AUTHOR AND EDITOR INFORMATION

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• Medication
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• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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Background

Gigantism refers to abnormally high linear growth due to excessive action of insulin-like growth factor-I (IGF-I) while the epiphyseal growth plates are open during childhood. Acromegaly is the same disorder of IGF-I excess when it occurs after the growth plate cartilage fuses in adulthood. Gigantism is a nonspecific term that refers to any standing height more than 2 standard deviations above the mean for the person's sex, age, and Tanner stage (ie, height Z score >+2). These disorders are placed along a spectrum of IGF-I hypersecretion, wherein the developmental stage when such excess originates determine the principal manifestations. The onset of IGF-I hypersecretion in childhood or late adolescence results in tall stature. This article focuses on IGF-I excess with an onset during childhood.

The most remarkable example of a person with gigantism was Robert Wadlow, called the Alton giant, who stood 8 feet 11 inches tall at the time of his death in his mid-20s (see Media file 1). A more recent person, widely known for his wrestling and movie roles, was Andre Roussimoff, or Andre the Giant. He was 6 feet 3 inches tall at age 12 years and reached a height of 7 feet 4 inches by adulthood.

More recently, scientific breakthroughs in the molecular, genetic, and hormonal basis of growth hormone (GH) excess have provided important insights into the pathogenesis, prognosis, and treatment of this exceedingly rare disease.

Pathophysiology

Causes of excess IGF-I action may be divided into 3 categories: (1) those originating from primary GH excess released from the pituitary; (2) those caused by increased GH-releasing hormone (GHRH) secretion or hypothalamic dysregulation; and (3) hypothetically, those related to the excessive production of IGF-binding protein, which prolongs the half-life of circulating IGF-I.

By far, most people with giantism have GH-secreting pituitary adenomas or hyperplasia. Although gigantism is typically an isolated disorder, rare cases occur as a feature of other conditions, such as multiple endocrine neoplasia (MEN) type I, McCune-Albright syndrome (MAS), neurofibromatosis, tuberous sclerosis, or Carney complex.

Approximately 20% of patients with gigantism have MAS (the triad of precocious puberty, café au lait spots, fibrous dysplasia) and may have either pituitary hyperplasia or adenomas (see Media file 2).

Frequency

United States

Gigantism is extremely rare, with approximately 100 reported cases to date. Acromegaly is more common than giantism, with an incidence of 3-4 cases per million people per year and a prevalence of 40-70 cases per million population.

Mortality/Morbidity

Because of the small number of people with gigantism, mortality and morbidity rates for this disease during childhood are unknown.

For individuals with acromegaly, the mortality rate is 2-3 times that of the general population. Successful treatment, with normalization of IGF-I levels, may be associated with a return to normal life expectancy. For persons with acromegaly, the most frequent causes of death are cardiovascular and respiratory complications.

Researchers disagree on whether malignancy is a significant cause of increased mortality. Although benign tumors (including uterine myomas, prostatic hypertrophy, and skin tags) are frequently encountered in acromegaly, documentation for overall prevalence of malignancies in patients with acromegaly remains controversial. Most studies suggest that as many as 30% of patients may have a premalignant colon polyp at diagnosis, and as many as 5% may have a colonic malignancy. However, the long-term effect of colonic lesions on morbidity and mortality has not been established.

No clear evidence supports an increased risk for lung, breast, or prostate cancer. As a significant cause of morbidity, sleep apnea may be both obstructive and central.

Race

No predilection has been reported.

Sex

IGF-I excess equally affects men and women.

In a series of 12 children, GH-secreting adenomas occurred with a female-to-male ratio of 1:2. Given the small size of this series, these disorders are unlikely to show a sex bias during childhood.

Age

Gigantism may begin at any age before epiphyseal fusion. The mean age for onset of acromegaly is in the third decade of life. For acromegaly, the delay from the insidious onset of symptoms to diagnosis is 5-15 years, with a mean delay of 8.7 years.

