Glucocorticoid Therapy and Cushing Syndrome

Cushing syndrome (CS) takes its name from Harvey Cushing, who, in 1912, was one of the first physicians to report a patient affected with excessive glucocorticoid.[1] More than 99% of cases of Cushing syndrome are due to administration of excessive amounts of glucocorticoid. This article discusses issues relating to both endogenous and exogenous glucocorticoid excess, with emphasis on the safest possible therapeutic use of glucocorticoids.

Although distinguishing endogenous from exogenous Cushing syndrome is usually straightforward, the investigation and differentiation of Cushing syndrome from other causes of hypercortisolism require a sound understanding of the physiology of the hypothalamic-pituitary-adrenal (HPA) axis. See the images below.

Glucocorticoid synthesis and release is strictly regulated by the pituitary and hypothalamus by negative feedback and, to a lesser extent, by catecholamines from the adrenal medulla and neural inputs from the autonomic system. In addition to the glucocorticoid effects that cortisol has because of binding to the glucocorticoid receptor (GR), cortisol can also bind to and activate the mineralocorticoid receptor (MR). When cortisol binds to the kidney, MR is physiologically inhibited by conversion of cortisol to its inactive metabolite cortisone by the enzyme 11beta-hydroxy-steroid dehydrogenase (11beta-OHSD2), which co-localizes with the MR.

The basal daily rate of cortisol secretion is approximately 6-8 mg/m2 body surface area, although this can increase as much as 10-fold in response to acute severe stress. Physiological replacement of cortisol requires higher doses of 10-15 mg/m2 because the oral bioavailability is 50-60%. Other natural and synthetic glucocorticoids are noted, all of which have different relative potencies as glucocorticoids and mineralocorticoids because of their differing structures and affinities for the GR and MR, as well as for 11beta-OHSD2. Table 1 summarizes the relative potencies and half-lives of main steroid hormones.

The glucocorticoid receptor is an intracellular protein that, in its ligand-bound form, acts as a nuclear transcription factor to regulate the expression of a diverse array of genes in many areas of the body. Factors that influence the spectrum of adverse effects observed in hypercortisolemic individuals include duration of treatment, potency of the steroid, dose and route of administration, and the site and rate of metabolism and clearance.

Since the late 1940s, when glucocorticoids first came into use for their anti-inflammatory and immunomodulatory effects, much work has been conducted by science and industry to maximize their beneficial effects while minimizing their adverse effects. Thus, many synthetic compounds with glucocorticoid activity have been manufactured and tested.

Alterations of the basic steroid nucleus and its side groups give rise to the pharmacologic differences between these chemicals. Such changes may affect the bioavailability of these steroid compounds, including their GI absorption; parenteral distribution; plasma half-life; their metabolism in the liver, fat, or target tissues; and their ability to interact with the GR and MR and modulate the transcription of glucocorticoid-responsive genes. In addition, structural modifications can diminish the natural cross-reactivity of glucocorticoids with the MR, eliminating their undesirable salt-retaining activity. Other modifications enhance their water solubility for parenteral administration or reduce their water solubility to enhance topical potency.

Most synthetic glucocorticoids (eg, methylprednisolone, dexamethasone) are minimally bound to cortisol-binding globulin and circulate freely, or they are weakly bound to albumin. A relatively constant percentage of synthetic glucocorticoids is bound to plasma proteins, and, because this percentage is concentration independent, the rate of metabolic clearance remains constant for synthetic glucocorticoids, regardless of dose. Table 1 shows the relative glucocorticoid and mineralocorticoid potencies of different, commonly used systemic glucocorticoids and their approximate plasma and biologic effect half-lives.

Glucocorticoid activity has been defined mostly in rat bioassays, which may not always reflect human responses, particularly the growth-suppressing properties of synthetic glucocorticoids, which have been markedly underestimated. Glucocorticoids can be categorized as short, intermediate, or long acting, based on their biologic effective half-life, which is defined as the duration of corticotropin (ACTH) suppression after a single dose of the compound.

Table 1. Glucocorticoid Equivalencies ^[2] (Open Table in a new window)

Cushing syndrome can be divided into ACTH-dependent and ACTH-independent forms. The proportion of adrenal and pituitary disease varies in different regions; however, in Western countries, 90-95% of cases of Cushing syndrome in children older than 5 years are ACTH-dependent, and 90-95% of those cases are due to Cushing disease caused by an ACTH-secreting pituitary adenoma. Tumors that ectopically secrete ACTH are rare, and tumors that secrete corticotropin-releasing hormone (CRH) are extremely rare, together accounting for fewer than 5% of cases of Cushing syndrome.

In children younger than 5 years, the proportion of ACTH-independent cases of Cushing syndrome approaches 50%. Such cases are due to a combination of congenital disorders of the adrenal cortex and adrenocortical neoplasms that result in autonomous overproduction of cortisol and other adrenal cortical hormones (summarized below). All children in this age group who have been proven to have ACTH-independent Cushing syndrome require adrenalectomy because of the significant incidence of malignancy in this age group.

Pathophysiology of ACTH-dependent Cushing syndrome

Relative frequency is as follows:

• Age younger than 5 years - 50% of Cushing syndrome cases

• Age older than 5 years - 80-90% of Cushing syndrome cases

ACTH-producing pituitary adenoma (corticotropinoma) represents 80-90% of ACTH-dependent Cushing syndrome cases in people of all ages. It is usually a microadenoma and may invade the cavernous sinus. It is associated with a risk of Nelson syndrome after bilateral adrenalectomy.

Ectopic ACTH production is very rare in children. Ectopic ACTH production is from carcinoid tumors (bronchial tumors most frequent, although may also be in GI tract), ACTH-producing pancreatic islet cell tumors (especially multiple endocrine neoplasia type 1 [MEN1]), pheochromocytoma, ganglioneuroma or other neuroendocrine tumor.

Ectopic CRH production is extremely rare.

Pathophysiology of ACTH-independent Cushing syndrome

Frequency is as follows:

• Age younger than 5 years - 50% of Cushing syndrome cases

• Age older than 5 years - 10-20% of Cushing syndrome cases

Adrenocortical neoplasms have a risk of malignancy significant in young children.

Macronodular disease is very rare in children.

Ectopic expression of receptors on cortisol-producing cells, resulting in hypercortisolemia shown in some cases[3]

Micronodular disease may include the following:

• Primary pigmented nodular adrenal disease (PPNAD)

• Carney complex (See Table 2.)

McCune-Albright syndrome may be present. See the discussion of McCune-Albright syndrome in Table 2.

Cushing syndrome can be classified as ACTH-dependent and ACTH-independent. ACTH-dependent causes can be further divided according to whether ACTH secretion arises from the pituitary or from an ectopic source. ACTH-independent causes can be divided further according to whether they are due to neoplasia or hyperplasia. Table 2 summarizes the causes of Cushing syndrome.

Exogenous Cushing syndrome occurs as the result of systemic absorption of pharmacologic doses of steroids with glucocorticoid activity. Most commonly, this results from oral or parenteral administration but may also be caused by inhaled steroids, topical steroids, and, occasionally, local steroid injections.

Table 2. Genetic Causes of Cushing Syndrome (Open Table in a new window)

 

United States data

Cushing syndrome is a rare disorder, with 90% of cases occurring during adulthood. Overall incidence is estimated to be 2 new cases per million population per year. Incidence in children is estimated at approximately 0.2 cases per million population per year.

The National Cancer Institute (NCI) estimates the incidence of adrenal cortical carcinoma as 2 cases per million population per year. Pituitary causes of Cushing disease are 5-6 times more common than adrenal causes.

Prevalence of exogenous Cushing syndrome depends on the frequency and spectrum of medical conditions requiring glucocorticoid treatment in a given population. Considerable variation in this frequency is observed in populations of different cultural and ethnic backgrounds.

International data

In certain regions of the world (eg, Japan, Brazil), adrenal tumors are more frequently observed. Whether this and other aberrations are due to a genetically determined founder effect in a small subset of the population or whether environmental factors may be acting to increase patient risk is unknown.

Sex- and age-related demographics

Endogenous Cushing syndrome of pituitary etiology is more prevalent in women than in men, with a female-to-male ratio of 9:1. Females are 8 times more likely than males to develop an ACTH-secreting pituitary adenoma and 3 times more likely to develop a cortisol-secreting adrenal tumor.

Onset of endogenous Cushing syndrome of pituitary etiology occurs primarily in the third and fourth decades of life.

As a result of the multiple adverse effects of chronic glucocorticoid excess, both endogenous and exogenous Cushing syndrome are associated with significant morbidity. Untreated, they are also associated with an increased risk of premature death. Specific information about the effects of glucocorticoids on different systems is summarized in Table 3.

Hypothalamic-pituitary-adrenal (HPA) axis recovery

More than 90-95% of patients have recovery of their HPA axis by 12 months after stopping treatment, with more than 50% of the remainder recovering in the following 6-12 months. Permanent adrenal insufficiency has been described, although it is rare. Early recognition and prompt treatment of the early signs of adrenal insufficiency is essential because this may be life threatening if not managed appropriately.

