The adrenal glands are small, yellowish organs that rest on the upper poles of the kidneys in the Gerota fascia. The right adrenal gland is pyramidal, whereas the left one is more crescentic, extending toward the hilum of the kidney. At age 1 year, each adrenal gland weighs approximately 1 g, and this increases with age to a final weight of 4-5 g. The arterial blood supply comes from 3 sources, with branches arising from the inferior phrenic artery, the renal artery, and the aorta. Venous drainage flows directly into the inferior vena cava on the right side and into the left renal vein on the left side. Lymphatics drain medially to the aortic nodes.
Each adrenal gland is composed of 2 distinct parts: the adrenal cortex and the adrenal medulla. The cortex is divided into 3 zones. From exterior to interior, these are the zona glomerulosa, the zona fasciculata, and the zona reticularis.
First detected at 6 weeks’ gestation, the adrenal cortex is derived from the mesoderm of the posterior abdominal wall. Steroid secretion from the fetal cortex begins shortly thereafter. Adult-type zona glomerulosa and fasciculata are detected in fetal life but make up only a small proportion of the gland, and the zona reticularis is not present at all. The fetal cortex predominates throughout fetal life. The adrenal medulla is of ectodermal origin, arising from neural crest cells that migrate to the medial aspect of the developing cortex.
The fetal adrenal gland is relatively large. At 4 months’ gestation, it is 4 times the size of the kidney; however, at birth, it is a third of the size of the kidney. This occurs because of the rapid regression of the fetal cortex at birth. It disappears almost completely by age 1 year; by age 4-5 years, the permanent adult-type adrenal cortex has fully developed.
Anatomic anomalies of the adrenal gland may occur. Because the development of the adrenals is closely associated with that of the kidneys, agenesis of an adrenal gland is usually associated with ipsilateral agenesis of the kidney, and fused adrenal glands (whereby the 2 glands join across the midline posterior to the aorta) are also associated with a fused kidney.
Adrenal hypoplasia occurs in the following 2 forms: (1) hypoplasia or absence of the fetal cortex with a poorly formed medulla and (2) disorganized fetal cortex and medulla with no permanent cortex present. Adrenal heterotopia describes a normal adrenal gland in an abnormal location, such as within the renal or hepatic capsules. Accessory adrenal tissue (adrenal rests), which is usually comprised only of cortex but seen combined with medulla in some cases, is most commonly located in the broad ligament or spermatic cord but can be found anywhere within the abdomen. Even intracranial adrenal rests have been reported.
The adrenal cortex secretes 3 types of hormones: (1) mineralocorticoids (the most important of which is aldosterone), which are secreted by the zona glomerulosa; (2) glucocorticoids (predominantly cortisol), which are secreted by the zona fasciculata and, to a lesser extent, the zona reticularis; and (3) adrenal androgen (mainly dehydroepiandrosterone [DHEA]), which is predominantly secreted by the zona reticularis, with small quantities released from the zona fasciculata.
All adrenocortical hormones are steroid compounds derived from cholesterol (see Media file 3).
Cortisol binds to proteins in the blood, mainly cortisol-binding globulin or transcortin. More than 90% of cortisol is transported in the blood in this bound form. In contrast, only 50% of aldosterone is bound to protein in the blood. All adrenocortical steroids are degraded in the liver and predominantly conjugated to glucuronides, with lesser amounts of sulfates formed. About 75% of these degradation products are excreted in the urine, and the rest is excreted in the stool by means of the bile.
Aldosterone accounts for 90% of mineralocorticoid activity, with some activity contributed by deoxycorticosterone, corticosterone, and cortisol. The normal concentration of aldosterone in the blood ranges from 2-16 ng/dL supine and 5-41 ng/dL upright, although the concentration exhibits diurnal variation, and the secretory rate is generally 150-250 mcg/d.
Aldosterone promotes sodium reabsorption and potassium excretion by the renal tubular epithelial cells of the collecting and distal tubules. As sodium is reabsorbed, water follows passively, leading to an increase in the extracellular fluid volume with little change in the plasma sodium concentration. Persistently elevated extracellular fluid volumes cause hypertension. This helps minimize further increases in extracellular fluid volume by causing a pressure diuresis in the kidney, a phenomenon known as aldosterone escape. Without aldosterone, the kidney loses excessive amounts of sodium and, consequently, water, leading to severe dehydration.
As sodium is actively reabsorbed, potassium is excreted. Imbalances in aldosterone thus lead to hypokalemia and muscle weakness if levels are increased and to hyperkalemia with cardiac toxicity if levels are decreased. In addition to sodium being exchanged for potassium at the renal tubules, hydrogen is also exchanged, although to a much lesser extent. Therefore, with aldosterone excess, mild metabolic alkalosis may develop.
In addition to the effects of aldosterone on the renal tubules, a smaller but similar effect is noted on the sweat glands and salivary glands. Aldosterone stimulates sodium chloride reabsorption and potassium secretion in the excretory ducts, which helps prevent excessive salivation and conserve body salt in hot climates. Aldosterone also affects sodium absorption in the intestine, especially the colon. Deficiency may cause a watery diarrhea from the unabsorbed sodium and water.
Many factors affect aldosterone secretion, the most important of which involve the renin-angiotensin system and changes in the plasma potassium concentration.