CLINICAL

Section 3 of 11  

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History

The presentation of patients with gigantism is usually dramatic, unlike the insidious onset of acromegaly in adults. Reasons for this difference include the close monitoring of growth in children and their relatively responsive growth-plate cartilage. Children with gigantism have few soft-tissue effects (eg, peripheral edema, coarse facial features) because of their rapid linear growth.

• Longitudinal acceleration of linear growth secondary to IGF-I excess is the cardinal clinical feature of gigantism.
• Tumor mass may cause headaches, visual changes due to optic nerve compression, and hypopituitarism.
• A common finding from pituitary GH excess is hyperprolactinemia, which manifests in childhood because mammosomatotrophs are the most common type of GH-secreting cells involved in childhood gigantism.

Physical

All growth parameters are affected, although not necessarily symmetrically. Over time, IGF-I excess is characterized by progressive cosmetic disfigurement and systemic organ manifestations. Physical manifestations include the following:

• Tall stature
• Mild-to-moderate obesity (common)
• Macrocephaly (may precede linear growth)
• Soft-tissue hypertrophy
• Exaggerated growth of the hands and feet with thick fingers and toes
• Coarse facial features
• Frontal bossing
• Prognathism
• Hyperhidrosis
• Osteoarthritis (a late feature of IGF-I excess)
• Peripheral neuropathies (eg, carpel tunnel syndrome)
• Cardiovascular disease (eg, cardiac hypertrophy, hypertension, left ventricular hypertrophy) if IGF-I excess is prolonged
• Benign tumors, including uterine myomas, prostatic hypertrophy, colon polyps, and skin tags, which are frequently in acromegaly (Documentation of a high prevalence of malignancies in patients with acromegaly remains controversial.)
• Frequently associated endocrinopathies (eg, hypogonadism, diabetes and/or impaired glucose tolerance, hyperprolactinemia)

Causes

Despite diverse pathophysiologic mechanisms, the final common abnormality is IGF-I excess. Elevated tissue levels of free IGF-I, which is produced primarily in hepatocytes in response to excess GH, mediate most if not all growth-related outcomes in gigantism. Transgenic mice that overexpress GH, GHRH, or IGF-I had dramatically accelerated somatic growth compared with control litter mates. One acromegalic patient had low serum GH levels and elevated serum total IGF-I levels; this finding implicates IGF-I as the key pathologic factor in this disease. Serum levels of IGF-I are consistently elevated in patients with acromegaly and, therefore, are used to monitor treatment success.

The conditions described below can cause IGF-I oversecretion.