Growth

Growth velocity usually normalizes and weight loss occurs in children once pharmacologic doses of glucocorticoids have been reduced to physiologic levels. However, catch-up growth is frequently disappointing, with a tendency not to achieve predicted final height.

Bone density

Patients with significant osteoporosis experience some recovery in bone density, provided they have adequate calcium and vitamin D replacement and regular exercise. Bisphosphonate treatment may be needed in severe cases. Residual deficits in bone density are more likely if treatment was prolonged and occurred at a time of peak bone mass accrual. The role of prophylactic treatment with bisphosphonates is still being studied.

Metabolic disorders

Diabetes and insulin resistance resolve with cessation of therapy, although patients who become frankly diabetic when on glucocorticoids are likely to have significant preexisting insulin resistance and are at risk of developing type 2 diabetes in later life. Dyslipidemia should also improve as insulin resistance resolves, although this also depends upon premorbid lipid status.

Cushing disease

With transsphenoidal pituitary surgery, the cure rate for uncomplicated cases is approximately 95% and the recurrence rate is about 5%. If evidence of cavernous sinus invasion is noted or if repeat surgery is required, the cure rate falls significantly and the complication rate also rises.

Adrenal neoplasms

For nonmalignant adrenal neoplasms, the cure rate remains excellent. For malignant tumors, surgery offers the best chance of cure or prolongation of survival, with excision of isolated metastases in the lung or lymph nodes being primary treatment. Results of chemotherapy and radiation therapy have been disappointing, and, although disease control has been achieved, cure with these methods is uncommon so they have a more palliative role.

Educate patients and parents to recognize situations where an increase in glucocorticoid dosage is required. Unfortunately, the medical profession often also needs education on this issue because physicians sometimes do not appreciate the urgency of treatment in the patient who is developing signs of adrenal insufficiency.

Ensure that parents and patients understand the importance of proper technique for administering their glucocorticoid treatments (eg, the need for a spacer device with asthma, the importance of using potent steroid creams sparingly).

Children with Cushing syndrome are commonly diligent workers. Warn the family that their school performance and concentration may suffer after successful treatment and that the child may also develop psychiatric symptoms, including anxiety and depression, possibly requiring psychiatric treatment.[5]

Siblings in the same household should not receive attenuated live-virus vaccines because of the risk of causing infection in the child who is affected by Cushing syndrome.

All patients receiving glucocorticoid therapy for longer than 1-2 months should be provided a medic-alert bracelet identifying them as dependent on steroids.

All patients with Cushing syndrome who receive pharmacologic glucocorticoid treatment develop Cushingoid features if exposed to a high enough dose for long enough (usually 1 mo or more). With the exception of abnormal growth, the signs of hypercortisolism are frequently subtler in pediatric patients than in adults. In children, the most common features that are observed include an increase in body weight due in part to an increase in appetite and a decrease in linear growth. Known side effects associated with chronic hypercortisolemia from any cause are outlined below.

Table 3. Effects of Glucocorticoids During Long-Term Therapy (Open Table in a new window)

Growth failure

The severity of disturbance in height and weight depends on the duration of treatment with pharmacologic steroids or the duration of Cushing syndrome before diagnosis. Previous measurements are helpful in determining whether growth velocity is normal or reduced. In contrast to children with hypercortisolism, children with simple exogenous obesity usually have a normal or even accelerated growth velocity and are tall.

Obesity

When evaluating a child with possible Cushing syndrome, obtain information about the duration and rate of the weight gain and any attempts to lose weight. Rigorous dieting and exercise can minimize weight gain, which may delay diagnosis.

In contrast to adults with Cushing syndrome, children may have more generalized obesity, rather than centripetal "lemon on toothpicks" obesity. The child with Cushing syndrome has a similar facies to that observed in adults, with fullness and redness of the cheeks and variable temporal muscle wasting.

The presence of dorsocervical and supraclavicular fat pads is of diagnostic help but is not pathognomonic because patients with significant obesity may also have these signs. The presence of striae and rapid weight gain are also relatively nonspecific signs. Children with simple obesity usually have a normal or accelerated growth velocity.

Premature pubarche

Prepubertal males and females with endogenous Cushing syndrome commonly have premature pubic hair development in addition to their rapid weight gain. Such development is the result of excessive adrenal androgen production that can occur in both corticotropin (ACTH)-dependent and ACTH-independent Cushing syndrome.

Pubertal delay/arrest

Information should be obtained about the time of onset of puberty and its progress. When Cushing syndrome develops during puberty, normal pubertal development does not occur and commonly arrests because glucocorticoid excess inhibits gonadotropin release and also directly inhibits sex steroid secretion from the gonads.

Males who develop Cushing syndrome at puberty commonly continue to show signs of virilization, with increased pubic and androgen-dependent hair, but they do not undergo testicular enlargement, indicating that the androgens are of adrenal origin.

Cutaneous manifestations

Children with endogenous Cushing syndrome commonly notice a generalized coarsening of body hair.

Hirsutism is common (increased hair in androgen-dependent regions of the body) and may be a presenting feature in females and prepubertal males.

Hyperandrogenemia commonly causes acne, comedones, and oily skin.

Striae may be present and are typically purple. Striae are due to the combination of rapid weight gain and impaired collagen synthesis (commonly observed on the thighs, proximal arms, abdomen, and breasts).

Poor wound healing may also be present.

Thinning of the skin and easy bruising are common symptoms in adults but are not frequently observed in children.

Monilial infections are more frequent in children with Cushing syndrome. Tinea cruris, tinea pedis, and Candida albicans infection all occur more commonly, especially if glucose intolerance is present.

Muscle weakness

Muscle weakness tends to be more evident in those patients with more severe disease. Proximal muscles are affected and muscle wasting may be observed in some cases. Children may report difficulty climbing stairs, getting out of chairs, or difficulty combing their hair. Hypokalemia can exacerbate the problems of muscle weakness.

Visual disturbance

Blurred vision may accompany hyperglycemia and lens sorbitol deposition.

Cataracts (uncommon in children) may occur with prolonged high-dose administration of synthetic glucocorticoids. Interestingly, patients with endogenous CS do not develop cataracts at an excessive rate.

Cavernous sinus invasion may infrequently occur in pituitary Cushing disease but is more common in Nelson syndrome, and it may affect the cranial nerves traversing the sinus (cranial nerves III, IV, V1, VI).

Bony symptoms

A history of focal pain over the midline raises the possibility of vertebral crush fractures. Such fractures can happen with prolonged hypercortisolemia causing severe glucocorticoid-induced osteoporosis, which significantly increases the risk of fracture.

Other bony disorders include avascular necrosis of the femoral head and slipped upper femoral epiphysis. Patients may present with a history of painful limitation of hip movement and a limp.

Renal disorders

A history of polyuria requires exclusion of diabetes, which may develop in people with preexisting insulin resistance.

Hypercalciuria and nephrolithiasis may occur with hypercortisolism and immobility (eg, juvenile rheumatoid arthritis [JRA]). Patients may present with severe colicky loin to groin pain with hematuria or a history of passing a kidney stone. This complication of Cushing syndrome is rare.

Neuropsychiatric symptoms

A history of school performance should be obtained. Children with Cushing syndrome are commonly conscientious and frequently compulsive workers at school with higher-than-average grades. Following cure of Cushing syndrome, children may experience a decline in school performance and an increase in anxiety symptoms.

Questions should be asked about sleep. Sleep disturbance, primarily insomnia, and depression are less frequent in children than in adults but may be present in adolescents. Obstructive sleep apnea may rarely occur in children with severe obesity.

Hematologic and immune disorders

High cortisol levels suppress innate immunity and T-cell responses, placing patients at risk of severe viral and opportunistic infections. Seek information about the severity of viral illnesses and speed of recovery from illness and, importantly, about previous tuberculosis exposure because that quiescent disease may be reactivated.

Physical examination of a child treated with long-term high-dose glucocorticoids should look for treatment-associated complications; for the child suspected of having Cushing syndrome, examination should aim to identify specific features that may indicate the diagnosis. The clinical features that result in presentation and diagnosis of endogenous Cushing syndrome depend on age, sex, duration of disease, and preexisting genetic background, as well as whether other adrenocortical steroids (eg, mineralocorticoids, androgens) are present in excess. See the image below.

Growth failure

Restricted growth is almost universal because linear growth is very sensitive to supraphysiologic glucocorticoid levels. In patients receiving pharmacologic glucocorticoid treatment, the primary illness for which treatment is administered may also contribute considerably to growth failure. Reduction in steroid dose or treatment of Cushing syndrome restores growth velocity to normal, although catch-up growth may be poor.

Obesity

Obesity is almost always present, unless the child has adhered to a severely restricted diet and a vigorous exercise regimen. The presence of supraclavicular fat pads and a dorsocervical hump (buffalo hump) is commonly observed with exogenous or endogenous Cushing syndrome but is not pathognomonic of cortisol excess.

Lipomastia is also commonly present and may be difficult to distinguish from true breast tissue. The latter tends to feel more firm and fibrous than nonglandular fat. If areolar development is present, this suggests increased estrogen levels, making true breast tissue more likely.

Pubertal development in females

Prepubertal girls may develop premature adrenarche.

