Diagnostic Considerations

Diagnosis of Nelson syndrome is based on the clinical triad of elevated plasma adrenocorticotropic hormone (ACTH) levels, hyperpigmentation, and tumor progression.^[11]Other conditions to consider include nonpituitary tumors, nonfunctioning pituitary adenomas, and ectopic ACTH syndrome.

Symptoms of associated endocrine conditions (including diabetes, thyroid disease, and vitiligo) should be sought. Very long chain fatty acids should be measured in males presenting with adrenal failure to evaluate for the possible diagnosis of X-linked adrenoleukodystrophy. Adrenal failure may precede the onset of neurologic symptoms in this condition.

Ectopic secretion of ACTH should be considered in pigmented patients with features of Cushing syndrome. This is a rare disorder in children that is frequently associated with very high levels of ACTH and other proopiomelanocortin (POMC) derivatives. The source of ACTH is commonly either a carcinoid, or neuroendocrine tumor. These may be found in embryologic derivatives of the foregut, including the lungs, pancreas, and proximal GI tract. Rarely, pheochromocytomas arising in the adrenal medulla may also secrete ACTH. See Glucocorticoid Therapy and Cushing Syndrome.

Other causes of hyperpigmentation may be considered, including hemochromatosis (see Hemochromatosis) and inherited disorders of skin pigmentation, such as Fanconi anemia.

Differential Diagnoses

Workup

Barber TM, Adams E, Ansorge O, Byrne JV, Karavitaki N, Wass JA. Nelson's syndrome. Eur J Endocrinol. 2010 Oct. 163(4):495-507. [Medline]. [Full Text].
Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing's disease. Endocr Rev. 2015 Aug. 36(4):385-486. [Medline]. [Full Text].
Nelson DH, Meakin JW, Dealy JB Jr, Matson DD, Emerson K Jr, Thorn GW. ACTH-producing tumor of the pituitary gland. N Engl J Med. 1958 Jul 24. 259(4):161-4. [Medline].
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].
Tiyadatah BN, Kalavampara SV, Sukumar S, et al. Bilateral simultaneous laparoscopic adrenalectomy in Cushing's syndrome: safe, effective, and curative. J Endourol. 2012 Feb. 26(2):157-63. [Medline].
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].
Osswald A, Plomer E, Dimopoulou C, et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing's disease. Eur J Endocrinol. 2014 Aug. 171(2):209-15. [Medline]. [Full Text].
[Guideline] Nieman LK, Biller BM, Findling JW, et al, for the Endocrine Society. Treatment of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015 Aug. 100(8):2807-31. [Medline]. [Full Text].
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].
Graffeo CS, Perry A, Carlstrom LP, et al. Characterizing and predicting the Nelson-Salassa syndrome. J Neurosurg. 2017 Dec. 127(6):1277-87. [Medline]. [Full Text].
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]. [Full Text].
Gundgurthi A, Kharb S, Garg MK, et al. Nelson's syndrome presenting as bilateral oculomotor palsy. Indian J Endocrinol Metab. 2013 Nov. 17(6):1114-6. [Medline]. [Full Text].
Barabash R, Moreno-Suarez FG, Rodriguez 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].
Lonser RR, Nieman L, Oldfield EH. Cushing's disease: pathobiology, diagnosis, and management. J Neurosurg. 2017 Feb. 126(2):404-17. [Medline]. [Full Text].
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].
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].
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].
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].
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].
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].
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].
Bunevicius A, Lavezzo K, Smith PW, Vance ML, Sheehan J. Stereotactic radiosurgery before bilateral adrenalectomy is associated with lowered risk of Nelson's syndrome in refractory Cushing's disease patients. Acta Neurochir (Wien). 2021 Mar 24. [Medline].
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].
Barber TM, Adams E, Wass JA. Nelson syndrome: definition and management. Handb Clin Neurol. 2014. 124:327-37. [Medline].
Cordeiro D, Xu Z, Li CE, et al. Gamma Knife radiosurgery for the treatment of Nelson's syndrome: a multicenter, international study. J Neurosurg. 2019 Jul 12. 1-6. [Medline].
Losa M, Detomas M, Bailo M, et al. Gamma knife radiosurgery in patients with Nelson's syndrome. J Endocrinol Invest. 2021 Feb 20. [Medline].
Fountas A, Karavitaki N. Nelson's syndrome: an update. Endocrinol Metab Clin North Am. 2020 Sep. 49(3):413-32. [Medline].
Lin AL, Sum MW, DeAngelis LM. Is there a role for early chemotherapy in the management of pituitary adenomas?. Neuro Oncol. 2016 Oct. 18(10):1350-6. [Medline]. [Full Text].
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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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, MBChB, FRACP Clinical Senior Lecturer, ANU Medical School; Pediatric Endocrinologist, Senior Staff Specialist, Canberra Health Services; Pediatric Endocrinologist, Calvary Paediatrics, Australia

Antony Lafferty, MBChB, FRACP 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: Nothing to disclose.

Chief Editor

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children's Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Angelo P Giardino, MD, MPH, PhD Professor and Chair, Department of Pediatrics, University of Utah School of Medicine; Chief Medical Officer, Primary 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: Nothing to disclose.

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.