• Primary pituitary GH excess: In most individuals with GH excess, the underlying anomaly is a benign pituitary tumor composed of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH-secreting and prolactin [PRL]-secreting cells) in the form of a pituitary microadenoma or an macroadenoma. The adenomas are most characteristically well-demarcated and confined to the anterior lobe of the pituitary gland. In some people with GH excess, the tumor spreads outside the sella, invading the sphenoid bone, optic nerves, and brain. GH-secreting tumors are more likely to be locally invasive or aggressive in pediatric patients than in adults.
• • Gs-alpha (Gsa) mutation: G proteins play an integral role in postligand signal transduction in many endocrine cells by stimulating adenyl cyclase, resulting in an accumulation of cyclic adenosine monophosphate (cAMP) and subsequent gene transcription. About 20% of patients with gigantism have MAS and pituitary hyperplasia or adenomas. Activating mutations of the stimulatory Gsa protein have been found in the pituitary lesions in MAS and are believed to cause the other glandular adenomas observed. Point mutations found in several tissues affected in MAS involve a single amino-acid substitution in codon 201 (exon 8) or 227 (exon 9) of the gene for Gsa. Somatic point mutations have been identified in somatotrophs of less than 40% of sporadic GH-secreting pituitary adenomas. The resulting oncogene (gsp) is thought to induce tumorigenesis by persistently activating adenyl cyclase, with subsequent GH hypersecretion.
  • Loss of band 11q13 heterozygosity: Loss of heterozygosity at the site of a putative tumor-suppressor gene on chromosome band 11q13 was first identified in tumors from patients with MEN type I and GH excess. Loss of heterozygosity at band 11q13 has also been observed in all types of sporadically occurring pituitary adenomas. It is associated with an increased propensity for tumoral invasiveness and biologic activity.
  • Abnormality at Carney loci on chromosomes 2 and 17: Carney complex is characterized by myxomas, endocrine tumors, and spotty pigmentation. It is transmitted as an autosomal dominant trait. About 8% of affected individuals have GH-producing pituitary adenomas. The causative gene for this disease was mapped to chromosome bands 2p16 and 17q22-24. Germline mutations in PRKAR1A (which encodes for the protein kinase A type I-alpha regulatory subunit, an apparent tumor-suppressor gene on chromosome arm 17q) were detected in several families with Carney complex.
• Secondary GH excess: Causes of secondary GH excess include increased secretion of GHRH due to an intracranial or ectopic source and dysregulation of the hypothalamic-pituitary-GH axis.
• • GHRH excess: Hypothalamic GHRH excess is postulated as a cause for gigantism, possibly secondary to an activating mutation in hypothalamic GHRH neurons. Excess GHRH secretion may be due to an intracranial or ectopic tumor. Several well-documented incidents of hypothalamic GHRH excess demonstrated intracranial gangliocytomas associated with gigantism or acromegaly. Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet-cell, and bronchial neoplasms. Prolonged tumoral secretion of GHRH leads to pituitary hyperplasia, with or without adenomatous transformation, that increases levels of GH and other adenohypophyseal peptides.
  • Disruption of somatostatin tone: Tumoral infiltration into somatostatinergic pathways are hypothesized to be the basis for GH excess in rare incidents of gigantism associated with neurofibromatosis and optic glioma or astrocytomas.

DIFFERENTIALS

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Other Problems to be Considered

Familial tall stature
Exogenous obesity
Cerebral gigantism (Sotos syndrome) from NSD1 gene mutation or other causes
Weaver syndrome
Estrogen receptor mutation

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• Serum IGF-I determination is a sensitive screening test for acromegaly.
• • An excellent linear dose-response correlation between serum IGF-I levels and 24-hour integrated GH secretion has been demonstrated. Elevated IGF-I values in a patient whose symptoms prompt appropriate clinical suspicion almost always indicates GH excess.
  • Potential confusion may arise in the evaluation of healthy adolescents because IGF-I levels can be substantially higher during puberty than during adulthood. Always compare the patient's measurement with age-matched and sex-matched IGF-I reference ranges published in the literature or established for the specific testing laboratory.
  • A single GH measurement is inadequate. Because GH is secreted in a pulsatile manner, use of a random GH measurement can lead to a false-positive or false-negative result.
  • The free serum IGF-I level can also be diagnostic, but testing this level not necessary because this test is relatively expensive and unavailable to most clinicians.
• An elevated serum insulin-like growth factor binding protein-3 (IGFBP-3) level may suggest the diagnosis of GH excess, although the diagnostic use of IGFBP-3 results for gigantism requires further study. In patients with confirmed somatotroph adenomas, increased IGFBP-3 levels are reported to be a sensitive marker of GH elevations and may be elevated even if total IGF-I levels are in the reference range.
• An inability to suppress serum GH level during an oral glucose-tolerance test (OGTT) is the criterion standard for diagnosing GH excess. Failure to suppress serum GH levels to less than 5 ng/dL within 3 hours after a 1.75-g/kg oral glucose challenge (not to exceed 75 g) is diagnostic of pituitary GH excess.

