eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Nelson Syndrome

Author: Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Coauthor(s): Vardhini Desikan, MBBS, MPH, Pediatric Endocrinology Fellow, Department of Pediatrics, State University of New York at Stony Brook; 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; Antony Lafferty, MB ChB, FRACP, Senior Lecturer of Pediatric Endocrinology, Monash University Department of Pediatrics, National Institutes of Health, Bethesda, MD, and Princess Margaret Hospital for Children, Perth, Western Australia
Contributor Information and Disclosures

Updated: Mar 4, 2009

Introduction

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. The first case was reported by Nelson et al in 1958.¹

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.² 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.

Frequency

International

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.³ 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.⁴ 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.

Mortality/Morbidity

The predominant cause of morbidity from Nelson syndrome is from local tumor extension or invasion. Patients with this disorder become deeply pigmented because the action of ACTH on melanocytes.  Malignant transformation of ACTH-secreting Nelson tumors has been reported, although this is very rare. Morbidity in Nelson syndrome may be due to loss of pituitary function because of compression or replacement of normal pituitary tissue or compression of structures adjacent to the pituitary fossa by the tumor. Lateral extension of the tumor may result in invasion of the cavernous sinuses and entrapment or compression of the cranial nerves that traverse it (the oculomotor, trochlear, and abducens nerves and the ophthalmic division of the trigeminal). Superior extension of the tumor can lead to compression or invasion of the optic apparatus or the hypothalamus. The visual symptoms or signs observed depend on the point at which the tumor impinges the optic apparatus.

Although headaches are common and are probably due to stretching of the dura of the diaphragma sellae by the tumor, obstruction of cerebrospinal fluid (CSF) flow is rare because this requires the tumor to be sufficiently large enough to obstruct the foramen of Monro in the third ventricle. Dural invasion with CSF leak and meningitis has been reported, although it is a rare complication.

During embryogenesis, adrenal cortical cells may migrate along the line of gonadal descent and may even be sequestered in the hilum of the testes, giving rise to adrenal rest tissue. In Nelson syndrome, this adrenal rest tissue may become stimulated. When in the testes, it can result in painful testicular enlargement and oligospermia. Rarely, the adrenal rest tissue can produce sufficient cortisol to normalize levels or even cause recurrence of Cushing syndrome.

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.

Clinical

History

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
  • 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.
    
    

    

    Physical findings in Cushing syndrome.

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    Physical findings in Cushing syndrome.

  • 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.
• Headache
  • 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.
• Visual disturbance
  • 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.

Physical

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: Height and growth velocity should be assessed as an index of growth hormone secretion, which may be affected by pituitary lesions.
• Weight: 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.
• Vital signs
  • 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.
• Eye examination
  • 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.
• Thyroid examination: 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.
• Abdominal examination
  • 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.
• Pubertal staging
  • 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.
• Neurologic examination
  • 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.
• Skin examination
  • 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.

Causes

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

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