Gigantism and Acromegaly Clinical Presentation

  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: May 18, 2012
 

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.
Next

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)
Previous
Next

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.
Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Alicia Diaz-Thomas, MD, MPH  Assistant Professor of Pediatrics, University of Tennessee Health Science Center, Memphis

Alicia Diaz-Thomas, MD, MPH is a member of the following medical societies: American Academy of Clinical Endocrinology, Endocrine Society, and Tennessee Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Melanie Shim, MD  Clinical Instructor, Department of Pediatrics, Division of Pediatric Endocrinology, University of California at Los Angeles School of Medicine

Melanie Shim, MD is a member of the following medical societies: American Diabetes Association and Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Phyllis W Speiser, MD  Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children's Medical Center of New York; Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine at Hofstra University

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD  Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Robert J Ferry Jr MD to the development and writing of this article.

References

  1. Izzard AS, Emerson M, Prehar S, et al. The cardiovascular phenotype of a mouse model of acromegaly. Growth Horm IGF Res. Oct 2009;19(5):413-9. [Medline].

  2. van der Lely AJ, Biller BM, Brue T, et al. Long-Term Safety of Pegvisomant in Patients with Acromegaly: Comprehensive Review of 1288 Subjects in ACROSTUDY. J Clin Endocrinol Metab. May 2012;97(5):1589-97. [Medline].

  3. Higham CE, Atkinson AB, Aylwin S, et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab. Apr 2012;97(4):1187-93. [Medline].

  4. Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B. Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur J Endocrinol. Aug 2005;153(2):195-201. [Medline].

  5. Weber DC, Momjian S, Pralong FP, Meyer P, Villemure JG, Pica A. Adjuvant or radical fractionated stereotactic radiotherapy for patients with pituitary functional and nonfunctional macroadenoma. Radiat Oncol. Dec 8 2011;6:169. [Medline]. [Full Text].

  6. Abe T, Tara LA, Ludecke DK. Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery. Neurosurgery. Jul 1999;45(1):1-10. [Medline].

  7. Ali O, Banerjee S, Kelly DF, Lee PD. Management of type 2 diabetes mellitus associated with pituitary gigantism. Pituitary. 2007;10(4):359-64. [Medline].

  8. Barkan AL, Burman P, Clemmons DR, et al. Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant. J Clin Endocrinol Metab. 2005;90:5684-5691. [Medline].

  9. Bera TK, Liu XF, Yamada M, Gavrilova O, Mezey E, Tessarollo L, et al. A model for obesity and gigantism due to disruption of the Ankrd26 gene. Proc Natl Acad Sci U S A. 2008;105(1):270-5. [Medline].

  10. Bonapart IE, van Domburg R, ten Have SM, et al. The 'bio-assay' quality of life might be a better marker of disease activity in acromegalic patients than serum total IGF-I concentrations. Eur J Endocrinol. 2005;152:217-224. [Medline].

  11. Cazabat L, Libe R, Perlemoine K, et al. Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. Eur J Endocrinol. Jul 2007;157(1):1-8. [Medline].

  12. Clemmons DR, Chihara K, Freda PU, et al. Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. J Clin Endocrinol Metab. Oct 2003;88(10):4759-67. [Medline].

  13. Cozzi R, Attanasio R, Barausse M, et al. Cabergoline in acromegaly: a renewed role for dopamine agonist treatment?. Eur J Endocrinol. Nov 1998;139(5):516-21. [Medline].

  14. Davoodi J, Kelly J, Gendron NH, MacKenzie AE. The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26. Proteomics. Jun 2007;7(13):2300-10. [Medline].

  15. Duncan E, Wass JA. Investigation protocol: acromegaly and its investigation. Clin Endocrinol (Oxf). Mar 1999;50(3):285-93. [Medline].

  16. Eugster EA, Pescovitz OH. Gigantism. J Clin Endocrinol Metab. Dec 1999;84(12):4379-84. [Medline].

  17. Ezzat S, Serri O, Chik CL et al. Canadian consensus guidelines for the diagnosis and management of acromegaly. Clin Invest Med. 2006;29:29-39. [Medline].

  18. Fuqua JS, Berkovitz GD. Growth hormone excess in a child with neurofibromatosis type 1 and optic pathway tumor: a patient report. Clin Pediatr (Phila). Dec 1998;37(12):749-52. [Medline].