Activation of the renin-angiotensin system: The juxtaglomerular apparatus senses decreased blood flow to the kidney secondary to hypovolemia, hypotension, or renal artery stenosis and releases renin in response. Renin is an enzyme that activates angiotensinogen to release angiotensin I. In the lung, ACE converts angiotensin I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone release by the adrenal gland.
Concentration of potassium in the extracellular fluid: Increases in the plasma potassium concentration stimulate the release of aldosterone to encourage potassium excretion by the kidney.
Concentration of sodium in the extracellular fluid: Decreases in sodium concentration also stimulate aldosterone release.
Adrenocorticotropic hormone (ACTH) secretion: ACTH secreted by the anterior pituitary primarily affects release of glucocorticoids by the adrenal but, to a lesser extent, also stimulates aldosterone release.
Approximately 95% of glucocorticoid activity comes from cortisol, with corticosterone, a glucocorticoid less potent than cortisol, making up the rest. The normal cortisol concentration in the blood averages 12 mcg/dL, with a secretory rate averaging 15-20 mg/d. Cortisol release is almost entirely controlled by the secretion of ACTH by the anterior pituitary gland, which is controlled by corticotropin-releasing hormone (CRH) secreted by the hypothalamus. In normal situations, CRH, ACTH, and cortisol secretory rates demonstrate a circadian rhythm, with a zenith in the early morning and a nadir in the evening. Various stresses also stimulate increased ACTH and, thus, cortisol secretion. A negative feedback effect of cortisol on the anterior pituitary and the hypothalamus help control these increases and regulate plasma cortisol concentrations.
Cortisol has many effects on the body.
Cortisol stimulates gluconeogenesis in the liver by stimulating the involved enzymes and mobilizing necessary substrates, specifically amino acids from muscle and free fatty acids from adipose tissue. It simultaneously decreases glucose use by extrahepatic cells in the body. The overall result is an increase in serum glucose (ie, adrenal diabetes) and increased glycogen stores in the liver.
Cortisol decreases protein stores in the body, except in the liver, by inhibiting protein synthesis and stimulating catabolism of muscle protein.
Cortisol has clinically significant anti-inflammatory effects, blocking the early stages of inflammation by stabilizing lysosomal membranes, preventing excessive release of proteolytic enzymes, decreasing capillary permeability and, consequently, edema, and decreasing chemotaxis of leukocytes. In addition, it induces rapid resolution of inflammation that is already in progress.
Immunity is adversely affected. Eosinophil and lymphocyte counts in the blood decrease with atrophy of lymphoid tissue.
The adrenal cortex continually secretes several male sex hormones, including DHEA, DHEA sulfate (DHEAS), androstenedione, and 11-hydroxyandrostenedione, with small quantities of the female sex hormones progesterone and estrogen. Most of the effects result from extra-adrenal conversion of the androgens to testosterone. All have weak effects, but they likely play a role in early development of the male sex organs in childhood, and they have an important role in women during pubarche. ACTH has a definite stimulatory effect on androgen release by the adrenal. Therefore, secretion of these hormones parallels that of cortisol.
The adrenal medulla is a completely different entity. Epinephrine (80%) and norepinephrine (20%), with minimal amounts of dopamine, are secreted into the bloodstream due to direct stimulation by acetylcholine release from sympathetic nerves. Preganglionic sympathetic nerve fibers pass from the intermediolateral horn cells of the spinal cord through the sympathetic chains and splanchnic nerves, without synapsing, into the adrenal medulla. These hormones are responsible for an increase in cardiac output and vascular resistance and for all the physiologic characteristics of the stress response.
Radiology of the Adrenal Gland
CT scanning is the imaging procedure of choice for the evaluation of adrenal lesions, although ultrasonography and, increasingly, MRI have their advantages.
Plain radiography has limited value but may reveal mass effect or calcifications that suggest possible neuroblastoma, previous hemorrhage, or chronic granulomatous disease.
Ultrasonography is often the first imaging study performed in children. It is safe and easy to perform without sedation. It can differentiate cystic from solid adrenal masses and is useful to assess for vascular involvement and liver metastases.
CT scanning most accurately defines the size, location, and appearance of adrenal lesions. In addition, it is useful for assessing local and vascular invasion, involvement of lymph nodes, or distant metastases. For certain lesions (eg, simple cysts, myelolipomas, often hemorrhage), CT scanning enables definitive diagnosis because the image is classic. For solid lesions, unenhanced or delayed–contrast enhanced CT scanning may help in distinguishing benign from malignant lesions by their attenuation. Benign lesions tend to have decreased attenuation because of an increased fat content. However, overlap is substantial; therefore, this finding is not always useful.
MRI is also an excellent study to define the full extent of an adrenal lesion, including its relationship to adjacent organs and major vessels. Its main benefit over CT is its improved ability, with gadolinium enhancement or with chemical shift imaging, to help in differentiating benign from malignant lesions. This is most important in adults with an incidentally discovered adrenal mass.