Peripubertal girls may undergo pubertal arrest, but they may also develop hirsutism (male pattern).

Postpubertal girls develop secondary amenorrhea, and they may notice softening of their breasts. Significant hyperandrogenism may cause clitoromegaly and should be looked for in those patients with other signs of significant hyperandrogenism.

The combination of premature pubic hair and lipomastia can be confusing, producing the appearance of precocious puberty.

Pubertal development in males

Prepubertally, males with Cushing syndrome may show signs of premature development of pubic hair, axillary hair, and possible phallic enlargement, although their testes remain small, indicating that androgens are of adrenal origin.

Peripubertal males do not experience testicular enlargement.

Postpubertal males may notice softening of their testes. High glucocorticoid levels cause hypogonadism, both at the level of the pituitary and also by a direct effect on the testes.

Patients with pure hypercortisolism do not develop these symptoms because the only steroid hormones present in excess are the glucocorticoids.

Blood pressure

Children and adolescents with Cushing syndrome frequently have elevated arterial blood pressure (BP). When measuring BP, ensure that the BP cuff is the appropriate size for the arm circumference because the use of a small cuff may result in artificially high readings.

Abdominal examination

Obesity makes abdominal examination difficult. High levels of ACTH may produce a linea nigra, a pigmented line extending from the umbilicus to the pubis. Palpate carefully to look for a malignant adrenal tumor, which may be large at presentation. Hepatomegaly may occur in patients with insulin resistance who have fatty liver infiltration.

Neurologic examination

Using slit-lamp microscopy, examine patients with exogenous Cushing syndrome for evidence of subcapsular cataracts.

Musculoskeletal examination

Frank muscle proximal wasting is uncommon in children, who usually have a shorter duration of disease at diagnosis and are more active. Features on examination include difficulty climbing stairs, positive Gower sign, and difficulty combing hair (proximal upper limb weakness).

Pain and restriction of hip movement may occur as a result of slipped upper femoral epiphysis or avascular necrosis of the femoral head. If such pain is present, it requires investigation. Pain may be in the hip joint or may be referred to the anterior or medial thigh or the knee. Consider focal tenderness over a spinous process of a vertebra to be a crush fracture until proven otherwise with radiologic confirmation.

With recurrent fractures in an infant with Cushing syndrome due to bilateral adrenal hyperplasia, suspect the possibility of polyostotic fibrous dysplasia due to McCune-Albright syndrome.

Skin examination

When examining the skin, look for signs of potential causes of Cushing syndrome, including pigmentation of scars, skin creases, areolae, and genitalia (associated with high ACTH levels); lentigines (Carney complex); lipomas (multiple endocrine neoplasia type 1 [MEN1]); and irregular-shaped hyperpigmented lesions (McCune-Albright syndrome).

Cutaneous complications of Cushing syndrome include striae, balding, hirsutism (androgen-dependent hair growth), facial fullness and plethora, fungal infections in skin folds, thinning of skin, and telangiectasia (particularly in long-term use of potent topical glucocorticoids).

Signs of insulin resistance (not specific for Cushing syndrome) can include acanthosis nigricans and skin tags. Acanthosis appears as thickened coarse skin, especially in axillae and groins, as well as around the back of the neck. Skin may have an unwashed appearance, although in pale-skinned children acanthosis may appear as thickened leathery skin with minimal pigmentation. The presence of skin tags frequently increases in hyperinsulinemia. Skin tags are commonly observed around the neck, upper chest, and axillae.

Infections

High glucocorticoid levels increase the risk of bacterial and fungal infections, particularly in warm moist areas of the body, including skin creases, the genitalia, under folds of fat, and on the feet.

Viral illnesses, such as varicella, may be much more severe because of relative immunosuppression and may become generalized. Patients with Cushing syndrome or those receiving pharmacologic steroids should avoid contact with varicella, they should receive zoster immunoglobulin if they do have contact, and they should receive acyclovir if they develop the illness. Siblings in the same household should not receive attenuated live-virus vaccines because of the risk of causing infection in the child who is affected. Extremely severe Cushing syndrome, usually as a result of ectopic ACTH secretion, may be associated with potentially lethal opportunistic infections.

Observe patients with evidence of previous infection with tuberculosis or who live in areas in which tuberculosis is endemic for signs of activation of disease.

Other disorders

Diagnosis can be complicated because many of the symptoms typical of Cushing syndrome can be associated with other afflictions. Disorders that may need to be ruled out include the following:

Simple exogenous obesity

Children who gain weight rapidly may have several signs in common with Cushing syndrome, including the presence of striae, dorsocervical and supraclavicular fat pads, acanthosis nigricans, skin tags, and premature pubarche. They are also at risk of slipped upper femoral epiphysis. Unlike children with Cushing syndrome, their growth velocity is usually faster than normal, and they tend to be tall for their age. Their striae are often narrower and may not be as purple, although this is not a sensitive predictor.

Hypothyroidism and growth hormone deficiency

Patients with acquired hypothyroidism have a poor height velocity that coincides with the onset of their disease, although they do not typically have a major increase in their weight. Similarly, patients with growth hormone (GH) deficiency tend to be slightly overweight but do not gain excessive amounts of weight.

Pseudohypoparathyroidism type 1a

Patients with pseudohypoparathyroidism type 1a commonly have short stature and obesity, although they also tend to have other features that include variable intellectual impairment and foreshortening of their fourth and/or fifth metacarpals and metatarsals. Patients may present in the neonatal period or in infancy with hypocalcemia and seizures, and they may have hypothyroidism due to thyrotropin (thyroid-stimulating hormone [TSH]) resistance. This disorder is due to an inactivating mutation of the stimulating G-protein (Gsa). The spectrum of severity is dependent upon the mutation, with patients who are mildly affected presenting in later childhood. This disorder should be easier to distinguish from Cushing syndrome because a patient's growth is likely to be consistently poor, as opposed to showing a sudden decline in growth velocity and increase in weight gain.

Hypothalamic disorders

Hypothalamic dysfunction most commonly occurs secondary to surgical treatment or radiation therapy for tumors in this region, including craniopharyngioma, gliomas, and germ cell tumors. This dysfunction may also rarely be due to primary hypothalamic tumors or hypothalamic failure. Symptoms of hypothalamic dysfunction include rapid weight gain due to altered satiety signaling, alteration in the sleep-wake cycle, disorders of thirst, and variable growth failure. Patients may have evidence of GH deficiency, dysregulation of GH secretion, and central hypothyroidism.

Genetic obesity syndromes

Most of these syndromes include the combination of short stature and obesity. Hypogonadism is also a common feature. Obesity is believed to be the result of dysregulation of the hypothalamus in most cases.

• Laurence-Moon syndrome (MIM 245800)

• Bardet-Biedl syndrome, 6 types (chromosome arms 2q31; 3p13-p12; 11q13; 15q22.3-q23; 16q21; 20p12)

• Smith-Magenis syndrome (MIM 182290; chromosome arm 17p11.2)

• Alström syndrome (MIM 203800; chromosome arm 2p13)

• Cherubism (MIM 118400; chromosome arm 4p16.3)

• Prader-Willi syndrome (MIM 176270; chromosome arm 15q11-13

Pseudo-Cushing disease

Patients with pseudo-Cushing disease have mild-to-moderate hypercortisolism that occurs as a result of chronic overactivity of the HPA axis. This disorder is observed in patients with chronic alcoholism, depression, or chronic stress, with urinary free cortisol (UFC) levels typically 100-200 mg/1.73 m2/24 h. Children with Cushing syndrome commonly have cortisol levels in this range.

Pseudo-Cushing disease is a diagnosis of exclusion because it is extremely rare in children, so all patients with UFC levels of greater than 70 mg/1.73 m2/d require further UFC measurements; if UFC levels are elevated on several occasions, patients should be investigated for Cushing syndrome.

In older adolescents and adults in whom the diagnosis of pseudo-Cushing is suspected, a dexamethasone-suppressed corticotropin-releasing hormone (CRH) test may be used to distinguish pseudo-Cushing disease from Cushing syndrome.[9]

In the investigation of patients with hypercortisolism, the first task is to determine whether the source is endogenous because the overwhelming majority of patients with Cushing syndrome (CS) take glucocorticoids for therapeutic or other purposes or, in rare cases, surreptitiously. If no evidence suggests exogenous glucocorticoid administration, the next task is to establish that cortisol levels are indeed elevated before determining the underlying cause. The following is a diagnostic approach to the patient with Cushing syndrome.

Tests to establish the presence of Cushing syndrome

Twenty-four–hour urinary free cortisol (UFC) assay

Reference range values are less than 70 mg/1.73 m2/24 h. Reference ranges vary, depending on the assay method and the antibody specificity. UFC values must be interpreted in light of the reference range for the local laboratory. Results must be corrected for body surface area in children.

Comeasurement of creatinine may help detect collections that are incomplete or mistimed because 24-hour creatinine excretion should be similar for each of the 3 collections. Perform a minimum of 3 collections if initial measurements are low because 5-10% of patients with Cushing syndrome have an intermittent or periodic pattern of excretion.