  19. Gagel RF. Multiple endocrine neoplasia. In: Williams Textbook of Endocrinology. 9th ed. 1627-1649.

  20. Geffner ME, Nagel RA, Dietrich RB, Kaplan SA. Treatment of acromegaly with a somatostatin analog in a patient with McCune-Albright syndrome. J Pediatr. Nov 1987;111(5):740-3. [Medline].

  21. Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab. Feb 2000;85(2):526-9. [Medline].

  22. Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab. Dec 1990;71(6):1427-33. [Medline].

  23. Herman-Bonert VS, Zib K, Scarlett JA, Melmed S. Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab. Aug 2000;85(8):2958-61. [Medline].

  24. Holl RW, Bucher P, Sorgo W, et al. Suppression of growth hormone by oral glucose in the evaluation of tall stature. Horm Res. 1999;51(1):20-4. [Medline].

  25. Keil MF, Stratakis CA. Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics. Expert Rev Neurother. Apr 2008;8(4):563-74. [Medline].

  26. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. Sep 2000;26(1):89-92. [Medline].

  27. Kunwar S, Wilson CB. Pediatric pituitary adenomas. J Clin Endocrinol Metab. Dec 1999;84(12):4385-9. [Medline].

  28. Lissett CA, Peacey SR, Laing I, et al. The outcome of surgery for acromegaly: the need for a specialist pituitary surgeon for all types of growth hormone (GH) secreting adenoma. Clin Endocrinol (Oxf). Nov 1998;49(5):653-7. [Medline].

  29. Malan V, De Blois MC, Prieur M, et al. Sotos syndrome caused by a paracentric inversion disrupting the NSD1 gene. Clin Genet. Jan 2008;73(1):89-91. [Medline].

  30. Melmed S. Medical progress: Acromegaly. N Engl J Med. Dec 14 2006;355(24):2558-73. [Medline].

  31. Melmed S, Casanueva F, Cavagnini F, Chanson P, Frohman LA, Gaillard R, et al. Consensus statement: medical management of acromegaly. Eur J Endocrinol. Dec 2005;153(6):737-40. [Medline].

  32. Melmed S, Casanueva F, Cavagnini F, et al. Consensus statement: medical management of acromegaly. Eur J Endocrinol. 2005;153:737-740. [Medline].

  33. Miyazaki R, Yoshida T, Sakane N, et al. Acromegalic gigantism with low serum level of growth hormone and elevated serum insulin-like growth factor-I. Intern Med. Mar 1995;34(3):183-7. [Medline].

  34. Moran A, Pescovitz OH. Long-term treatment of gigantism with combination octreotide and bromocriptine in a child with McCune-Albright syndrome. Endocr J. 1994;2:111-113.

  35. Mussig K, Gallwitz B, Honegger J, et al. Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma. Exp Clin Endocrinol Diabetes. Mar 2007;115(3):198-202. [Medline].

  36. Nanto-Salonen K, Koskinen P, Sonninen P, Toppari J. Suppression of GH secretion in pituitary gigantism by continuous subcutaneous octreotide infusion in a pubertal boy. Acta Paediatr. Jan 1999;88(1):29-33. [Medline].

  37. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. Aug 1998;83(8):2730-4. [Medline].

  38. Ray M, Malhi P, Bhalla AK, Singhi PD. Cerebral gigantism with West syndrome. Indian Pediatr. Jul 2003;40(7):673-5. [Medline].

  39. Schmidt H, Kammer B, Grasser M, Enders A, Rost I, Kiess W. Endochondral gigantism: a newly recognized skeletal dysplasia with pre- and postnatal overgrowth and endocrine abnormalities. Am J Med Genet A. Aug 15 2007;143(16):1868-75. [Medline].

  40. Schwartz TH, Stieg PE, Anand VK. Endoscopic transsphenoidal pituitary surgery with intraoperative magnetic resonance imaging. Neurosurgery. 2006;58:44-51. [Medline].

  41. Sotos JF. Overgrowth. Hormonal Causes. Clin Pediatr (Phila). Nov 1996;35(11):579-90. [Medline].

  42. Stratakis CA, Carney JA, Lin JP, et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest. Feb 1 1996;97(3):699-705. [Medline].

  43. Thapar K, Kovacs K, Stefaneanu L, et al. Overexpression of the growth-hormone-releasing hormone gene in acromegaly-associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior. Am J Pathol. Sep 1997;151(3):769-84. [Medline].

 
Previous
Next
 
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.
Photograph shows a 12-year-old boy with McCune-Albright syndrome. His growth-hormone excess manifested as tall stature, coarse facial features, and macrocephaly.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.