Nelson Syndrome 

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

Overview

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]

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.

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.

 

Presentation

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.

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).[8]

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.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Adrenocorticotropin (ACTH) measurement

ACTH levels are markedly elevated in Nelson syndrome, usually in the thousands of picograms per milliliter. Levels of other derivatives of the precursor peptide, proopiomelanocortin (POMC), are also elevated, although their measurement is not required for diagnosis. Patients with Nelson syndrome often have an exaggerated ACTH response to corticotropin-releasing hormone (CRH). This test is not required for diagnostic purposes.

Thyroid function tests

Central hypothyroidism, which is not always clinically detectable, may be present. Free thyroxine (T4) levels are commonly just below the lower limit of the reference range, and thyroid-stimulating hormone (TSH) levels may be low, normal, or even mildly elevated.

Prolactin measurement

Any lesion that disrupts the pituitary stalk or hypothalamic-pituitary portal system results in mild hyperprolactinemia (< 100 ng/dL) because of loss of dopaminergic inhibition. Patients with prolactin-secreting pituitary adenomas typically have levels that exceed 150-200 ng/dL, with levels being many times greater in patients with macroadenomas.

Growth hormone measurement

Insulinlike growth factor–1 (IGF-1) and insulinlike growth factor–binding protein-3 (IGF-BP3) measurement is a useful means of screening for growth hormone deficiency in children older than 3 years. These results must be interpreted according to age-appropriate, sex-appropriate, and pubertal stage–appropriate reference range values. If these are low, more formal testing should be performed (see Short Stature).

Gonadotropin measurement

Measure gonadotropin levels in adolescents in whom pubertal arrest or delay is suggested. Hyperprolactinemia causes hypogonadotropic hypogonadism. If androgenization with testicular enlargement, symptoms of pituitary or visual disturbance, and suppressed gonadotropins are present, human chorionic gonadotropin (HCG) should be measured to exclude a germ cell tumor.

Urine osmolality or specific gravity tests

Central diabetes insipidus occurs if the tumor has destroyed the posterior pituitary gland or disrupted the stalk. This is a rare occurrence because vasopressin secretion can occur more proximally if impingement on the neurohypophysis is gradual.

If an history of polyuria and polydipsia is noted, an early morning urine specimen should be collected. In healthy children, the urine osmolality should be greater than 600-700 mOsm/kg or the specific gravity should be greater than 1.010 in the morning. If the early morning urine is dilute, a water deprivation test should be performed.

Imaging Studies

MRI of the pituitary and parasellar region

A gadolinium-enhanced MRI of the pituitary and parasellar region with 3-mm cuts through the pituitary adequately demonstrates the tumor and provides evidence of compression or invasion of surrounding structures.

In young children and patients with claustrophobia, sedation or anesthesia is required to obtain good quality images.

Other Tests

Visual field assessment

All children with large masses in the region of the pituitary or optic nerves should be referred for formal visual field assessment by a pediatric ophthalmologist. Patients, especially children, do not always report visual symptoms.

Histologic Findings

Tumors immunostain positive for ACTH.

Crooke hyaline change, observed in Cushing disease, is not usually present because patients with Nelson syndrome are not hypercortisolemic.

Little histologic difference is observed between the ACTH-secreting adenoma observed in Cushing disease and that of Nelson syndrome, except that the latter is usually much larger and more likely to exhibit aggressive behavior.

Nelson syndrome tumors may have cytological features that include increased cellular proliferation, with mitoses and cellular and nuclear pleomorphism. At the molecular level, this aggressive behavior may reflect the development of genetic mutations in oncogenes and genes regulating pituitary growth and differentiation, although this has not been investigated.

 

Treatment

Medical Care

Although Nelson syndrome was previously thought to be primarily due to a pituitary macroadenoma, and medical treatment alone was thought to be rarely curative, recent high-resolution MRI that allows detection of microadenomas and the use of a newer class of drugs have shown promising results for medical treatment alone to be possible in some cases.

Case reports have demonstrated successful remission of Nelson syndrome with cabergoline (dopamine receptor agonist), with decline and normalization of adrenocorticotropin (ACTH) levels and resolution of the pituitary macroadenoma or microadenoma.[9, 10, 11]

Various other drugs that have been used in an attempt to medically control tumor growth, with variable success, include octreotide (a parenterally administered somatostatin analog), cyproheptadine with and without bromocriptine, and sodium valproate. Octreotide or other analogue of somatostatin may be helpful to control ACTH levels, although it is only useful as a means of controlling levels until definitive treatment is undertaken because it does not result in appreciable tumor shrinkage. Because it suppresses other hormones, including insulin, it may result in other problems, such as carbohydrate intolerance. In addition, it may cause sludging within the gall bladder.