Radioisotope scanning can be helpful in some situations. Iodocholesterol-labeled analogs (eg, iodine-131 6beta-iodomethyl-19-norcholesterol [NP-59]) are used to detect primary adrenocortical adenomas, carcinomas, or metastases. Dexamethasone administered before the scan enhances sensitivity by suppressing normal ACTH-responsive adrenal tissue. Metaiodobenzylguanidine (MIBG) scans may be used to detect adrenal medullary tumors, pheochromocytomas, and neuroblastomas. This is especially useful in localizing such tumors in extramedullary sites, enabling the entire body to be imaged at once.
More recently positron emission technology (PET) scanning has been introduced in the evaluation of recurrent or metastatic adrenal tumors, especially neuroblastoma. Its role has yet to be fully defined.
Adrenal pathology can manifest in various ways, including the following:
Ambiguous genitalia with or without salt wasting in the newborn
Palpable abdominal mass
Incidental finding of an adrenal mass on imaging
Glucocorticoid excess or Cushing syndrome
In the newborn period, ambiguous genitalia, with or without associated salt wasting, is strongly suggestive of congenital adrenal hyperplasia. This is an inherited autosomal recessive disorder caused by deficiency of 1 of the enzymes necessary for adrenal steroid production, especially cortisol. Cortisol deficiency leads to excessive secretion of adrenocorticotropic hormone (ACTH) with resultant bilateral adrenal hyperplasia; thus, a deficiency of the end products of blocked pathways and excess production of steroids in open pathways results.
The most common enzyme deficiency is 21-hydroxylase, which accounts for more than 90% of cases. This is seen in 2 forms: classic (more severe) and nonclassic (less severe).
The classic form, which occurs with an incidence of 1 case per 12,000-15,000 population, is characterized by cortisol deficiency and female virilization at birth secondary to excess adrenal androgen production, with salt wasting in 75% of cases secondary to aldosterone deficiency. This is the most common cause of ambiguous genitalia in a newborn girl. The diagnosis must be suspected early on and treatment instituted without delay because congenital adrenal hyperplasia can be life threatening in the newborn period.
The diagnosis is based on elevated baseline and ACTH-stimulated levels of serum 17-hydroxyprogesterone (17-OHP) and adrenal androgens, which are suppressed with the administration of glucocorticoids. When associated salt wasting occurs, the plasma renin-to-aldosterone ratio is also elevated.
Treatment involves replacement glucocorticoids aimed at decreasing ACTH secretion (maintenance hydrocortisone at 10-20 mg/m2/d orally [PO] divided 3 times per day [tid]), and, if salt wasting is prominent, a mineralocorticoid (9-alphafluorohydrocortisone, which is commonly known as fludrocortisone [Florinef], at 0.05-0.3 mg/d PO) and sodium chloride (1-3 g/d PO) are also used. Surgery for clitoral recession and vaginoplasty with correction of the urogenital sinus (usually present) may be performed in early infancy, if the degree of virilization in the newborn girl mandates it.
In the nonclassic (relatively mild) form, patients present late with precocious pubarche or problems related to androgen excess, including hirsutism, menstrual irregularities, and infertility. This is said to be the most common autosomal recessive disorder in humans.
The diagnosis is confirmed with elevated ACTH-stimulated levels of serum 17-OHP and adrenal androgens as in the classic form. Baseline levels are usually not as high because they are in the classic form and may even be normal.
Lowered doses of hydrocortisone can be administered as treatment, although some patients never require any therapy. See Congenital Adrenal Hyperplasia for more information.
Palpable Abdominal Mass
A palpable abdominal mass has a large differential diagnosis; adrenal lesions are included.
Neuroblastoma is a malignant tumor derived from neural crest cells in the adrenal medulla or anywhere along the sympathetic chain. About 75% of neuroblastomas arise from within the abdomen or pelvis, with half of these from the adrenal medulla itself, 20% originating from the posterior mediastinum, and 5% coming from the neck. With an overall incidence of 1 case per 10,000 population, it is the most common solid extracranial tumor of childhood. It can manifest in numerous ways, but the most common presentation is as a fixed abdominal mass extending from the flank towards the midline. See Neuroblastoma for more information. Ganglioneuroma, the benign counterpart of neuroblastoma, can also appear as a large palpable abdominal mass.
Another adrenal medullary tumor of neuroendocrine origin that can also be found in extra-adrenal sites is pheochromocytoma. This usually manifests with symptoms attributable to the excess catecholamine secretion by the tumor. In rare cases, an abdominal mass may be noted first.
Adrenal cortical tumors, and especially carcinomas because these tend to be larger than adenomas, can present with a palpable abdominal mass. However, signs and symptoms of excess adrenocortical hormone secretion usually prompt a workup and diagnosis of such tumors. Adrenal cysts are rare in childhood but can be large enough to produce a palpable mass.
Incidental Finding of Adrenal Mass
An adrenal lesion may be incidentally detected during abdominal ultrasonography or CT scanning performed for other reasons. The differential diagnosis of an adrenal mass is extensive.