Twenty-four–hour urine 17-hydroxy (17-OH) steroids test

This test includes all cortisol metabolites with the 17-(OH)2-acetone side chain. 17-OH steroids are not routinely used because they are difficult to assay, and UFC measurements are equally reliable. Reference range values are less than 6 mcg 17-OH steroids per gram of creatinine.

Low-dose dexamethasone suppression test

Administer 15 mcg/kg dexamethasone at 11 pm. Patients with Cushing syndrome do not suppress their cortisol to less than 3 mcg/dL at 8 am the following morning. This test is associated with a less than 3% false-negative rate and a 20-30% false-positive rate.

Patients with psychiatric disorders that cause corticotropin-releasing hormone (CRH) overactivity (eg, anxiety, depression, posttraumatic stress disorder) may not suppress with low-dose dexamethasone.

Diurnal serum cortisol measurement

Patients with Cushing syndrome who have hypercortisolemia at the time of assessment have loss of the normal nocturnal fall in cortisol. Measurements should be taken at 11:30 pm and midnight and then at 7:30 am and 8:00 am through a cannula that has been inserted 1-2 hours before and with the patient fasting since the evening meal. A single cortisol measurement at midnight through an indwelling cannula and with no food since the evening meal is equally sensitive. The result should be less than 5 mcg/dL. Patients with intermittent or periodic disease may have normal diurnal variation, if disease is quiescent at the time of assessment. This test is very sensitive; the main disadvantage is the requirement of overnight admission.

Tests to establish the cause of Cushing syndrome

Corticotropin (ACTH) measurements

Correct collection of ACTH is essential. The ACTH peptide is unstable and should be collected in ethylenediaminetetraacetic acid (EDTA)–containing tubes on ice, spun soon after collection, and stored at -20°C until assay.

Comeasurement of cortisol and ACTH can distinguish ACTH-independent Cushing syndrome from ACTH-dependent Cushing syndrome because ACTH is suppressed in the former if hypercortisolemia is present at the time of measurement. Absence of full suppression of ACTH does not exclude ACTH-independent Cushing syndrome because, in mild disease or in periodic Cushing syndrome, ACTH responsiveness may persist, particularly if the disease process is quiescent when sampling occurs.

Random measurements of ACTH are of limited value, although elevation of paired ACTH and cortisol measurements in the evening is suggestive of Cushing disease.

Patients with Cushing syndrome due to ectopic ACTH secretion typically present earlier with more florid symptoms, and associated hypokalemia may be present.

Ectopic ACTH production may lack the normal processing so that ACTH-precursor molecule levels are commonly elevated. Radioimmunoassays (RIAs) are the least specific and may detect a greater proportion of precursor molecules than the more specific double-antibody immunoradiometric assays (IRMAs) or chemiluminescent assays. Assay by more than one technique may help to demonstrate disparate values, indicating the presence of incompletely processed molecules, as observed in ectopic tumors.

CRH stimulation test (ovine or human CRH)

The purpose is to distinguish Cushing syndrome from ectopic ACTH secretion.

This test is performed in the morning, after an overnight fast. Measure ACTH and cortisol at -5 minutes, at baseline, and at 15-minute intervals for 90 minutes. Administer 1 mcg/kg of ovine or human CRH intravenously.

A positive response to this test can also be observed in healthy people; consequently, confirming hypercortisolemia before interpreting the results is important.

A rise in cortisol of 20% or more at 15 minutes and 30 minutes and cortisol levels above baseline at -5 minutes and 0 minutes is 91% sensitive and 88% specific. A rise in the mean of the ACTH values of greater than 35% above baseline levels is 91% sensitive and more than 99% specific in diagnosing Cushing syndrome.

Patients with ectopic ACTH secretion tend to have a rise in ACTH of less than 35%, although the probability of Cushing disease remains high at all levels of responses, which suggests that, in the absence of a discrete lesion on pituitary imaging, performing a second test (ie, high-dose dexamethasone suppression test, bilateral inferior petrosal sinus sampling [BIPSS]) to confirm the diagnosis is prudent.

High-dose overnight dexamethasone suppression test

This test has a role in differentiation of ACTH-dependent Cushing syndrome due to a pituitary adenoma from ectopic ACTH production.

On the day that dexamethasone is to be administered, measure the cortisol level at 8 am. The dexamethasone dose of 120 mcg/kg, maximum dose 8 mg, is administered at 11 pm, and a further cortisol measurement is obtained at 8 am the following morning.

Cortisol suppression of greater than 50% has a sensitivity that is comparable with the 85% sensitivity of the formal Liddle test for diagnosing Cushing syndrome.

Some ectopic sources of ACTH production produce false-positive results, and some large ACTH-producing macroadenomas may not suppress with high-dose dexamethasone. This test has the advantages of being inexpensive and requiring no admission or timed urine collections. Interindividual variation in the pharmacodynamics of dexamethasone metabolism is significant, which must be considered if the test results are equivocal or at odds with other test results. This problem can be overcome by measuring dexamethasone levels at the time of the second cortisol measurement, although the assay is not widely available.

Other tests used in the investigation of Cushing syndrome

Metyrapone test

The metyrapone test can also be used to differentiate ACTH-secreting pituitary adenomas from ectopic ACTH-secreting tumors. Metyrapone blocks the adrenal enzyme 11-hydroxylase, the most prominent place of inhibition being the conversion of 11-deoxycortisol to cortisol.

The classic test entails the administration of oral metyrapone with food at 4-hour intervals for 24 hours, with measurement of plasma 11-deoxycortisol concentrations before and 4 hours after the last dose. Cortisol is also measured 4 hours after the last dose to confirm adequacy of the blockade of 11-hydroxylase. In patients with Cushing syndrome, serum 11-deoxycortisol levels increase to greater than 5 mg/dL (144 nmol/L) in the presence of a low or undetectable cortisol level.

Concomitant measurement of 24-hour 17-OH steroid measurements (cortisol degradation products) improves the sensitivity to 60%, with a specificity of 77%.

Twenty-four–hour 17-OH steroids should rise by greater than 70% over baseline. Levels are measured on the day before, during, and after metyrapone administration. The resulting fall in cortisol levels triggers an increase in ACTH by both the normal pituitary and ACTH-secreting pituitary adenomas but not by ectopic sources of ACTH.

Liddle dexamethasone suppression test

The Liddle test has been used to differentiate Cushing syndrome due to ACTH-secreting pituitary tumors from ectopic ACTH production and ACTH-independent Cushing syndrome. Grant Liddle developed this test in the late 1950s, before reliable ACTH assays were available. With the advent of reliable assays for ACTH and the demonstration that the Liddle test is of equal sensitivity to the high-dose overnight dexamethasone suppression test, it is used less frequently today. The main reason for the less frequent use of this test is that it requires an inpatient stay and takes 6 days to perform.

Dexamethasone is administered at a dose of 7.5 mg/kg every 6 hours for 2 days (low dose), then 30 mg/kg every 6 hours for 2 days (high dose). Twenty-four–hour urine collections for UFC and 17-OH steroids are performed for 2 days before the test and then during the test.

Patients with pseudo-Cushing states suppress with low-dose dexamethasone. In patients with Cushing disease, the abnormal corticotrophs are sensitive to glucocorticoid inhibition only at the high dose of dexamethasone. Patients with the ectopic ACTH syndrome or cortisol-secreting adrenal tumors usually do not respond even to high doses. The criterion for a positive response consistent with Cushing disease is a greater than 50% fall in 17-OH excretion on day 2 of high-dose dexamethasone (80% diagnostic accuracy). However, diagnostic accuracy of the test increases to 86% by measuring excretion of both UFC and 17-OH and by requiring greater suppression of both steroids (>64% and 90%, respectively, for 100% specificity).

Dexamethasone-suppressed CRH test

This is used to distinguish Cushing disease from pseudo-Cushing disease. Reserve this test for patients with borderline or mild hypercortisolemia or for patients in whom cortisol suppression did not occur following low-dose (ie, 15 mcg/kg) overnight dexamethasone test, when the diagnosis of Cushing disease is uncertain.

Administer 7.5 mcg/kg of dexamethasone, not to exceed 0.5 mg, every 6 hours for 48 hours starting at noon and finishing at 6 am. At 8 am on the morning that the dexamethasone is completed, CRH (1 mcg/kg) is administered intravenously and cortisol and ACTH are measured at -10, 0, +5, and +15 minutes.

A 15-minute cortisol level that exceeds 1.5 mcg/dL (38 nmol/L) is diagnostic of Cushing disease. In pseudo-Cushing disease, dexamethasone results in corticotroph suppression by negative feedback on the pituitary, hence failure to respond to CRH. The dexamethasone-CRH test achieves nearly 100% specificity, sensitivity, and diagnostic accuracy.

Thyroid function tests

Thyroid function tests and measurement of insulinlike growth factor-1 (IGF-1) and insulinlike growth factor–binding protein-3 (IGF-BP3) are effective to screen for hypothyroidism and GH deficiency. Patients with a low IGF-1 or IGF BP3 must have further testing to confirm the diagnosis of growth hormone (GH) deficiency and establish the cause.

Establishment of parathyroid hormone (PTH) resistance

Establishment of the presence of PTH resistance (low calcium, elevated phosphate, elevated PTH with reference range 25-OH vitamin D, and measurement of urinary cyclic adenosine monophosphate [cAMP] response to PTH) with or without thyroid-stimulating hormone (TSH) resistance can be used to identify patients with pseudohypoparathyroidism.