Imaging Studies

• If laboratory findings suggest GH excess, obtain an MRI to confirm the presence of a pituitary adenoma. In rare cases, a pituitary mass may not be identified because of an occult pituitary microadenoma or an ectopic tumor.
• CT scanning is an acceptable imaging study if MRI is unavailable.
• Chest or abdominal imaging may reveal the rare ectopic GH-secreting or GHRH-secreting tumor.

Other Tests

• Although testing with an intravenous administration of thyrotropin-releasing hormone (TRH) is not necessary to make the diagnosis, 50-80% of patients with GH excess have a paradoxic rise in GH levels after the challenge.
• Circulating GHRH blood levels may confirm peripheral ectopic GHRH secretion in the presence of an ectopic tumor. However, in the presence of a hypothalamic GHRH-secreting tumor, circulating GHRH levels may be normal.

Histologic Findings

• Mammosomatotrophs are the most common type of GH-secreting cells involved in childhood gigantism.
• Coexistence of both GH and PRL in the secretory granules of the tumor cells is clearly demonstrated on immunohistochemical staining.

TREATMENT

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Medical Care

• Surgery clearly fails to cure a notable number of patients with IGF-I excess. Therefore, medical therapy has taken on an important role in treating these patients. The most remarkable recent progress in treating this disorder has been in medical therapy. Well-tolerated, long-acting somatostatin analogs and dopamine agonists improve adherence and efficacy.
• The goals of medical therapy goals are the following:
• • Remove or shrink the pituitary mass
  • Restore GH secretory patterns to normal
  • Restore serum total IGF-I and IGFBP-3 levels to normal
  • Retain normal pituitary secretion of other hormones
  • Prevent recurrence of disease
• Somatostatin analogs are highly effective in treating patients with GH excess.
• • Octreotide suppresses serum GH level to less than 2.5 mcg/L in 65% of patients with acromegaly and normalizes circulating IGF-I levels in 70% of patients.
  • Studies of patients with GH excess for longer than 14 years demonstrated that effects of octreotide are well sustained over time.
  • Tumor shrinkage, although generally modest, also occurs with octreotide.
  • Consistent GH suppression was achieved with a continuous subcutaneous pump infusion of octreotide in a pubertal boy with pituitary gigantism.
  • New long-acting formulations, including long-acting octreotide and lanreotide, were recently demonstrated to produce consistent GH and IGF-I suppression in patients with acromegaly with once-monthly or biweekly intramuscular depot injections.
  • Sustained-released preparations have not been tested in children.
• Dopamine agonists (eg, bromocriptine, cabergoline) bind to pituitary dopamine type 2 (D2) receptors and suppress GH secretion, although their precise mechanism of action remains unclear.
• • PRL levels are often adequately suppressed. However, circulating GH and IGF-I levels rarely normalize with this therapy. Less than 20% of patients achieve GH levels less than 5 ng/mL, and less than 10% achieve normal IGF-I levels.
  • Tumor shrinkage occurs in a few patients.
  • Dopamine agonists are generally used as adjuvant medical treatments for GH excess, and their effectiveness may be added to that of octreotide.
  • Although long-acting formulations are available, no data about the long-term control of GH and IGF-I with these agents are available.
• Tests of a novel hepatic GH-receptor antagonist (pegvisomant [Somavert]) demonstrated effective suppression of GH and IGF-I levels in patients with acromegaly due to pituitary tumors or ectopic GHRH hypersecretion.
• • Normalization of IGF-I levels occurs in as many as 90% of patients treated daily with this drug for 3 months.
  • Long-term studies are underway, but pegvisomant has not been tested in children.