The differential diagnosis of an adrenal mass is as follows:
Chronic granulomatous disease (eg, tuberculosis [TB], histoplasmosis)
Metastases (eg, malignant melanoma, breast carcinoma, hepatocellular carcinoma, squamous cell lung carcinoma)
The differential diagnosis of bilateral adrenal enlargement or mass is as follows:
Adrenal nodular hyperplasia
Ectopic ACTH or corticotropin-releasing hormone (CRH) production
In adults, most incidentally discovered adrenal solid masses are adenomas; therefore, such tumors less than 4-5 cm in size, of benign appearance on imaging, and with no extra-adrenal disease are simply observed. In children, the most common adrenal mass is neuroblastoma. In a study of 26 children with an incidentally detected adrenal mass, 30% were found to be malignant; upon review of the imaging, neither size nor appearance could distinguish between benign and malignant.1 Thus, all pediatric adrenal masses found incidentally should be resected.
Glucocorticoid Excess or Cushing Syndrome
The clinical findings associated with excess cortisol secretion in children most commonly include obesity with moonlike facies, growth failure, hirsutism, and acne. Other findings include hypertension, muscle weakness, osteoporosis, glucose intolerance, easy bruising, striae, hyperpigmentation and thin skin, menstrual irregularities, and psychiatric disturbances. Patients with cortisol excess also have impaired wound healing and an increased susceptibility to infection.
The differential diagnosis of Cushing syndrome is as follows:
Use of exogenous steroids
Adrenal nodular hyperplasia
Pituitary adenoma (Cushing disease)
Ectopic ACTH or CRH production from tumors (eg, medullary thyroid cancer, carcinoid tumor, thymoma, Wilms tumor, adrenal rest tumor, pancreatic tumor)
In children younger than 10 years, unlike in older children and adults, primary adrenal pathology (eg, adenoma, adrenal nodular hyperplasia) is the most common cause of Cushing syndrome after use of exogenous corticosteroids and instead of a pituitary adenoma.
In a patient with suspected Cushing syndrome, the first step is to confirm hypercortisolemia (see Media file 1). The best screening test is measurement of free cortisol or 17-hydroxycorticosteroid (17-OHCS) levels in 2-3 consecutive 24-hour urine collections. Normal 24-hour urinary free cortisol values are in the range of 25-75 mcg/m2/d. Plasma levels of cortisol can also be obtained. However, because of the normal diurnal variation, this test is less reliable than urine measurement. The low-dose or overnight dexamethasone suppression test should be used as a confirmatory test when 24-hour urinary levels of 17-OHCS or cortisol are borderline. This involves PO administration of dexamethasone (30 mcg/kg) at 11 pm, with measurement of plasma cortisol at 8 am the next morning. Plasma cortisol levels are normally suppressed to less than 5 mcg/dL. In Cushing syndrome, cortisol secretion is not suppressed.
The next step is to distinguish between ACTH-dependent and ACTH-independent causes, which involve plasma ACTH level measurement. ACTH levels are normally 10-100 pg/mL, with a diurnal variation that parallels that of cortisol but precedes it by 1-2 hours. However, plasma ACTH is low (<5 pg/mL) in patients with adrenocortical neoplasms, intermediate (15-500 pg/mL) in patients with pituitary adenomas and resultant adrenocortical hyperplasia, and highest (usually >1000 pg/mL) in patients with ectopic ACTH-producing tumors.
To further distinguish between the causes of ACTH-dependent Cushing syndrome, the high-dose dexamethasone suppression test is used. It is based on the principle that a high dose of dexamethasone at least partially suppresses adrenal cortisol secretion secondary to an ACTH-secreting pituitary adenoma, whereas secretion secondary to adrenal tumors and ectopic ACTH production is not. Dexamethasone (120 mcg/kg/d given PO divided 4 times a day [qid]) is given for 48 hours. On the second day, a 24-hour urine collection is obtained to measure free cortisol and 17-OHCS levels. In patients with a pituitary adenoma, urinary free cortisol levels are suppressed by 90% to less than 30 mcg/d in 60-70% of patients, and urinary 17-OHCS levels are reduced to less than 3 mg/d.
Another test that can be used to distinguish between Cushing disease and ectopic ACTH production is the metyrapone stimulation test. Because metyrapone blocks the enzyme 11-hydroxylase, which is responsible for conversion of 11-deoxycortisol to cortisol, its administration at 15 mg/kg (or 750 mg for adolescents) PO every 4 hours for 24 hours decreases plasma cortisol and increases ACTH values. The normal response is an increase in plasma 11-deoxycortisol levels to more than 10 mcg/dL and an increase in 24-hour urine 17-OHCS levels to twice the baseline. Patients with pituitary adenomas show this response, whereas those with ectopic ACTH secretion do not. The CRH stimulation test, whereby 1 mcg/kg of CRH is administered and ACTH levels are measured, is also performed to distinguish Cushing disease in most cases. Within 60-180 minutes, patients with Cushing disease had the normal increase in ACTH, and those with other causes of hypercortisolemia do not.
After these distinctions are made, imaging can be used to localize these lesions. Gadolinium-enhanced MRI of the sella turcica is the best imaging modality for assessing pituitary adenomas, with a sensitivity approaching 100%. Sampling of the bilateral inferior petrosal sinuses for ACTH can help identify a pituitary adenoma if imaging does not. Thin-section high-resolution CT scanning or MRI of the adrenals identifies adrenal abnormalities with more than 95% sensitivity. CT or MRI of the chest and abdomen may help in identifying an ectopic ACTH-producing or CRH-producing tumor.