Choose imaging studies as directed by the results of the clinical assessment and the initial biochemical investigations. Always obtain imaging studies of the pituitary if the results indicate that the patient has an ACTH-dependent cause of Cushing syndrome, even if the results suggest a possible ectopic cause, because very large ACTH-secreting pituitary adenomas behave more like ectopic ACTH-producing tumors.

Investigations that should be performed both in patients with hypercortisolism and in those with proven Cushing syndrome are as follows:

Bone age

Perform bone age radiography as part of the assessment of the child with short stature. Children receiving pharmacologic doses of glucocorticoids may have a delayed bone age either because of their treatment or because of their primary disease. On the other hand, a child with Cushing syndrome may have a bone age that is only mildly delayed or even equal to the chronologic age because of the coexistence of hyperandrogenemia. In the latter case, this has a significant adverse impact on the child's final height.

Assessment of bone mineral density

Assessment of bone mineral density (BMD) is important whenever hypercortisolism has been present for a significant length of time. In patients receiving pharmacologic doses of glucocorticoids, assess at baseline and at 12-month intervals thereafter while the patient is receiving steroid treatment.[10]

In patients with Cushing syndrome, perform BMD measurement once the diagnosis has been established. Loss of bone density is a sensitive marker of hypercortisolism; therefore, BMD may be helpful in cases where the diagnosis is uncertain and cortisol levels are elevated only mildly.

When assessing BMD in children, use a technique that has established reference range values that are age and sex appropriate, ensuring the necessary volumetric correction is made for the size of the child.

Imaging methods for children suspected of having Cushing disease are outlined below.

Pituitary MRI

MRI is the modality of choice for imaging the pituitary gland. This technique is preferred to CT scanning because of its superior resolution. Moreover, image quality is not lost because of the surrounding bone of the skull base, and images can be obtained in multiple planes. MRI should include sagittal and coronal images taken through the pituitary and parasellar region at 2-mm to 3-mm intervals following intravenous gadolinium. Pituitary adenomas typically appear as round or oval hypoenhancing lesions. Relative hypoenhancement is due to enhancement of the surrounding normal gland with gadolinium and delayed uptake in the tumor.

False-positive results can occur because of the phenomenon of signal averaging, or excessive noise, if cuts are too thin. False-negative results may occur if the time taken between gadolinium injection and imaging is too long because gadolinium uptake by the tumor eventually occurs. To be confident of the result, the tumor should ideally be visible on at least 2 images. Otherwise, or if other results are equivocal, the patient should undergo inferior petrosal sinus sampling.

CT scanning

CT scanning is not recommended because the image resolution may not allow detection of microadenomas. Refer the patient to a center with a powerful MRI scanner and with personnel experienced in performing and interpreting scans.

Adrenal imaging

Contrast enhanced CT scanning is the modality of choice for imaging the adrenal glands. Because adrenal adenomas are frequently small and may be missed, this technique is superior to ultrasonography. CT scanning can readily distinguish adrenal glands that are high in fat content from adjacent liver, spleen, and kidney, which are of lower attenuation. If significant insulin resistance is present, the liver may appear brighter than normal on an unenhanced scan, suggesting fatty infiltration.

Cortisol-secreting adrenal adenomas lead to suppression of pituitary ACTH production, with resultant atrophy of the contralateral adrenal gland and the remainder of the ipsilateral gland.

Consider any adrenal mass in a child suspicious because incidental tumors are rare. The presence of bilateral hyperplasia or nodularity of the adrenal glands should raise suspicion of an ACTH-dependent process or a congenital abnormality of the adrenal gland that leads to hyperplasia and autonomous cortisol hypersecretion, such as McCune-Albright syndrome or Carney complex. Patients with McCune-Albright syndrome who develop Cushing syndrome usually present in infancy and have fairly extensive disease. Other manifestations of McCune-Albright syndrome include bony lesions (detectable on bone scanning or plain radiography), patchy skin pigmentation, and other endocrine manifestations. Modern CT scanners are able to resolve lesions as small as 5-10 mm in size. Although adrenal masses may develop hemorrhagic areas, calcification is unusual in benign cortical lesions; thus, calcification suggests the possibility of malignancy or of pheochromocytoma.

T2-weighted MRI is the modality of choice for suspected ACTH-secreting adrenal pheochromocytomas or malignant adrenocortical carcinomas.

Iodocholesterol scanning

Iodocholesterol scanning can be used to identify adrenal cortical tumors, although it has no benefit over thin section CT scanning with a modern CT scanner, and it is mainly used as a second-line imaging modality. This test is useful in the localization of ectopic adrenocortical tissue or adrenocortical tissue that was not removed in a bilateral adrenalectomy.

Ectopic-ACTH secretion studies

Imaging studies performed in cases of suspected ectopic-ACTH secretion are outlined as follows:

Small cell carcinoma of the lung is the most common cause of ectopic ACTH secretion in adults. Ectopic ACTH secretion is very rare in children, commonly arising from a carcinoid tumor in the chest or abdomen, although it may arise from a neuroendocrine tumor in the pancreas (especially multiple endocrine neoplasia [MEN1]) or rarely from ganglioneuromas and pheochromocytomas of the adrenal medulla. Perform CT scanning of the chest (ie, for bronchial carcinoid, thymic neoplasms, possible mediastinal metastases) and the abdomen with intravenous and gastrointestinal contrast, focusing on the pancreas, the liver, the duodenum, and the appendix. MRI may detect lesions missed by CT scanning and should be used adjunctively in cases where ectopic ACTH secretion is suspected.

ACTH-producing neuroendocrine tumors may also be detected using radioisotope scanning. Octreotide scanning and fluoro-dopamine positron emission tomographic (PET) scanning may aid in the identification of small neuroendocrine tumors. These techniques are still investigational and are not routinely recommended in children.

The two procedures required in the workup of a patient with Cushing syndrome are BIPSS and bilateral adrenal vein sampling. These procedures both require a high level of technical expertise and should only be performed when indicated in centers that perform such sampling regularly.

Complications may arise from the invasive testing that some patients with Cushing syndrome require. Adrenal vein sampling can be associated with hemorrhage into the adrenal gland, which, if it occurs in the unaffected side, may render the patient permanently adrenally insufficient, following excision of their adenoma. Inferior petrosal sinus sampling can rarely cause bleeding or thrombosis of petrosal sinuses with neurologic sequelae. Therefore, reserve these procedures for occasions when findings from prior investigations are either contradictory or inconclusive.

BIPSS with injection of CRH

Venous blood from the anterior pituitary drains into the cavernous sinus and subsequently into the superior and inferior petrosal sinuses.

This is performed to differentiate Cushing disease from ectopic ACTH-secreting tumors.

BIPSS involves the simultaneous sampling of ACTH from each inferior petrosal sinus and from a peripheral vein before and after the injection of CRH. Catheters are advanced into both inferior petrosal sinuses via the ipsilateral femoral veins. Samples are simultaneously collected for ACTH from each inferior petrosal sinus and a peripheral vein before and after (at 2 min, 5 min, and 10 min) injection of 1 mcg/kg intravenous of ovine or human CRH.

Patients with the ectopic ACTH syndrome have no ACTH concentration gradient either between the inferior petrosal sinuses or between the central and peripheral samples. A ratio greater than or equal to 2 in basal ACTH samples between either or both of the inferior petrosal sinuses and a peripheral vein is highly suggestive of Cushing disease (95% sensitivity, 100% specificity).

Stimulation with CRH during the procedure, with the resulting outpouring of ACTH, increases the sensitivity of BIPSS for detecting corticotroph adenomas to 100% when peak central to peripheral ACTH ratio is greater than or equal to 3.

Petrosal sinus sampling must be performed bilaterally and simultaneously because the sensitivity of the test drops to less than 70% with unilateral catheterization. BIPSS is technically difficult and, like all invasive procedures, can never be risk free, even in the most experienced hands. Reserve BIPSS only for patients with possible Cushing disease and negative or equivocal findings on MRI of the pituitary and for patients with positive findings on pituitary MRI but equivocal findings on suppression and stimulation tests. In the former group, BIPSS unequivocally distinguishes ACTH-secreting pituitary adenomas from ectopic sources of ACTH production, and it may provide lateralization data of potential value to the surgeon. In the latter group, BIPSS findings exclude the possibility of a pituitary incidentaloma (rare in children but present in as many as 10% of adults).

Lateralization of pituitary adenomas with BIPSS assumes that blood flow is equal on each side. As a result, if vascular drainage is aberrant or if the sinuses are not of equal size, false-positive lateralization may occur. Similar to other biochemical tests for Cushing syndrome, the results of the BIPSS are valid only when the patient is hypercortisolemic.

Bilateral adrenal vein sampling

Cortisol is synthesized only in adrenal cortical tissue. Perform sampling in a patient with apparent ACTH-independent Cushing syndrome when the tumor is not identified on imaging studies or when the source of cortisol excess (ie, unilateral or bilateral) is not clear.

