, sex, AND Tanner stage – an elevated level is the most reliable initial marker for GH excess. 1, 2

Critical interpretation caveats:

• Marginal elevation during peak adolescent growth spurt requires cautious interpretation 1
• IGF-1 may be falsely normal or low in severe hypothyroidism, malnutrition, or acute infection 1, 2
• IGF-1 may be falsely elevated in poorly controlled diabetes, hepatic failure, or renal failure 1, 2
• Oral estrogen therapy reduces hepatic IGF-1 production, potentially masking GH excess 1, 2
• Inter-assay variability is substantial – use local Tanner stage-matched, sex-matched, and age-matched reference ranges 1

Confirmatory Dynamic Testing

Perform oral glucose tolerance test (OGTT) with serial GH measurements – failure to suppress GH below 1 μg/L after glucose load indicates GH excess. 1, 2

Critical interpretation caveats:

• Approximately 30% of children with tall stature fail to suppress GH <1 μg/L despite not having GH excess, making this test challenging in the tall pediatric population 1, 2
• GH nadir is sex- and pubertal stage-specific: highest levels occur in mid-puberty (Tanner stage 2-3), particularly in girls (mean ± 2 SD: 0.22 ± 0.03–1.57 μg/L in girls vs. 0.21 ± 0.09–0.48 μg/L in boys) 1
• Complete GH suppression is difficult to achieve in normal adolescence 1

Additional Hormonal Assessment

• Serum prolactin – elevated in 65% of pediatric acromegaly and 34-36% of gigantism cases, contributing to pubertal delay 2
• TSH and free T4 – hypothyroidism can confound IGF-1 interpretation 1, 2
• Morning fasting total testosterone (or free/bioavailable if total is normal) – to assess hypogonadism 3
• LH, FSH – to evaluate gonadotropin deficiency from mass effect 1

Imaging Studies

Contrast-enhanced pituitary MRI is the imaging modality of choice for detecting somatotroph adenomas once biochemical GH excess is confirmed. 2

• Most pediatric patients have large adenomas at presentation, often with suprasellar extension 1, 4, 5
• Serial imaging may be needed to detect recurrence or residual tumor after surgery 4

Genetic Evaluation

Systematic genetic assessment and testing are mandatory in all children and adolescents with gigantism, as approximately 50% have an identifiable genetic basis. 1, 2, 6, 5

Specific Genetic Syndromes to Screen For

X-linked acrogigantism (X-LAG):

• Tall stature onset before age 5 years (usually before age 2) 1, 2
• Disproportionately enlarged hands, feet, teeth separation, acanthosis nigricans, markedly increased BMI and appetite 1, 2

McCune-Albright syndrome:

• Early-onset GH excess (from age 3 onwards), café-au-lait pigmentation, fibrous dysplasia, precocious puberty 1, 2

Carney complex:

• Characteristic skin pigmentation, cardiac and cutaneous myxomas, testicular and adrenal disease 1

Familial isolated pituitary adenomas (FIPA) including AIP mutations:

• Family history of pituitary adenomas 1, 7, 6

Multiple endocrine neoplasia (MEN-1 and MEN-4):

• Associated hyperparathyroidism, pancreatic neuroendocrine tumors 6

Diagnostic Algorithm Summary

1. Identify clinical red flags: Height >2 SDS, growth velocity >2 SDS, acromegalic features, pubertal delay
2. Obtain serial height measurements and review growth charts – essential for timing disease onset 1
3. Measure age-, sex-, and Tanner stage-adjusted serum IGF-1 as first-line screening 1, 2
4. Perform OGTT with GH measurements if IGF-1 is elevated, recognizing limitations in adolescents 1, 2
5. Assess prolactin, TSH, and gonadotropins to identify co-secretion and mass effects 1, 2
6. Order contrast-enhanced pituitary MRI when biochemical testing confirms GH excess 2
7. Conduct comprehensive genetic evaluation including clinical assessment for syndromic features and targeted genetic testing 1, 2, 6, 5
8. Obtain hand radiograph for bone age – delayed bone age despite tall stature supports gigantism 1, 2

Critical Pitfalls to Avoid

• Do not dismiss tall stature in adolescents without evaluating for acromegalic features and growth velocity trends – early diagnosis is essential to prevent irreversible excessive linear growth 2, 5
• Do not rely solely on GH suppression testing in adolescents, as approximately 30% of tall children fail to suppress GH below 1 μg/L despite not having GH excess 1, 2
• Do not overlook genetic testing – nearly 50% of pediatric cases have identifiable mutations, and early identification guides family screening and genetic counseling 1, 2, 6, 5
• Do not ignore hyperprolactinemia evaluation, given its high prevalence (65% in pediatric acromegaly) and role in pubertal delay 2
• Do not interpret IGF-1 in isolation – consider nutritional status, thyroid function, diabetes control, and medication use (especially oral estrogens) 1, 2
• Serial height measurements and photographic documentation are essential for accurately determining disease onset and progression 1