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Nelson Syndrome

  • Author: Thomas A Wilson, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Dec 11, 2015
 

Background

Nelson syndrome refers to a spectrum of symptoms and signs arising from an adrenocorticotropin (ACTH)–secreting pituitary macroadenoma after a therapeutic bilateral adrenalectomy. The spectrum of clinical features observed relates to the local effects of the tumor on surrounding structures, the secondary loss of other pituitary hormones, and the effects of the high serum concentrations of ACTH on the skin.[1] The first case was reported by Nelson et al in 1958.[2]

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Pathophysiology

Almost all cases of Nelson syndrome follow bilateral adrenalectomy in patients who have Cushing disease due to an ACTH-secreting pituitary adenoma. Recently, high-resolution MRI has allowed for detection of microadenomas at an early phase of Nelson syndrome. Most adenomatous corticotropes still retain their responsiveness to corticotropin-releasing hormone (CRH). Following bilateral adrenalectomy and normalization of cortisol levels that had suppressed hypothalamic CRH production, an increase in CRH occurs, which then has a trophic effect on the tumor, stimulating its growth. Regulatory gene mutations and mutations in the glucocorticoid receptor may also be important in determining tumor behavior.

Studies have demonstrated the difference in the mechanism of increased ACTH secretion in Nelson syndrome and untreated Cushing disease. Detailed analyses delineate marked ACTH secretory burst mass amplification and anomalous regularity of successive pulse size and timing in Nelson syndrome, compared with Cushing disease or controls.[3] Authors of these studies speculate that these distinctions are due to unique tumoral secretory properties, concurrently required glucocorticoid replacement, and/or hypothalamic injury associated with prior radiotherapy in Nelson syndrome.

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Epidemiology

Frequency

Nelson syndrome is a rare disorder, making accurately determining its incidence difficult. One review indicates that Nelson syndrome may be seen in anywhere from 8-44% of patients who have undergone bilateral adrenalectomy for Cushing disease.[4, 5, 6] Fewer series were published in the 1990s than in the 1980s, suggesting that the syndrome is becoming increasingly less common. This decline in prevalence can be attributed to significant improvements in all aspects of the assessment and management of patients with Cushing syndrome in the last 10-20 years.[7] These include introduction of the sensitive ACTH assay, the advent of high-resolution MRI, the availability in some centers of inferior petrosal sinus sampling, the refinement of the transsphenoidal pituitary surgery, and advances in pituitary radiation therapy, which have made bilateral adrenalectomy a less attractive therapy for Cushing disease.

Even in early series, only 20-40% of patients with a pituitary adenoma who had bilateral adrenalectomy developed Nelson syndrome. Younger age and pregnancy appeared to be risk factors. The former possibly represents a bias because younger patients have a longer time for tumor growth to occur and symptoms to become manifest.

Race

No data on this issue are available.

Sex

Corticotroph adenomas are observed predominantly in females; thus, Nelson syndrome is more common in women than men.

Age

Corticotroph adenomas are observed predominantly in young and middle-aged women. The risk of developing Nelson syndrome appears to be higher in younger individuals than in older individuals.

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Contributor Information and Disclosures
Author

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Coauthor(s)

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Antony Lafferty, MB, BCh 

Antony Lafferty, MB, BCh is a member of the following medical societies: Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Received grant/research funds from Eli Lilly for pi; Received grant/research funds from NovoNordisk for pi; Received consulting fee from NovoNordisk for consulting; Partner received consulting fee from Onyx Heart Valve for consulting.

Chief Editor

Stephen Kemp, MD, PhD Former 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Angelo P Giardino, MD, MPH, PhD Professor and Section Head, Academic General Pediatrics, Baylor College of Medicine; Senior Vice President and Chief Quality Officer, Texas Children’s Hospital

Angelo P Giardino, MD, MPH, PhD is a member of the following medical societies: Academic Pediatric Association, American Academy of Pediatrics, American Professional Society on the Abuse of Children, Harris County Medical Society, International Society for the Prevention of Child Abuse and Neglect, Ray E Helfer Society

Disclosure: Received grant/research funds from Health Resources and Services Administration (HRSA) Integrated Community Systems for CSHCN Grant for other; Received advisory board from Baxter Healthcare Corporation for board membership.