Sensitivity and specificity are optimized when simultaneous sampling of both adrenal veins and a peripheral vein is performed after stimulation with Cortrosyn. Adrenal venous cortisol levels usually should be greater than peripheral levels. Marked elevation of cortisol in one adrenal vein with reference range or suppressed levels in the other is suggestive of a neoplasm on the side with elevation. Levels in the suppressed side are still likely to be higher than peripheral levels. If they are the same as peripheral levels, then consider the possibility that the cannula has slipped out of the vein (this is particularly likely on the right side).

This procedure has a significant risk of morbidity from hemorrhage into the adrenal if the catheter is flushed.

Pituitary adenomas show evidence of acinar expansion, clonal expansion of a population of cells immunopositive for ACTH. Loss of the normal reticulin pattern is evident. The Crooke hyaline change may also be observed because of the hypercortisolism.

The histologic appearance of the tumor is similar in Nelson syndrome, except that the latter is more likely to show evidence of nuclear and cellular pleomorphism. Pituitary malignancies are extremely rare. Adrenal cortical neoplasms may be benign or malignant. Malignant tumors usually have evidence of nuclear pleomorphism. Mitoses are uncommon, and their presence with vascular invasion is diagnostic of malignancy.

In the absence of distant metastases, correlation between histologic appearance and tumor behavior is not predictable. A correlation between tumor size at diagnosis and risk of malignancy is observed. Tumors less than 100 g are more likely to be benign.

Treatment of Cushing syndrome involves identifying the underlying cause, whereas management of exogenous hypercortisolism involves optimization of glucocorticoid dose and route and use of glucocorticoid-sparing agents to minimize the glucocorticoid dose. Adjunctive treatments also aim to reduce the effect of glucocorticoid treatment.[11, 12, 13]

Drug treatment may be required in patients with exogenous hypercortisolism or endogenous Cushing syndrome in the following three situations:

1. Replacement therapy may be required in patients who have adrenal suppression following successful treatment of Cushing syndrome or after withdrawal of glucocorticoids that have been used for therapeutic purposes. In this situation, the aim of treatment is to prevent symptoms of acute or chronic adrenal insufficiency, while allowing recovery of the HPA axis. In either case, choose a medication with a short half-life to maximize the chance of recovery of the hypothalamic-pituitary-adrenal (HPA) axis. Hydrocortisone is the glucocorticoid of choice in this situation because of its short half-life. Following pituitary adenoma resection or unilateral adrenalectomy, mineralocorticoid replacement is not usually required.

2. Following bilateral adrenalectomy, no prospect of HPA axis recovery exists and the aim is to replace the absent glucocorticoid and mineralocorticoid hormones. Again, hydrocortisone is the treatment of choice in growing children because it has the mildest growth-suppressing effects. Intermediate-acting glucocorticoids are reasonable as second-line glucocorticoids but should be used with caution because of their potential to suppress growth. Fludrocortisone acetate is the only available mineralocorticoid in most countries. Fludrocortisone has some glucocorticoid activity.

3. Medication is also required when the patient has Cushing syndrome due to ectopic corticotropin (ACTH) and the primary source cannot be found or when surgery has not cured the hypercortisolism. In this situation, the aim of treatment is to suppress glucocorticoid production and, in the case of malignancy, to reduce tumor growth.

When possible, minimize the dose and duration of glucocorticoid treatment. Additionally, ensure that the patient uses the most appropriate method of delivery of glucocorticoid to the affected area. Avoid systemic or topical use of fluorinated steroids where possible. Preferably, choose a glucocorticoid with a short or intermediate half-life and, when disease activity permits, reduce dose to the minimum required to control the disease. In patients being treated with long-acting glucocorticoids, consider alternate daily dosing. If the primary disease activity does not permit dose reduction, then consider adding steroid-sparing agents (eg, cyclophosphamide in steroid-resistant nephrotic syndrome [NS], methotrexate and other immunosuppressive agents in juvenile rheumatoid arthritis [JRA], anti-tumor necrosis factor [TNF] and other agents in inflammatory bowel disease).

When long-term glucocorticoid treatment is required, take measures to ensure minimization of side effects, including ensuring adequate dietary calcium intake with supplementation if required and vitamin D supplementation in the form of a multivitamin tablet. Monitor urinary calcium excretion to ensure that patients do not become hypercalciuric because this predisposes them to kidney stones. Actively screen for potential complications to ensure that prompt treatment is instituted as needed.

In cases of documented osteoporosis (with low bone mineral density [BMD]) or when vertebral or other fractures occur, consider treatment with intravenous bisphosphonates.[14] Studies are in progress to determine the benefit of prophylactic bisphosphonates in children undergoing long-term treatment with glucocorticoids.

When possible, avoid other medications known to cause gastric irritation, including nonsteroidal anti-inflammatory agents and, possibly, oral bisphosphonates. When these drugs cannot be avoided, prophylactic treatment with histamine 2 (H2) antagonists or proton pump blockers is indicated.

Monitor children's growth every 3 months until age 5 years and every 6 months until growth ceases. At each visit, measure weight, height (or length in younger children), and blood pressure and perform fundoscopy for cataracts and examination for bony complications. Check bone age and bone density annually. For children receiving high-dose steroids, measure fasting and 2-hour postprandial blood glucose (particularly if a family history of type 2 diabetes mellitus is noted) and serum electrolytes.

Prevention of complications related to long-term glucocorticoid treatment requires constant attention to ensure that the drug being used is appropriate for the condition, that systemic absorption of glucocorticoid is minimized, that the duration of treatment is as short as possible, and that the dose is the lowest required to control disease activity.

Because glucocorticoids are immunosuppressive, take care to determine whether latent infections, such as mycobacterial disease, are present before treatment begins. Following is a summary of management issues for disorders that require treatment with high-dose glucocorticoids.

Respiratory disease

This includes asthma, cystic fibrosis (CF), other chronic lung diseases. Most patients with asthma do not require long-term inhaled steroid treatment. For those individuals who do require steroids, coadministration of long-acting beta-adrenergic agonists and use of spacer devices are two strategies that may reduce the dose required. Having the patient rinse out the mouth and oropharynx after inhaler use further reduces systemic absorption of inhaled steroids. Different inhaled steroids have varying degrees of systemic absorption. Fluticasone, for example, has more systemic effects than budesonide and beclomethasone or mometasone at therapeutic doses. Most patients experience adrenal suppression if inhaled steroid doses exceed the recommended range.

Inhaled and systemic steroids are also used in some patients with CF and other inflammatory diseases of the lung. Management issues are the same as for children with asthma, except that children with CF frequently have a high metabolic rate, a poor appetite, and chronic ill health that compound problems with growth and pubertal delay.

Intranasal glucocorticoid may also be used to treat patients with allergic rhinitis. These patients are frequently atopic, also having asthma and/or eczema, which further increases their potential steroid exposure.

Skin disorders

Severe eczema can be a debilitating condition that can be extensive, especially in infants with multiple food allergies. Steroid ointments are a major component of treatment, in association with moisturizing creams and occlusive dressings of the severely affected areas. Secondary infection is a common cause of disease exacerbation. Young children have a high body surface area–to–volume ratio and, hence, are at greater risk of significant steroid absorption. Factors that also increase the likelihood of systemic absorption and side effects include the following:

• Extent of affected skin and whether it is intact

• Preparation of the topical steroid: Absorption of ointments is greater than absorption of creams.

• Half-life of the topical steroid: Systemic effects associated with fluorinated steroids (eg, dexamethasone, triamcinolone acetonide, betamethasone, beclomethasone) are greater.

• Amount of local metabolism: Mometasone (Elocon) is reported to have fewer systemic effects because of increased local metabolism.

• Use of occlusive dressings: Occlusive dressings result in increased absorption.

Unfortunately, other than dietary manipulation and ensuring aggressive treatment of areas with secondary infection, few alternatives to topical steroids are available at present to treat this disease.

Take care to avoid prolonged use of potent steroids because they can cause significant localized damage, including depigmentation, thinning and atrophy of the skin, and the formation of telangiectasia.

Rheumatologic diseases

These include JRA, systemic lupus erythematosus (SLE), polymyositis, and dermatomyositis.

Systemic glucocorticoids have been used extensively in the management of patients with systemic-onset JRA and polyarticular disease. In the past decade, attempts have been made to reduce long-term systemic steroid treatment by using intra-articular injections and steroid-sparing agents, such as methotrexate and azathioprine. However, glucocorticoid treatment still has an important therapeutic role. With the development of more specific immunomodulators, this role may possibly decline in the future.

Renal disease

NS is the main renal disease that steroids are used for in pediatric practice. Minimal change disease is the most common cause of NS, followed by focal and segmental glomerulosclerosis and, less commonly, SLE. Some of this disease is short lived, with exacerbations and remissions that require 1-2 short courses of high-dose prednisolone. However, a proportion of cases are chronic and relapsing and some are steroid resistant. All patients who have multiple relapses or who are steroid dependent or resistant must be seen by a pediatric nephrologist. Steroid-sparing agents, such as cyclophosphamide, are increasingly used, although the steroid-sparing benefits of cytotoxic drugs must be weighed against their potential toxic effects in young children.