Radiotherapy is important in the treatment of patients with Nelson syndrome.[12]  Historically, the irradiated field needed to be large, which led to increased risk of damage to the surrounding brain. The most serious long-term problems have included learning and memory difficulties, radiation-induced visual damage, and, most importantly, the risk of secondary tumors. With the advent of newer means of reducing radiation scatter (eg, linear accelerator [LINAC], gamma radiosurgery[13, 14, 15] ), radiotherapy-associated morbidity has significantly decreased and may be helpful in tumors that are not amenable to surgery.

Surgical Care

Surgery remains one of the best hopes of cure for patients with Nelson syndrome and is the treatment of choice for large tumors that are producing acute compression of the optic apparatus and other vital structures.

Transsphenoidal surgery by an experienced surgeon is optimal because it offers the lowest risk of hypothalamic injury.[16]

Stereotactic radiosurgery, called gamma knife surgery (GKS), has been successfully performed in secretory pituitary tumors (including Nelson syndrome tumors) that are refractory to other surgical interventions.[13, 14, 15, 17, 18]

Determinants of success include the degree of tumor invasion of brain parenchyma, optic apparatus, cavernous sinuses, dura, and bone and the skill of the surgeon.

The goal of surgery is to remove all macroscopic tumor tissue without compromising vital structures.

In cases of incomplete removal or where invasion is present, adjunctive irradiation reduces that rate of recurrence and improves the prognosis.

Incidence of treatment-associated hypopituitarism is high, particularly with large tumors.

Consultations

See the list of potential consultations below:

  • Pediatric endocrinologist

  • Pediatric ophthalmologist

  • Pediatric neurosurgeon (with expertise in transsphenoidal and/or gamma knife surgery)

  • Radiation oncologist (stereotactic radiosurgical center)

Diet

No restrictions on diet are necessary.

Activity

No activity restrictions are initially necessary, although standard restrictions occur following surgical resection of the tumor (see Glucocorticoid Therapy and Cushing Syndrome).

 

Medication

Medication Summary

Because most patients who develop Nelson syndrome have had bilateral adrenalectomy, they need to have adrenal steroid replacement.

Glucocorticoids

Class Summary

Steroid hormones with multiple activities are used for replacement therapy in patients with adrenal insufficiency or for the therapy of many diverse diseases.

Hydrocortisone (Hydrocortone, Hydrocort, Cortef, Solu-Cortef)

Hydrocortisone is the glucocorticoid of choice for replacing cortisol. Its short half-life necessitates a twice-daily dose schedule. The morning dose should be the largest, administering approximately two thirds of the total daily dose immediately after waking. A second dose is usually administered in the early afternoon. Longer-acting glucocorticoids are not recommended until growth is complete because they can compromise growth. In children who have stopped growing and in adults, prednisone and dexamethasone can be administered. Dexamethasone has the advantage of daily dosing but is unsuitable for long-term replacement therapy in children.

Mineralocorticoids

Class Summary

Mineralocorticoid replacement is necessary to maintain circulatory volume, blood pressure, and prevent hyperkalemia and hyponatremia in patients that have mineralocorticoid deficiency. Inadequate mineralocorticoid replacement results in increased glucocorticoid requirement that may make the patient cushingoid.

Fludrocortisone acetate (Florinef)

Fludrocortisone acetate possesses very little glucocorticoid activity at recommended doses. The dose requirement is determined by measuring blood pressure (hypertension indicates overreplacement) and supine plasma renin activity (PRA). Suppression of PRA indicates overreplacement and elevation indicates underreplacement. Dosages vary considerably among individuals and must be tailored to the individual patient. They can vary from 50-500 mcg/d. Dose adjustment is typically not required for acute illness, although some physicians advocate increasing the dose for severe GI illnesses.

Dopamine receptor agonist

Class Summary

Cabergoline is a long-acting dopamine receptor agonist that has a high affinity for D2 receptors. It has been used as an oral medication for the treatment of hyperprolactinemia. Cabergoline has been reported in 2 case reports to control serum adrenocorticotropin (ACTH) concentrations with appreciable tumor shrinkage or disappearance in Nelson syndrome.

Cabergoline (Dostinex)

Cabergoline acts on dopamine receptors, with a high affinity to the D2 receptor. It inhibits growth hormone secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.

Somatostatin analogs

Class Summary

Octreotide, like natural somatostatin, inhibits growth hormone secretion, insulin secretion, and glucagon secretion. Following intravenous administration, basal serum growth hormone, insulin, and glucagon levels are lowered. It also inhibits prolactin secretion via vasoactive intestinal peptide–mediated and thyrotropin-releasing hormone–mediated secretion of prolactin. Used to treat acromegaly and hormone-secreting tumors. When used in Nelson syndrome, octreotide is only useful as a means of controlling serum ACTH concentrations until definitive treatment is undertaken because it does not result in appreciable tumor shrinkage.

Octreotide (Sandostatin)

Octreotide acts primarily on somatostatin receptor subtypes II and V. It inhibits growth hormone secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.