Surgical resection of the offending lesion is the initial treatment of choice for all forms of Cushing syndrome, including bilateral adrenalectomy for bilateral nodular adrenal hyperplasia, transsphenoidal partial hypophysectomy for pituitary adenomas, and unilateral adrenalectomy for adrenal tumors.
Presenting features of mineralocorticoid excess include hypertension, headache, tachycardia, fatigue, proximal muscle weakness, polyuria, and polydipsia.
The differential diagnosis of hyperaldosteronism is as follows:
Idiopathic adrenal nodular hyperplasia (idiopathic hyperaldosteronism)
Secondary – Elevated renin secretion secondary to renal artery stenosis, a renin-producing tumor, congestive heart failure, and Bartter syndrome (ie, juxtaglomerular hyperplasia)
Primary hyperaldosteronism, characterized by elevated plasma aldosterone, low plasma renin levels, hypokalemia, and hypertension, is rare in children. Unlike in adults, the most common cause is bilateral adrenal hyperplasia, with only a handful of aldosterone-secreting adenomas (ie, Conn syndrome) reported.2 Because adenomas are a curable cause of hypertension, they must be considered in children presenting with hypertension, despite their rarity.
Bilateral adrenal hyperplasia as a cause of hyperaldosteronism occurs in nodular adrenal hyperplasia and in a unique autosomal dominant condition called glucocorticoid-suppressible hyperaldosteronism. This has all of the clinical and biochemical features noted in other causes of primary hyperaldosteronism but demonstrates complete and rapid suppression of aldosterone secretion by administration of dexamethasone.
Adrenocortical carcinoma as a cause of primary hyperaldosteronism is exceptionally rare, with an incidence of 1% in a large series of adults and no reported cases in children.
The first step in the workup of a patient with suspected hyperaldosteronism is to confirm the diagnosis (see Media file 2). Elevated plasma aldosterone levels, hypokalemia (<3.5 mEq/L), and kaliuresis (>30 mEq/d) confirm the diagnosis. A suppressed plasma renin level is compatible with a primary cause. In addition, patients with primary hyperaldosteronism exposed to salt-loading by ingestion of a high-sodium diet for 3-5 days (or by infusion of isotonic sodium chloride solution in a patient who is salt deprived) fail to show suppression of plasma or 24-hour urinary aldosterone. Upright posture and salt depletion also fail to cause a rise in plasma renin activity.
The next step is to distinguish among the various causes of primary hyperaldosteronism. Response to administration of dexamethasone rapidly confirms the diagnosis of glucocorticoid-suppressible hyperaldosteronism. The postural test is most helpful in distinguishing between nodular hyperplasia and adrenal neoplasm. This test is based on the observation that aldosteronomas are sensitive to ACTH and, therefore, exhibit a diurnal variation in aldosterone secretion, whereas adrenal nodular hyperplasia does not.
The patient is kept supine overnight. At 8 am, baseline plasma levels of cortisol, aldosterone, renin, and potassium are measured. The patient stands up and remains upright for 4 hours, at which point all laboratory studies are repeated. An aldosterone-secreting tumor typically results in a drop in aldosterone levels, paralleling the change of cortisol in its natural daytime fall, which the change in posture does not affect. In patients with adrenal hyperplasia, aldosterone responds to the postural change, increasing by more than 33%. Before any of these tests are performed, patients should be potassium replete and not taking any antihypertensive medications for at least 4 weeks.
If an aldosterone-secreting tumor is suspected, imaging is obtained. High-resolution CT scanning can be done to localize approximately 90% of such tumors. Because the lesions are often small, NP-59 scanning can be useful if CT fails to depict the tumor; sensitivity is 70-80% and specificity is 100% in this situation.
As an alternative, selective adrenal venous sampling can be used to definitively identify a tumor. However, it is invasive and technically difficult and, therefore, is used only rarely. Intravenous (IV) ACTH is administered, and adrenal venous blood samples are simultaneously obtained to measure aldosterone and cortisol. An aldosterone-to-cortisol ratio higher than 4:1 is diagnostic of an aldosteronoma and is unilateral as opposed to bilateral.
Aldosterone-secreting tumors are treated by surgical resection. Glucocorticoid-suppressible hyperaldosteronism is treated with glucocorticoids. Bilateral adrenal nodular hyperplasia is treated medically with potassium-sparing diuretics, such as spironolactone or amiloride. Surgery is reserved for cases refractory to medical therapy because less than 20-30% of patients with this disease are cured with adrenalectomy.
The predominant clinical feature of hyperandrogenism in the newborn girl is ambiguous genitalia.3 In the older child or adolescent, signs and symptoms include pseudoprecocious puberty in boys and hirsutism, acne, clitoromegaly, deepening of voice, and oligomenorrhea in girls. In both sexes, linear growth and skeletal maturation (ie, bone age) are accelerated.
The differential diagnosis of hyperandrogenism is as follows:
Use of exogenous anabolic steroids
Congenital adrenal hyperplasia4
Ovarian tumors- most commonly arrhenoblastoma
Testicular tumors- most commonly Leydig cell tumors
Adrenal hyperplasia secondary to a pituitary adenoma or ectopic secretion of ACTH or CRH
In infants with failure to thrive, salt wasting and (most obviously in baby girls with clitoromegaly, fused labia, and a persistent urogenital sinus) congenital adrenal hyperplasia must be ruled out. The same is true in boys who present with pseudoprecocious puberty and in older girls with signs and symptoms of hyperandrogenism, although, in teenage girls, polycystic ovary is the most common cause.
