Nelson Syndrome Clinical Presentation
- Author: Thomas A Wilson, MD; Chief Editor: Stephen Kemp, MD, PhD more...
When obtaining a history of a child in whom Nelson syndrome is suggested, questions should determine whether symptoms common to this disorder are present, while also investigating the presence of symptoms of important differential diagnoses. Specifically, inquiry should be made about the frequency and nature of headaches, visual symptoms, and symptoms of pituitary insufficiency in addition to ensuring the adequacy of adrenal steroid replacement in the case of children who have congenital or acquired causes of adrenal insufficiency.
Hypopituitarism occurs when the hypothalamic-pituitary portal system is disrupted or normal pituitary tissue is destroyed by the adenoma. Hypopituitarism may be partial and involves the adenohypophysis (anterior pituitary) more commonly than the neurohypophysis (posterior pituitary). Frequently, only partial hormone deficiencies occur. Information should be obtained about growth, the presence of symptoms of hypothyroidism, age of pubertal onset and its progression (in adolescents), presence of galactorrhea, and polyuria and polydipsia.
When no previous growth measurements are available, information should be obtained about the child's rate of growth compared with friends or siblings. Information about growth may also be obtained indirectly by inquiring about the frequency with which larger clothes or shoes have been purchased for the child. Other diseases also need to be taken into account when obtaining a growth history. Patients with Cushing syndrome grow poorly because of hypercortisolemia.
Provided the epiphyses are open, growth should return to normal in these patients once adrenalectomy has been performed. If it does not, further investigation, including evaluation for possible hypothyroidism and growth hormone deficiency, is required.
Central hypothyroidism is usually mild and may be asymptomatic other than poor growth. Questions should focus on cold intolerance (whether the child feels the cold more than before or more than other family members), constipation, slowing of mentation, dry skin and coarse hair, and change in the shape of the face in addition to poor growth. Weight gain may occur but is not usually marked.
When looking for evidence of pubertal delay in girls, questions should establish the age at which breast development (thelarche) started (this may be difficult in the setting of obesity because of previous Cushing syndrome), with specific questioning about the age at which areolar enlargement began. A reduction in breast size or a noticeable softening in previously firm breasts is suggestive of hypoestrogenism.
In boys, questions should focus on when scrotal development and testicular enlargement commenced.
Pubarche (the development of pubic hair) is not a sensitive indicator of pubertal development in either sex because adrenal hyperandrogenemia commonly accompanies hypercortisolemia in Cushing syndrome. In addition, pubic hair may precede puberty in healthy girls and boys.
Hyperprolactinemia from interruption of the hypothalamic-pituitary portal axis may cause galactorrhea in pubertal or post-pubertal females.
Diabetes insipidus should be considered in patients with polyuria and polydipsia. Inadequate glucocorticoid replacement following adrenalectomy may mask these symptoms because glucocorticoids are required for normal water excretion. Inquiry should be made about the frequency, volume, and concentration of the urine being passed. During overnight sleep, the urine normally becomes concentrated because of a reduction in glomerular filtration rate and increased vasopressin secretion. The presence of nocturia or dilute urine on the first void in the morning is suggestive of diabetes insipidus.
Headaches are a common symptom in patients with pituitary masses and are probably the result of stretching of the diaphragma sellae.
Raised intracranial pressure due to obstruction of cerebrospinal fluid (CSF) flow is a late and uncommon sign because it requires a tumor large enough to extend into the third ventricle and obstruct the foramen of Monro.
Loss of vision can occur as a result of invasion or compression of the visual apparatus. This may be insidious and may not be noticed by the patient. The symptoms and signs vary depending upon where the optic apparatus is pressured by the pituitary lesion.
Prechiasmatic lesions usually result in symptoms affecting one eye only, while chiasmatic lesions result in the classic bitemporal hemianopia or quadrantanopsia. Postchiasmatic lesions can result in homonymous hemianopia.
Inquiry should be made about loss of peripheral vision (eg, bumping into walls or corners of tables, not seeing objects "out of the corner of the eye"), or visual loss in one eye or in one direction.
The physical examination of a patient in whom Nelson syndrome is suggested needs to include assessment of adequacy of steroid replacement, in addition to assessment of vision, cranial nerves, and general skin pigmentation.
Height and growth velocity should be assessed as an index of growth hormone secretion, which may be affected by pituitary lesions.
Measurement of weight should be performed in older children when they are lightly clothed, in younger children when they are in their underclothes, and in infants when they are naked.
Pulse: The pulse may be slow if significant hypothyroidism is present, although symptoms of central hypothyroidism are commonly mild. In acute adrenal insufficiency, reduced pulse volume with tachycardia may be present.
Blood pressure: Blood pressure is frequently elevated in patients with hypercortisolism or if mineralocorticoid replacement is excessive. Hypotension or a postural fall in blood pressure may be present in patients with adrenal insufficiency as a result of inadequate replacement or because of acute adrenal crisis.
Loss of vision can occur as a result of invasion or compression of the optic apparatus.
Initial assessment should include assessment of visual acuity in each eye, confrontation testing to look for visual field defects, and examination of the optic fundi to look for papilledema or optic nerve atrophy.