Neurologic disease

Steroids have been used for many years to treat seizures, as well as inflammatory and neoplastic diseases of the brain.

Hypercortisolemia leads to acute reductions in cerebral volume and reduced inflammation around an area of injury or infarct, features that are exploited in patients with raised intracranial pressure due to tumors and cerebral inflammation and in patients who have undergone spinal trauma. Chronic hypercortisolism leads to cerebral atrophy, as observed in patients undergoing MRI as part of the investigation of Cushing disease.

Short courses of high-dose steroids have no reported long-term side effects. Longer-term treatment with ACTH or glucocorticoids for hypsarrhythmia (eg, infantile spasms, West syndrome) may have adverse effects on the baby.

Vigabatrin appears to be more efficacious in this disorder, but it can cause significant retinopathy; therefore, it has fallen out of favor. With the advent of newer anticonvulsant agents, other options may become available.

Malignancy

Hematopoietic malignancy of the lymphoid system is usually very sensitive to glucocorticoids. High-dose prednisone is still in common use for treatment of acute lymphoblastic leukemia (ALL) and lymphoma. Modern multidrug regimens minimize the use of long-term high-dose steroids and thus have fewer steroid-related complications.

Immunosuppression

High-dose glucocorticoids are used for their antirejection properties in patients who have undergone organ and bone marrow transplantations. With modern multidrug immunosuppressive regimens, minimizing and, in some cases, avoiding glucocorticoid use is possible.

Overtreatment of patients with adrenal insufficiency

Patients with both congenital and acquired forms of adrenal cortical insufficiency require physiologic glucocorticoid replacement. Overtreatment is a common problem in patients who are treated by physicians unfamiliar with the aims of treatment. Examples include attempts to normalize ACTH levels in acquired adrenal insufficiency or 17-OH progesterone levels in congenital adrenal hyperplasia (CAH).

Use of glucocorticoids in utero and in the neonatal period

Numerous animal models have demonstrated the phenomenon of programming, where exposure to a substance in utero or in the neonatal period results in persistence of abnormal responses into adulthood. Animals exposed to high-dose steroids in the perinatal period are at increased risk of later developing hypertension, insulin resistance, and the spectrum of metabolic derangement known as syndrome X or dysmetabolic syndrome. Preliminary data suggest that humans react similarly. This finding may have significant implications for the antenatal treatment of fetuses that may be affected with CAH and also may have implications for the use of perinatal high-dose steroids for both prophylactic and therapeutic management of acute and chronic respiratory disease in premature infants. Clearly, this area requires further study, and physicians must carefully weigh the risks and benefits of pharmacologic therapy in this age group.

Treatment of Cushing syndrome

Wherever possible, treatment of patients with Cushing syndrome should focus on removal of the cause of the glucocorticoid excess, with blockade of cortisol production or adrenalectomy reserved for cases when the source of ACTH cannot be found or when the patient must be prepared for surgery.

Transfer

Age of transfer to adult care varies between institutions, ranging from 16-21 years. Patients who have had adrenalectomy require lifelong care by an endocrinologist. Patients who have achieved full height can switch to a longer-acting steroid, such as dexamethasone, which has the advantage of only one daily dose. Fludrocortisone dosing must also be continued.

Surgery is the first line of treatment for patients with endogenous Cushing syndrome.

Cushing disease (ACTH-secreting pituitary adenoma)

Transsphenoidal surgical excision remains the treatment of choice for Cushing disease, with a cure rate of 50-95% for the first exploration, depending on the experience of the surgeon, the size and position of the tumor, and the duration of follow-up care. Compared with the transcranial approach, transsphenoidal surgery has the advantage of lower morbidity from injury to the pituitary stalk, hypothalamus, the vessels of the circle of Willis, or the optic apparatus.

Exploration of the entire pituitary gland is sometimes necessary to localize a pituitary tumor. Intraoperative ultrasonography can be a useful adjunct in identifying tumors.

In cases when exploration of the gland fails to identify the adenoma and testing suggests Cushing disease, a hemi-hypophysectomy on the side of lateralization of bilateral inferior petrosal sinus sampling (BIPSS) is recommended (ACTH gradient >1.5). In 70-85% of cases, this approach has proven successful. If the first surgery is noncurative or if disease recurs, repeat exploration has only a 50% chance of cure, even with the most skilled physician.

If repeat surgery fails to correct hypercortisolism or if the tumor is unresectable because of invasion of the cavernous sinus or other vital structure, the next line of therapy is pituitary irradiation. Traditionally, this therapy has been delivered as 4500-5000 Gy in 30 fractions over a period of 6 weeks.

In association with mitotane (op'-DDD), a remission rate of about 80% can be expected in the first year. Remission can increase further in the second year, but the sustained remission rate after discontinuing mitotane therapy drops significantly to about 50-70%. Mitotane can be discontinued after 1 year if urinary free cortisol (UFC) has normalized; if hypercortisolemia recurs, it can be reinstituted. After 3 years, 80-90% of patients achieve biochemical remission of Cushing syndrome and no longer require mitotane because the effects of irradiation become established.

The major complications of conventional irradiation include hypopituitarism, which may be progressive and occur over 5-10 years, and impairment of vision, learning, and memory.

Radioactive cobalt-based gamma knife radiosurgery was first developed in the 1960s, but it has become a feasible treatment option in the last 10-15 years with the advent of appropriate computer control and MRI for accurate planning and treatment. It uses up to 60 sources of stereotactically focused beams of cobalt 60. The main advantage over conventional radiotherapy is that treatment is delivered in one single dose (ie, 25-30 Gy for secretory tumors, 20 Gy for nonfunctioning tumors), producing more rapid control of hypersecretion and fewer local effects than conventional radiotherapy. The greatest role of radioactive cobalt-based gamma knife radiosurgery appears to be in the treatment of residual tumor that cannot be safely removed surgically.

Linear acceleration (LINAC)–based radiosurgery, which was developed more recently, is rapidly becoming more readily available. This therapy may be as safe and effective as, or even safer and more effective than, gamma knife radiosurgery.

Bilateral adrenalectomy is now the last line of treatment for patients with proven Cushing disease. Reserve bilateral adrenalectomy for cases when radiotherapy and mitotane therapy do not cure the patient or when mitotane therapy is not tolerated. Bilateral adrenalectomy commits the patient to lifelong replacement therapy and carries a significant risk (10-30%) for subsequent development of Nelson syndrome.

Endoscopic pituitary surgery

The development of transsphenoidal endoscopic surgery may confer an additional benefit over conventional transsphenoidal surgery. This form of surgery has the potential to reduce the morbidity of this procedure, but studies published to date have limited long-term follow-up that includes endocrine data, so these results should be regarded as preliminary.

Treatment of adrenal causes of Cushing syndrome

Surgically resect all adrenal tumors in children and adolescents. Incidence of adrenal incidentaloma in this age group is negligible, while the risk of malignancy is considerable. The posterior approach, via unilateral or bilateral flank incisions respectively, has the advantage of better patient acceptability, with reduced operative morbidity, including ileus and intra-abdominal adhesions or accidental bowel perforation, which are risks of the transabdominal approach. Laparoscopic adrenalectomy has become increasingly popular because of its low morbidity and shortened postoperative recovery time.

Aggressive surgical resection offers the best chance of cure and long-term survival for patients with adrenocortical carcinomas.[15] Resectable lesions should be removed, even if the operation is not curative. Make an anterior transabdominal approach with careful examination of the liver, the great veins, and the pararenal structures. Mitotane may be added to maximally tolerated levels of toxicity when complete resection of the tumor is unsuccessful. With aggressive surgery, the average survival time of patients with adrenal carcinoma is 4 years.

Some neoplasia syndromes require special mention. In any child with an adrenocortical carcinoma, looking for germline mutations in the TP53 tumor suppressor gene is important if the child does not have Beckwith-Wiedemann syndrome or hemihypertrophy because this has important genetic implications for future tumors in the child, as well as posing a genetic risk to other family members (Li-Fraumeni syndrome).

In treating nonneoplastic causes of Cushing syndrome, micronodular and massive macronodular adrenal diseases are almost always multifocal and bilateral and require treatment with bilateral adrenalectomy. Massive macronodular disease due to aberrant ectopic receptors has not been described in children but is theoretically possible.

Treatment of Cushing syndrome due to ectopic ACTH secretion

Surgery is the primary mode of treatment for ectopic sources of ACTH secretion, once they have been identified. Carcinoid tumors are by far the most common tumors that produce the ectopic ACTH syndrome. These tumors arise most commonly from the lung, but they may also be found in the proximal GI tract. However, carcinoid tumors should not be considered benign; they may be extremely slow growing but have the potential for both local invasion and distant metastasis. Also consider other sources of ectopic ACTH, including neuroendocrine tumors of the pancreas, especially patients with multiple endocrine neoplasia type 1 (MEN1), pheochromocytoma (almost exclusively pheochromocytomas arising from the adrenal medulla), ganglioneuroma, and medullary thyroid carcinoma (especially patients with multiple endocrine neoplasia 2 [MEN2]).