Congenital adrenal hyperplasia can be reliably diagnosed with a dexamethasone suppression test. Apart from a few rare causes of hyperandrogenism including exaggerated adrenarche secondary to adrenal hyperresponsiveness to ACTH, hyperprolactinemia, and acromegaly, congenital adrenal hyperplasia is the only virilizing condition in which androgen secretion is suppressed by dexamethasone. ACTH levels can be used to confirm the diagnosis if it is still questionable. An increase in plasma 17-OHP to more than 1200 ng/dL at 60 minutes in response to an IV injection of 250 mcg of cosyntropin is diagnostic of congenital adrenal hyperplasia.
Adrenocortical tumors must always be considered in the differential diagnosis. They are reported to occur from infancy throughout adolescence and well into adulthood. The vast majority of these tumors are virilizing, with 50-80% causing virilization alone and an added 20-40% causing Cushing syndrome in addition to virilization. Rare adrenocortical tumors are predominantly mineralocorticoid secreting or feminizing.
As a group, these tumors are rare, with a childhood incidence of 0.3 per million. Certain children are at increased risk, including those with a family history of p53 mutations, those with Beckwith-Wiedemann syndrome, and those with isolated hemihypertrophy. Distinguishing between benign and malignant adrenocortical lesions is difficult, even pathologically, and the clinical behavior of the tumor is the best determinant of malignancy. Most common sites of metastases are lung and liver, with regional lymph nodes, bone, brain, and pancreatic metastases observed relatively infrequently.
Radical resection, including en bloc resection of locally invaded organs, offers the best chance for cure of adrenocortical tumors. Metastases should also be resected if possible. No survivors after partial resection of tumor have been reported. Adjuvant therapy has shown disappointing results. Mitotane is the most extensively used agent. Although it has not been shown to prolong survival, it can substantially ameliorate the symptoms of hyperandrogenism. It can, however, have significant GI and neurologic side effects. Other, more conventional chemotherapeutic drugs have shown poor results thus far, and radiotherapy has not been proven effective. Pediatric series reveal overall survival rates for adrenocortical tumors of 43-91%. (See Adrenal Carcinoma for more information.)
Distinguishing between ovarian and adrenal virilizing disorders in young girls depends on physical examination, biochemical test, and imaging study findings. Virilizing ovarian tumors are often large, and most are palpable on physical examination. Serum testosterone levels are virtually always elevated. In virilizing adrenocortical tumors, plasma levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione are high, whereas those of testosterone (mainly due to peripheral conversion of androstenedione to testosterone) are elevated much less often and to a lesser extent. Adrenal tumors also result in elevated urinary and plasma 17-ketosteroid levels that are normal or only minimally elevated in ovarian tumors.
In boys, a testicular examination can help determine the source of androgen excess. If both testes are enlarged, they are the most likely source of the androgens in response to gonadotropins (luteinizing hormone [LH], representing central precocious puberty) or a human chorionic gonadotropin (hCG)-secreting tumor. If both testes are prepubertal in size, the most likely source of the androgens is adrenal. Finally, if one testis is enlarged, the likely source is a testicular tumor.
The clinical manifestations of catecholamine excess include hypertension (either sustained or paroxysmal) orthostatic hypotension, tachycardia or bradycardia, arrhythmias, headache, fatigue, visual blurring, sweating and heat intolerance, weight loss, abdominal pain, and polyuria and polydipsia. These symptoms should prompt biochemical testing to confirm excess catecholamine secretion characteristic of pheochromocytoma.
Measurement of urinary catecholamines, epinephrine and norepinephrine, and their metabolites (ie, metanephrine, homovanillic acid, and vanillylmandelic acid) in a 24-hour urine collection is a sensitive (>90%) test for the diagnosis of pheochromocytoma. Plasma catecholamine levels can also be diagnostic when performed at rest. Levels of more than 2000 pg/mL are diagnostic of a pheochromocytoma. However, the diagnosis can be missed in patients with paroxysmal symptoms.
Various stimulation and suppression tests have been developed to improve diagnostic accuracy. The clonidine suppression test relies on the fact that clonidine suppresses centrally mediated release of catecholamines (to <500 pg/mL) within 2-3 hours of PO administration but does not affect release of catecholamines from a pheochromocytoma. The stimulation tests are dangerous and should only be performed in a monitored setting in situations in which the blood pressure and plasma catecholamine levels are near normal. The glucagon stimulation test demonstrates a more than 3-fold increase in catecholamines or an absolute plasma level of more than 2000 pg/mL after an IV bolus of glucagon in the presence of a pheochromocytoma. Neuroblastoma is also characterized and diagnosed by demonstrating increased catecholamine secretion. However, patients are typically asymptomatic.