Formal ophthalmologic assessment is necessary.
The thyroid gland should be examined to look for enlargement due to autoimmune hypothyroidism or hyperthyroidism that may accompany autoimmune adrenal insufficiency, one of the differential diagnoses in the hyperpigmented child.
In a hyperpigmented child, the abdominal examination should exclude hepatomegaly and splenomegaly (ie, possible liver disease), although the appearance is typically different in jaundice (yellow color with scleral involvement) or in hemochromatosis (bronze color). Inspection should also include a review of scars, which may indicate prior adrenalectomies. Scars may be hyperpigmented.
Liver disease is suggested if hepatomegaly, small liver, splenomegaly, or peripheral signs of liver disease are present.
All children of pubertal age should undergo an assessment of pubertal stage, looking for evidence of incomplete pubertal development or hypogonadism.
Premature appearance of pubic hair may occur in either sex because of excessive adrenal androgens in patients with Cushing syndrome. Other features observed are sex specific.
In females, secondary hypoestrogenism results in soft breasts and an unestrogenized vaginal mucosa.
In males, loss or softening of androgen-dependent body hair, small soft testes, increased upper–to–lower segment ratio, and gynecoid fat distribution are possible. Adrenal rest tissue may cause testicular enlargement that may be painful and can be unequal.
Hyporeflexia and delayed relaxation time of reflexes are signs that may be present in patients with hypothyroidism.
Cranial nerve involvement in a patient with Nelson syndrome can occur if tumor invasion of the ipsilateral cavernous sinus occurs. Examination should include assessment of sensation on the forehead (first division of trigeminal nerve) and ocular movements (III, IV, VI).
Visual examination should include assessment of visual acuity in each eye, visual field assessment, and examination of the optic nerve for evidence of papilledema or optic nerve atrophy.
Hyperpigmentation of the skin is usually obvious and is not limited to sun-exposed areas. The degree of pigmentation varies depending on the racial origin of the child and the serum concentrations of adrenocorticotropin (ACTH).
Patients usually appear hyperpigmented with a linea nigra (pigmentation extending up the midline from the pubis to the umbilicus) and pigmentation of scars, gingivae, scrotum and areolae. Distinguishing this type of pigmentation from that of hemochromatosis, which is more of a bronze color, and jaundice, which also affects the sclera, is not usually difficult.
More than 99% of cases of Nelson syndrome arise following bilateral adrenalectomy in a patient with Cushing disease. Other diagnoses should be considered in patients with hyperpigmentation who have not undergone adrenalectomy or in patients who have signs of pituitary or visual dysfunction but without pigmentation.
The most common cause of pigmentation associated with a high ACTH level is primary adrenal insufficiency. This can be either congenital or acquired. Congenital causes of adrenal insufficiency include congenital adrenal hyperplasia or hypoplasia.
Acquired causes of bilateral adrenal insufficiency include Addison disease (autoimmune adrenal failure), adrenoleukodystrophy (in males), infection, and destruction. The patient with acquired adrenal insufficiency may present either acutely with adrenal crisis (eg, vomiting, hypotension, hypoglycemia) or with symptoms of chronic insufficiency, such as fatigue, lethargy, anorexia, nausea, abdominal pain, weight loss, postural hypotension, myalgias, and diarrhea.
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.
Hypopituitarism (without pigmentation)
The presence of a combination of visual disturbance, hypopituitarism, diabetes insipidus, and/or headaches in the absence of hyperpigmentation should arouse the suspicion of a lesion in the region of the pituitary gland or its stalk. The most common childhood tumor in this region is the craniopharyngioma, derived from the remnants of the Rathke pouch, the anlagen of the anterior pituitary gland.
The most frequent hormone-secreting pituitary tumor in childhood is the prolactinoma, which has its peak pediatric incidence in the postpubertal years. Patients usually present with symptoms similar to Nelson syndrome but without evidence of hyperpigmentation. Frequently, arrested puberty and primary or secondary amenorrhea occur with this tumor. Galactorrhea may occur but may be missed unless the areolae are squeezed to express the milk. Prolactin levels are unequivocally elevated. Milder elevation of prolactin (usually < 150 ng/mL) may occur as a result of compression of the pituitary stalk by other space-occupying lesions in the region. Some medications (especially phenothiazines and some anticonvulsants) are dopamine receptor antagonists and may also cause mild hyperprolactinemia (usually < 100 ng/mL).
Even less common are growth–hormone secreting pituitary adenomas that result in excessive growth velocity (pituitary gigantism).
Nonfunctioning pituitary adenomas are extremely rare in children.
Patients with nonpituitary tumors may also present with symptoms of hypopituitarism. These include germ cell tumors that may produce human chorionic gonadotropin (HCG). This protein may stimulate Leydig cells, resulting in gonadotropin–independent precocious puberty in males. Optic gliomas may also result in hypopituitarism. Neurofibromatosis type-1 should be excluded in patients with an optic glioma.
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
Azad TD, Veeravagu A, Kumar S, Katznelson L. Nelson Syndrome: Update on Therapeutic Approaches. World Neurosurg. 2015 Jun. 83 (6):1135-40. [Medline].