Acknowledgements

Vardhini Desikan, MBBS, MPH Pediatric Endocrinology Fellow, Department of Pediatrics, State University of New York at Stony Brook

Vardhini Desikan, MBBS, MPH is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

References
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  2. Nelson DH, Meakin JW, Dealy JB, et al. ACTH-producing tumor of the pituitary gland. N Engl J Med. 1958 Jul 24. 259(4):161-4. [Medline].

  3. van Aken MO, Pereira AM, van den Berg G, Romijn JA, Veldhuis JD, Roelfsema F. Profound amplification of secretory-burst mass and anomalous regularity of ACTH secretory process in patients with Nelson's syndrome compared with Cushing's disease. Clin Endocrinol (Oxf). 2004 Jun. 60(6):765-72. [Medline].

  4. Chapuis Y, Pitre J, Conti F, et al. Role and operative risk of bilateral adrenalectomy in hypercortisolism. World J Surg. 1996 Sep. 20(7):775-9; discussion 779-80. [Medline].

  5. Tiyadatah BN, Kalavampara SV, Sukumar S, Mathew G, Pooleri GK, Prasanna AT, et al. Bilateral Simultaneous Laparoscopic Adrenalectomy in Cushing's Syndrome: Safe, Effective, and Curative. J Endourol. 2012 Feb. 26(2):157-63. [Medline].

  6. Rizk A, Honegger J, Milian M, Psaras T. Treatment Options in Cushing's Disease. Clin Med Insights Oncol. 2012. 6:75-84. [Medline]. [Full Text].

  7. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Jul. 93(7):2454-62. [Medline].

  8. Barabash R, Moreno-Suárez FG, Rodríguez L, Molina AM, Conejo-Mir J. [Nelson syndrome: a rare cause of generalized hyperpigmentation of the skin]. Actas Dermosifiliogr. 2010 Jan-Feb. 101(1):76-80. [Medline].

  9. Casulari LA, Naves LA, Mello PA, Pereira Neto A, Papadia C. Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res. 2004. 62(6):300-5. [Medline].

  10. Pivonello R, Faggiano A, Di Salle F, Filippella M, Lombardi G, Colao A. Complete remission of Nelson's syndrome after 1-year treatment with cabergoline. J Endocrinol Invest. 1999 Dec. 22(11):860-5. [Medline].

  11. Shraga-Slutzky I, Shimon I, Weinshtein R. Clinical and biochemical stabilization of Nelson's syndrome with long-term low-dose cabergoline treatment. Pituitary. 2006. 9(2):151-4. [Medline].

  12. Petit JH, Biller BM, Yock TI, et al. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab. 2008 Feb. 93(2):393-9. [Medline].

  13. Kobayashi T, Kida Y, Mori Y. Gamma knife radiosurgery in the treatment of Cushing disease: long-term results. J Neurosurg. 2002 Dec. 97(5 Suppl):422-8. [Medline].

  14. Wolffenbuttel BH, Kitz K, Beuls EM. Beneficial gamma-knife radiosurgery in a patient with Nelson's syndrome. Clin Neurol Neurosurg. 1998 Mar. 100(1):60-3. [Medline].

  15. Mauermann WJ, Sheehan JP, Chernavvsky DR, Laws ER, Steiner L, Vance ML. Gamma Knife surgery for adrenocorticotropic hormone-producing pituitary adenomas after bilateral adrenalectomy. J Neurosurg. 2007 Jun. 106(6):988-93. [Medline].

  16. Patel J, Eloy JA, Liu JK. Nelson's syndrome: a review of the clinical manifestations, pathophysiology, and treatment strategies. Neurosurg Focus. 2015 Feb. 38 (2):E14. [Medline].

  17. Vik-Mo EO, Oksnes M, Pedersen PH, et al. Gamma knife stereotactic radiosurgery of Nelson syndrome. Eur J Endocrinol. 2009 Feb. 160(2):143-8. [Medline].

  18. Barber TM, Adams E, Wass JA. Nelson syndrome: definition and management. Handb Clin Neurol. 2014. 124:327-37. [Medline].

  19. Azad TD, Veeravagu A, Kumar S, Katznelson L. Nelson Syndrome: Update on Therapeutic Approaches. World Neurosurg. 2015 Jun. 83 (6):1135-40. [Medline].

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