 

Follow-up

Further Outpatient Care

Monitor patients at 3-month to 4-month intervals with measurement of growth parameters, blood pressure, and assessment of thyroid function and pubertal development. Loss of pituitary function after pituitary radiotherapy is inevitable, although the time taken for this to occur varies and depends on the dose and number of fractions of radiation that are administered. Growth failure may precede biochemical evidence of growth hormone deficiency with pharmacologic testing. Overnight growth hormone sampling is thought to be more sensitive than pharmacologic testing because the hypothalamus is more radiosensitive than the pituitary and neurosecretory dysfunction may precede actual growth hormone (GH) deficiency. For this reason, patients who have received pituitary radiation need ongoing follow-up of their growth and thyroid function at 3-month and 6-month intervals by an endocrinologist, and patients may require pubertal induction or treatment of hypogonadism in addition to their ongoing replacement with hydrocortisone and fludrocortisone.

Thyroid function should be measured at least every 6 months or more frequently if growth velocity is declining and deficiency is evolving. Thyroxin supplementation is necessary when the free T4 levels are below the reference range. Thyroid-stimulating hormone (TSH) is not helpful in determining adequacy of thyroxin replacement in patients with central hypothyroidism.

Patients with central diabetes insipidus require treatment with desmopressin acetate (DDAVP). The dosage required varies among individuals and can range from 50-400 mcg/d administered as a single or twice daily dose orally. It may also be administered as a nasal spray, in which case the dose is 5-40 mcg/d usually in 2 divided doses. The evening dose is usually larger to reduce problems with nocturia.

Children who receive DDAVP need to have regular sodium measurements, with the frequency determined by the stability of the child. More frequent measurements are needed if the child develops increased fluid losses due to intercurrent illness, hot ambient temperatures, or GI losses.

Patients with a normal sense of thirst should be allowed to drink ad libitum because by doing so they regulate their own osmolality. Fluid management is difficult in patients with diabetes insipidus who lack normal thirst sensation. Regular weighing on accurate scales is important, and prescribed fluid intake must be administered based upon the size of the child and the environmental conditions. Greater vigilance and more frequent measurements of sodium are needed in these children.

Some physicians believe that children receiving DDAVP should be allowed to "break through" and become polyuric periodically to avoid the risk of hyponatremia. Mixed opinion exists about the frequency with which breakthrough is required.

Patients with Nelson syndrome who have undergone radiotherapy and have multiple pituitary hormone deficiencies require lifelong endocrine follow-up. Transition is ideally achieved in the late adolescent years in a clinic that has both adult and pediatric endocrinologists.

Inpatient & Outpatient Medications

Replacement of hormones depends upon those that are found to be deficient. Regular clinical and biochemical assessment identifies these deficiencies. These may include the need for pubertal induction and sex hormone replacement and growth hormone replacement in addition to adrenal hormone replacement. Patients with central diabetes insipidus also require DDAVP, available as a nasal spray or tablet.

Deterrence/Prevention

Nelson syndrome has become increasingly uncommon because of the significant improvements in all aspects of biochemical and radiological diagnosis and surgical and medical management of Cushing syndrome.

Hyperpigmentation with adrenocorticotropin (ACTH) levels above 154 pg/mL have been shown to have a high positive predictive value of Nelson syndrome or ectopic ACTH syndrome.

These patients should have an MRI of the pituitary. If no tumor is detected, and ectopic ACTH syndrome is ruled out, MRI of the pituitary should be periodically repeated.

Appropriate workup should enable accurate early identification of nearly all cases of ACTH-secreting pituitary adenoma, enabling prevention of virtually all cases; thus, Nelson syndrome should become a disease of the past.

Complications

The following are the potential complications in patients with pituitary macroadenomas:

  • Related to the primary disease - Visual loss, hypopituitarism, and cranial nerve complications

  • Related to surgical intervention - Infection, stroke, hypothalamic damage, hypopituitarism, and visual loss

  • Related to radiotherapy - Hypopituitarism, damage to vision, difficulties with learning or memory, and the risk of developing second tumors

Prognosis

The prognosis for patients with Nelson syndrome is good with early recognition, prompt coordinated treatment with surgeons and radiotherapists, and appropriate hormone replacement.[19] The falling incidence and lack of longitudinal studies suggest that good recent epidemiological data are lacking.

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.

Patient Education

The main educational requirements for patients with Nelson syndrome relate to their need to increase replacement glucocorticoid doses with intercurrent illness, physical stress, or anesthesia and the need for parenteral steroids before anesthesia or with vomiting or severe diarrhea.

Patients receiving other treatment also require education specific to that treatment (eg, administration of growth hormone injections or DDAVP).

All patients on steroid replacement should wear a Medic Alert bracelet or medallion.

If patients have hypogonadotropic hypogonadism, they also require counseling at an appropriate age about the availability of assisted reproduction.

For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism Center. Also, see eMedicineHealth's patient education articles Hypopituitarism in Children and Anatomy of the Endocrine System.