Pheochromocytomas are rare tumors that arise from the neural crest–derived chromaffin cells found in the adrenal medulla and sympathetic ganglia. Compared with pheochromocytomas in adults, in children incidences of extra-adrenal tumors (30% vs 10%) and bilateral tumors (30% vs 10%) increase, as does the tendency for a familial occurrence, and the incidence of malignancy is lowered (3.5% vs 10%). Also, pheochromocytomas in children secrete norepinephrine more commonly than they secrete epinephrine; this change may simply reflect the heightened incidence of extra-adrenal tumors. The most common extra-adrenal site is the upper periaortic ganglia, followed by the organs of Zuckerkandl at the base of the inferior mesenteric artery. Other sites include the base of the brain, the chest, and bladder.
Patients at increased risk for pheochromocytomas include those with multiple endocrine neoplasia type II (MEN II) syndrome and neurocutaneous syndromes (eg, Von Recklinghausen disease, tuberous sclerosis, von Hippel–Lindau disease, Sturge-Weber syndrome). In children with a pheochromocytoma, headache is the most common symptom (75%), followed by sweating, nausea, and vomiting. Other frequent symptoms include visual complaints, weight loss, and polyuria and polydipsia.
Hypertension is seen in almost all patients and is sustained in 80-90%, unlike in adults who tend to have paroxysmal hypertension. The hypertension is also more severe in children than in adults, with more than 40% of affected individuals having signs of hypertensive retinopathy, and 40% having signs of cardiomyopathy.
Localization of pheochromocytomas is best accomplished with CT scanning or, particularly, MRI. CT scanning has 94% sensitivity for detection of adrenal tumors and 64% sensitivity for extra-adrenal tumors, with 98% specificity. MRI has 97% sensitivity for detection of adrenal tumors and 88% sensitivity for extra-adrenal tumors, with 100% specificity. Metaiodobenzylguanidine (MIBG) scanning is also highly specific for pheochromocytoma but is less sensitive than MRI. It is most useful to help localize an extra-adrenal pheochromocytoma, which can then be imaged in most detail with CT scanning or MRI.
After the diagnosis is confirmed and the tumor localized, preparations for surgical resection must be started. Patients should be treated with an alpha-adrenergic blocker, such as phenoxybenzamine, with the dose gradually increased to achieve blood pressure and symptom control (0.25-1 mg/kg/d PO in divided doses). Once alpha blockade is accomplished, a beta-adrenergic blocker (eg, propranolol) can be used if arrhythmias occur. Such treatment is begun preferably at least 3 weeks before planned surgery. During surgery, the anesthetist must be prepared for hypertensive episodes, which can be controlled with an agent such as nitroprusside, and for hypotension after the tumor is removed, which responds well to fluids.
The surgical approach of choice is transabdominal. This allows the exploration of both adrenal glands and the sympathetic chain, early ligation of the adrenal vein to prevent excessive catecholamine release with tumor manipulation, and resection of locally invaded organs if necessary. Despite this, extraperitoneal approaches have been used for small tumors. Also, increasingly, a laparoscopic approach is used in adults and children. An attempt should be made to resect the primary tumor in all cases, with resection of metastases if possible, because most of the morbidity and mortality associated with these tumors are the result of the excess catecholamine secretion.
Intensive chemotherapy, principally in the form of cisplatin and doxorubicin, can render some unresectable tumors resectable and should be tried in such cases. Adjuvant chemotherapy is also indicated for residual disease postsurgery and for metastatic disease. It has a response rate of approximately 50% and provides good palliation in a substantial number of patients for years. Radioactive MIBG treatment has also been used and has been shown to provide good palliation in metastatic disease.
As with adrenocortical tumors, the distinction between benign and malignant lesions is not obvious, even pathologically, and only the clinical course of the tumor can define malignancy (either local infiltration or metastases). The most common sites of metastases are the lungs, liver, lymph nodes, and bone. The long-term survival rate of patients with malignant pheochromocytoma is more than 50%.5 Long-term follow-up is essential to detect metastases and metachronous lesions, especially in patients with a familial syndrome. Such lesions have been reported to occur more than 10 years after resection of the initial tumor. Therefore, annual blood pressure and catecholamine measurements should be considered.
Some believe that patients with a familial syndrome should undergo bilateral adrenalectomy at the first operation because the risk of a metachronous tumor is approximately 50%. An important additional issue in children is screening. Children with a familial syndrome and a molecular genetic test that reveals a ret proto-oncogene mutation characteristic of MEN II should undergo annual screening for pheochromocytoma, starting at a young age.
This subject is covered extensively in Adrenal Insufficiency. In brief, adrenal insufficiency may be acute or chronic. Chronic adrenal insufficiency may be primary, secondary, or tertiary. Acute adrenal insufficiency results when an acute stress is superimposed on chronic adrenal insufficiency of any type.
Symptoms of chronic adrenal insufficiency may be explained by the lack of adrenal hormones and by the unopposed secretion of ACTH. Hypotension, fatigue, weight loss, anorexia, nausea, vomiting, abdominal pain, salt craving, hypoglycemia, and syncope can occur. Skin and mucous membrane hyperpigmentation result from unopposed secretion of ACTH and melanocyte-stimulating hormone. Hyponatremia, along with hyperkalemia, is sometimes observed and can be explained by the chronic insufficiency of aldosterone. The diagnosis should not be based on the presence or absence of these abnormalities. The loss of secondary sex characteristics is seen only in women with the disease.