Surgical Care

• For well-circumscribed pituitary adenomas, transsphenoidal surgery to completely remove the tumor is the treatment of choice, and it may be curative.
• • The likelihood of a surgical cure greatly depends on the surgeons' expertise and on the size and extension of the mass.
  • Intraoperative GH measurements can improve the results of tumor resection.
  • Transsphenoidal surgery to resect tumors is as safe in children as it is in adults.
  • A transcranial approach is sometimes necessary.
• The primary goal of treatment is to normalize GH levels.
• • As determined by using GH assays available to date, GH levels should be normalized (<1 ng/mL for >50% of the points measured during the day) in all patients.
  • Because this change is impractical to test, GH levels (<1 ng/mL within 2 h after a glucose load) and serum IGF-1 levels (within 2 standard deviations of the reference range adjusted for age, sex, and Tanner stage) are the best results for defining a biochemical cure.
• If surgery does not normalize GH secretion, options include pituitary radiation and medical therapy.
• • In general, radiation therapy is recommended if GH hypersecretion is not normalized with surgery. Radiation prevents further growth of the tumor in more than 99% of patients after surgical resection.
  • The main disadvantage of irradiation is delayed efficacy in decreasing GH levels. Approximately 50% of the efficacy of this therapy is lost by 2 years, 75% is lost by 5 years, and nearly 90% is lost by 15 years.
  • Hypopituitarism is a predictable outcome, occurring in 40-50% of patients within 10 years after irradiation.

MEDICATION

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Analogs of somatostatin are the most effective medical therapies for GH excess. Dopamine-receptor agonists are best used as adjuvant treatments.

Drug Category: Somatostatin analogs

Like natural somatostatin, octreotide inhibits the secretion of GH, insulin, and glucagon. After an intravenous administration, basal serum GH, insulin, and glucagon levels fall. Octreotide also inhibits PRL release by means of vasoactive intestinal peptide (VIP)-mediated and TRH-mediated secretion of PRL. Octreotide is used to treat acromegaly and several hormone-secreting tumors.

Drug Category: Dopamine agonists

Dopamine-receptor agonists are other pharmacologic options. However, these drugs are effective in only a few patients. Cabergoline is well tolerated.

Drug Category: GH-receptor antagonist

This novel class of drugs have demonstrated efficacy to suppress GH and IGF-I levels.

FOLLOW-UP

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Further Outpatient Care

• Evaluate long-term efficacy of surgery and radiotherapy by using anatomic tools, including MRI and visual-field evaluation.
• After surgery and after the start of medical treatment, perform biochemical assessment at 6-12 weeks; normalization of IGF-I levels may occur several months later.
• All patients with a history of GH excess require periodic life-long evaluation.
• In one series, the long-term recurrence rate for GH-secreting adenomas in children was 13.3% after surgery.¹

Complications

• Hypopituitarism may develop as the result of the pituitary mass or as a complication of surgery or radiation therapy.
• Treat pituitary failure with appropriate hormone-replacement therapy.

Patient Education

• For excellent patient education resources, visit eMedicine's Acromegaly Center. Also, see eMedicine's patient education articles Acromegaly, Acromegaly FAQs, and Understanding Acromegaly Medications.
• Also, refer patients to the Hormone Foundation for additional information.

MISCELLANEOUS

Section 9 of 11  

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• Miscellaneous
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Medical/Legal Pitfalls

• Failure to recognize and treat coexisting hyperprolactinemia
• Failure to diagnose associated conditions, such as cardiovascular disease, tumors (eg, colon polyps, benign prostatic hypertrophy), and diabetes
• Failure to monitor for and detect tumoral recurrence after surgical treatment

MULTIMEDIA

Section 10 of 11  

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• Clinical
• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Image shows the coauthor with a statue of Robert Wadlow, who was called the Alton giant. He was the tallest person ever recorded and was 8 feet 11 inches tall at the time of his death.
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Media type:  Photo

Media file 2:  Photograph shows a 12-year-old boy with McCune-Albright syndrome. His growth-hormone excess manifested as tall stature, coarse facial features, and macrocephaly.
	View Full Size Image
Media type:  Photo

REFERENCES

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Article Last Updated: Jul 1, 2008