Blockade of steroidogenesis is indicated for cases when initial investigation does not identify the origin of the ectopic ACTH. In this situation, the patient should undergo repeat surveillance at 6-month intervals to try to localize the source. Pharmacologic blockade is also indicated in cases where complete surgical excision of the tumor is not possible because of its position or the presence of metastases. In this situation, blockade can be combined with chemotherapy and/or radiation therapy.

Ketoconazole is the most useful agent for blockade of steroidogenesis. This agent produces blockade at several levels, the most important being blockade of the 20-22 desmolase enzyme, which catalyzes the conversion of cholesterol to pregnenolone, thus avoiding accumulation of steroid biosynthesis intermediates that can cause or worsen hypertension and/or hirsutism. Reversible side effects, including elevations of hepatic transaminases and gastrointestinal irritation, may occur and may be dose-limiting. In this case, metyrapone can be added to achieve eucortisolemia. Other blocking agents that may be used alone or in combination with ketoconazole and/or metyrapone include aminoglutethimide and trilostane.

Undertake repeat searches for the tumor every 6-12 months. If after 2 years the tumor has escaped detection, consider bilateral adrenalectomy. In case of toxicity from ketoconazole or other drugs or of interference with growth and pubertal progression, bilateral adrenalectomy may need to be performed earlier in children.

Pediatric endocrinologist

Because of the complexity of workup for patients with suspected endogenous Cushing syndrome, a pediatric endocrinologist should be involved in the assessment of all children with suspected Cushing syndrome.

Disease-specific subspecialist

Regular review by a subspecialist for the relevant disorder is needed for patients requiring long-term treatment with pharmacologic doses of glucocorticoids.

Pediatric neurosurgeon and endocrine surgeon

Consultation with a subspecialist surgeon is required once the underlying cause of the Cushing syndrome has been identified.

Pediatric oncologist

For a patient with a known or suspected malignancy, consult with a pediatric oncologist for advice about staging and the need for adjunctive treatment.

Radiation therapist

Consultation may be required if the patient has a tumor that is not controlled using surgical or medical treatment (eg, incompletely resected pituitary tumor, bony metastases of adrenal carcinoma).

Nephrologist

All patients with NS who have multiple relapses or are steroid dependent or resistant must be seen by a pediatric nephrologist.

Pulmonologist

All patients requiring long-term steroid treatment for asthma should be periodically evaluated by a pediatric pulmonologist in addition to their regular visits to a pediatrician.

Nutritionist

Supervision of a pediatric nutritionist is essential in children.

Patients receiving pharmacologic doses of glucocorticoid or who have current or previous Cushing syndrome require a high-protein, calorie-restricted diet that is rich in potassium, calcium, and vitamin D and is low in sodium.

If evidence of significant insulin resistance is present, carbohydrate intake may also need modification.

Patients with Cushing syndrome who remain active tend to gain less weight and develop less muscular atrophy or osteopenia. Encourage patients with high cortisol levels from any cause to remain active as much as their disease permits.

Advise patients with significant osteoporosis not to participate in high-impact sports that may put them at risk of fractures.

In patients with Cushing syndrome, the length of time before return to normal activities depends on the type of surgery. Patients who have undergone transsphenoidal surgery are advised to avoid bending and other activities that raise intracranial pressure for 6 weeks. After abdominal surgery, patients should avoid heavy lifting for about 6 weeks. In the case of laparoscopic adrenal surgery, patients can return to their normal activities in 1-2 weeks.

Pituitary adenoma

One of the most common surgical complications is invasion of the walls of the cavernous sinuses or other surgically inaccessible places, which may occur with failure of surgical cure.

Complications of transsphenoidal surgery include bleeding due to injury to the carotid arteries, paresis, fracture of the orbit with optic nerve entrapment, or trapping of orbital muscles. Hypopituitarism, infection, and damage to the optic nerves or their blood supply may also occur. Frequency of these complications depends on the extent of the tumor and the skill of the surgeon. Diabetes insipidus (DI) occurs transiently in approximately 25% of cases and is more common with repeat surgery and with tumors near the posterior lobe. In about 25% of cases, DI is permanent. Again, this tends to occur with large tumors and repeat surgeries.

Less frequently, transiently excessive secretion of vasopressin may occur (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]), which requires careful management of fluid intake. Nelson syndrome used to occur in 10-30% of patients with incurable pituitary adenoma treated with adrenalectomy. With advances in radiotherapy techniques and surgical techniques, this condition is likely to be avoided.

Surgical approach

Morbidity associated with adrenal surgery is reduced considerably if an anterior abdominal approach is avoided, unless carcinoma is suspected and staging of the liver and lymph nodes must be performed. Where possible, employ a laparoscopic approach. Risk of bleeding is always present and may require converting to open procedures in a percentage of cases.

Regular follow-up care is required for patients with Cushing syndrome (CS) who are receiving adrenal steroid replacement. Obtain a history of the number of illnesses, frequency with which stress doses are administered, and symptoms of adrenal insufficiency at 3-month assessments. Measure height (growth velocity should normalize unless another pathology is present), weight, and blood pressure and look for signs of overtreatment. Encourage patients to adhere to a diet that is rich in calcium (at least 1-1.5 g/d during teenage years) and vitamin D. Patients should also participate in regular exercise to improve muscle tone, to lose weight, and to strengthen bones.

Perform Cortrosyn stimulation testing at 6-month intervals to determine when HPA axis recovery occurs. Once a 30-minute cortisol exceeds 18 mcg/dL, hydrocortisone can be weaned and stopped.

Patients who have had bilateral adrenalectomy require similar follow-up care, with the exception of the Cortrosyn testing. Plasma renin activity (PRA) should be measured to ensure adequacy of fludrocortisone acetate Florinef) replacement. These patients may also require saline tablets in warm humid weather. If Florinef requirements appear excessive, glucocorticoid doses should be reviewed because high requirements may occur with inadequate glucocorticoid replacement.

Patients with ectopic corticotropin (ACTH) production should be seen every 3 months to ensure that they have no signs of toxicity from their ketoconazole (including checking liver function tests) or other steroid synthesis inhibitor. Patients should undergo reassessment at 6-month intervals to look for the origin of the tumor.

Management of exogenous hypercortisolism involves optimization of glucocorticoid dose and route. Glucocorticoid-sparing agents are used to minimize the glucocorticoid dose; adjunctive treatments aim to reduce the effect of glucocorticoid treatment. Other drugs that may be considered include bisphosphonates, in cases of osteoporosis or fractures; prophylactic treatment with H2 antagonists, when medications known to cause gastric irritation cannot be avoided; zoster immunoglobulin for immunosuppressed children who come into contact with varicella; inhaled steroid treatment; intranasal glucocorticoids; and steroid ointments.

In patients with endogenous Cushing syndrome, the same medications are used in inpatient and outpatient care, with the exception of etomidate, which is intravenously administered in very sick inpatients.

Class Summary

These agents are used for replacement or supplementation of endogenous glucocorticoid in situations of adrenal suppression or following bilateral adrenalectomy.

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

Water-soluble drug that can be administered PO (tab or susp) or IV. PO bioavailability approximately 50-60%. Usual dose 10-15 mg/m2/d split into 2-3 doses. Used parenterally in emergencies if PO medication not tolerated or not absorbed.

Dexamethasone (Decadron)

A synthetic fluorinated steroid that has a long life and therefore is not suitable for steroid replacement in children until growth is completed. Mainly used in investigation of patients with suspected Cushing syndrome, it is also used in high doses to suppress the inflammatory response in several conditions, including management of raised intracranial pressure.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Intermediate-acting glucocorticoids. See Table 1 for more details. Second line of treatment because of the potential for growth suppression. Detectable in urinary free cortisol assay.

Class Summary

Synthetically manufactured corticotropin-releasing hormone (CRH) is used to aid in the diagnostic workup of the patient suspected of having Cushing syndrome.

Corticotropin-releasing hormone (CRH)

CRH is a 41–amino acid peptide hormone derived from the hypothalamus that is also made in many parts of the nervous system. Stimulates the pituitary to release ACTH and is helpful to improve sensitivity and specificity of inferior petrosal sinus sampling, to distinguish pituitary from ectopic sources of ACTH, and following dexamethasone. Used to diagnose the presence of pseudo-Cushing disease.

Class Summary

These drugs are used for blockade of steroid hormone synthesis.

Ketoconazole (Nizoral)

First used as antifungal agent but also inhibits steroid synthesis. Steroid inhibition is exploited in the patient who is not cured by surgery and the patient in whom the primary source of ectopic ACTH cannot be found.

Class Summary

Mitotane is an antineoplastic agent that selectively inhibits the adrenal cortex. Use in control of cortisol production when the adrenal carcinoma is inoperable or removal is incomplete. In this situation, treatment may improve survival, but it is not curative.

Mitotane (Lysodren)

Decreases production of cortisol by causing adrenal atrophy and affecting mitochondria in adrenal cortical cells.

Class Summary

Etomidate is an ultrashort-acting nonbarbiturate hypnotic that blocks steroidogenesis. No published experience with etomidate in children exists. However, the drug may be the only available option for children with severe Cushing syndrome who cannot receive oral medication.

Etomidate (Amidate)

Effective in blocking steroidogenesis and can be administered IV diluted in isotonic sodium chloride solution as a continuous infusion.