Acute adrenal insufficiency is a medical emergency and must be identified and promptly treated. The hallmarks of acute adrenal insufficiency are circulatory collapse with abdominal pain that can simulate an acute abdomen. Profound hypoglycemia, elevated core temperature, and potentially cardiac dysrhythmias are also observed.
Chronic primary adrenal insufficiency results when the adrenal glands themselves are destroyed or infiltrated. Causes include congenital adrenal hyperplasia, bilateral hemorrhage (eg, as in the Waterhouse-Friderichsen syndrome), infection with TB, human immunodeficiency virus (HIV) infection, histoplasmosis, and infiltrative diseases (eg, sarcoidosis). Autoimmune destruction of the adrenal glands is referred to as Addison disease.
Secondary adrenal insufficiency results from diminished release of ACTH from the pituitary. Causes include trauma, pituitary tumors, and pituitary hemorrhage (Sheehan syndrome).
Tertiary adrenal insufficiency results from suppression of the hypothalamic-pituitary-adrenal axis. This is observed with the long-term administration of exogenous steroids. An important distinguishing feature of tertiary adrenal insufficiency is that adrenal medullary and androgen-secreting functions are preserved.
Treatment of chronic adrenal insufficiency is based on the replacement of missing adrenal hormones (hydrocortisone at 15-20 mg/m2/d PO divided tid; fludrocortisone at 0.05-0.1 mg/d). Stress doses of glucocorticoids must be given when any physiologic stress is encountered.
Treatment of acute adrenal insufficiency is life saving and often must be empirically started whenever the entity is suspected. Aggressive fluid resuscitation is the rule and support of the cardiovascular system with the use of exogenous catecholamines may be required in severe cases. Hypoglycemia requires early and often continuous administration of IV dextrose. Hydrocortisone is given as an IV bolus of 50-100 mg/m2 (approximately 50 mg for small children and 100-150 mg for large children and adolescents). Subsequent doses are administered as a continuous IV infusion with 100 mg/m2/d added to the IV fluid infusion or further IV boluses q4-6h until the patient can tolerate PO corticosteroids. Mineralocorticoid replacement is unnecessary in the acute management. Hyperkalemia should be controlled, if present.
Approximately 2% of children with neuroblastoma present with opsoclonus-myoclonus. The cause of this manifestation is unclear.
Prenatal Diagnosis of a Suprarenal Mass
With improvements in prenatal ultrasonography, an increasing number of abnormalities are being prenatally detected, including masses in the suprarenal region. These may be cystic, solid or mixed. The differential diagnosis of a suprarenal mass includes:
Adrenal or renal cortical cysts
Distinguishing between these diagnoses on prenatal imaging alone is difficult and even on postnatal imaging. Adrenal hemorrhage and neuroblastoma are the most common. Unlike neuroblastoma diagnosed later in childhood, neonatal neuroblastoma is usually associated with favorable histology with no N-myc amplification, portending a very good prognosis. It can also spontaneously regress. An adrenocortical tumor is reportable in the newborn. The remaining diagnoses are not urgent. Therefore, babies born with prenatally detected suprarenal masses should undergo postnatal ultrasonography, metaiodobenzylguanidine (MIBG) scanning, and measurement of urinary catecholamine levels, although the latter may be normal even with a diagnosis of neuroblastoma. Small lesions, especially cystic ones that are known to regress more often, should be followed closely.
Monthly follow-up with physical examination and ultrasonography should ensue, with surgery reserved for masses that increase in size or persist. This helps avoid unnecessary surgery for adrenal hemorrhages and spontaneously regressing neuroblastomas. Of course, large masses or any mass that is concerning to family or physician may undergo earlier surgery for definitive diagnosis.
Surgical Approaches to the Adrenal Gland
The 2 main surgical approaches to the adrenal gland are transperitoneal and retroperitoneal, both of which can be used with an open or laparoscopic technique. Advantages of laparoscopic adrenalectomy are early mobilization and oral intake, shortened hospitalization, decreased requirement for narcotics, and similar surgical complication rates. With increasing experience in pediatric laparoscopic adrenalectomy, operative times are comparable with an open approach and the indications are expanding. In the past, larger tumors or suspicion of malignancy were considered contraindications to a laparoscopic approach; currently, absolute size is less important than tumor size in relation to patient size, and successful laparoscopic adrenalectomies for pheochromocytomas, neuroblastomas, and adrenocortical tumors have been reported.
The retroperitoneal laparoscopic approach, compared with a transperitoneal laparoscopic one, is associated with reduced respiratory and hemodynamic effects caused by the pneumoperitoneum and avoids the need to mobilize the abdominal organs to access the adrenal gland. When bilateral adrenal exploration is preferable (eg, for a pheochromocytoma), a transperitoneal approach is preferred. Otherwise, a unilateral lesion can easily be accessed from a retroperitoneal approach with decreased pain and postoperative ileus and with no intraperitoneal adhesion formation. In children, most laparoscopic adrenalectomies have been performed through the transperitoneal route.
The main advantages of a transperitoneal approach include access to the entire abdomen to search for synchronous lesions and metastases and the ability to rapidly identify and resect locally invaded organs en bloc with the primary tumor. In children, an open approach is still most often used mainly because most adrenal tumors in this age group are neuroblastomas that usually present as very large infiltrating lesions.