Cushing's syndrome differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Overview

Cushing's syndrome must be differentiated from other diseases that cause hypertension, obesity, and hyperandrogenism, such as Metabolic syndrome X and pseudo-Cushing's syndrome.

Differentiating Cushing's Syndrome From Other Diseases

Differentials based on hypertension, hyperandrogenism and obesity

The table below summarizes the findings that differentiate Cushing's disease from other conditions that may cause hypertension, hyperandrogenism, and obesity. Facial plethora, skin changes, osteoporosis, nephrolithiasis and neuropsychiatric conditions should raise the concern for Cushing's syndrome.[1][2][3][4]

Conditions Causes Associated features Diagnostic approach
Cushing's syndrome
Pseudo-Cushing's syndrome
Metabolic syndrome X

Differentials based on virilization and hirsutism

Cushing's syndrome must be differentiated from diseases that cause virilization and hirsutism in female:[5][6][7]

Disease name Steroid status Other laboratory Important clinical findings
Cushing's syndrome
Non-classic type of 21-hydroxylase deficiency Increased:
  • No symptoms in infancy and male
11-β hydroxylase deficiency Increased:

Decreased:

3 beta-hydroxysteroid dehydrogenase deficiency Increased:

Decreased:

Polycystic ovary syndrome
Adrenal tumors
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Ovarian virilizing tumor
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Hyperprolactinemia

Differentials based on galactorrhea, amenorrhea and infertility

Cushing's syndrome should also be differentiated from other causes of hyperprolactinemia that may present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females) including:

Disease Clinical Findings Laboratory findings Management
Somatotroph adenoma:

Acromegaly

Clinical features of acromegaly are due to high level of human growth hormone (hGH):
Corticotroph adenoma: Cushing's syndrome Clinical features of Cushing's syndrome are due to increased levels of cortisol:
Hypothyroidism Clinical features of hypothyroidism are due to deficiency of thyroxine:
  • Fullness in the throat and neck
Levothyroxine
Chronic renal failure There are no pathognomonic symptoms associated with chronic renal failure. Common non-specific symptoms of chronic renal failure include: Urinalysis:

Fluid and electrolyte disturbances:

Endocrine and metabolic disturbances:

Hematologic abnormalities:

Liver disease: Cirrhosis The clinical features of liver cirrhosis are very nonspecific. These include:
Seizure disorder The clinical features of seizure disorder may include:
  • Change in alertness, orientation and time perception
  • Mood changes, such as unexplainable fear, panic, joy, or laughter
  • Changes in sensation of the skin, usually spreading over the arm, leg, or trunk
  • Vision changes, including seeing flashing lights
  • Rarely, hallucinations (seeing things that aren't there)
  • Falling, loss of muscle control, occurs very suddenly
  • Muscle twitching that may spread up or down an arm or leg
  • Muscle tension or tightening that causes twisting of the body, head, arms, or legs
  • Shaking of the entire body
  • Tasting a bitter or metallic flavor
Electroencephalogram
Medication-induced Clinical features of hyperprolactinemia after a specific period of regular medication ingestion Discontinuation of the medication for 3 days and remeasurement of prolactin levels[20] Change to alternate medication

Differentials based on irregular menstruation and hirsutism

Cushing's syndrome must be differentiated from other causes of irregular menses and hirsutism. The differentials include:

Disease Differentiating Features
Pregnancy
  • Pregnancy should always be excluded in a patient with a history of amenorrhea
  • Uterine enlargement is detectable on abdominal examination at approximately 14 weeks of gestation
Hypothalamic amenorrhea
  • Diagnosis of exclusion
  • Seen in athletes, people on crash diets, patients with significant systemic illness, and those experiencing undue stress or anxiety
  • Predisposing features are as follows weight loss, particularly if features of anorexia nervosa are present or the BMI is <19 kg/m2
  • Recent administration of depot medroxyprogesterone, which may suppress ovarian activity for 6 months to a year
  • Use of dopamine agonists (eg, antidepressants) and major tranquilizers
  • Hyperthyroidism
  • In patients with weight loss related to anorexia nervosa, fine hair growth (lanugo) may occur all over the body, but it differs from hirsutism in its fineness and wide distribution
Primary amenorrhea
Cushing syndrome
Hyperprolactinemia
  • Mild hyperprolactinemia may occur as part of PCOS-related hormonal dysfunction
  • Other causes include stress, lactation, and use of dopamine antagonists
  • A prolactinoma of the pituitary gland is an uncommon cause and should be suspected if prolactin levels are very high (>200 ng/mL)
  • Physical examination findings are usually normal
  • As in patients with PCOS, hyperprolactinemia may be associated with mild galactorrhea and oligomenorrhea or amenorrhea; however, galactorrhea also can occur with nipple stimulation and/or stress when prolactin levels are within normal ranges
  • A large prolactinoma may cause headaches and visual field disturbance due to pressure on the optic chiasm, classically a gradually increasing bi-temporal hemianopsia
Ovarian or adrenal tumor
  • Benign ovarian tumors and ovarian cancer are rare causes of excessive androgen secretion; adrenocortical tumors also can increase the production of sex hormones
  • Abdominal swelling or mass, abdominal pain due to fluid leakage or torsion, dyspareunia, abdominal ascites, and features of metastatic disease may be present
  • Features of androgenization include hirsutism, weight gain, oligomenorrhea or amenorrhea, acne, clitoral hypertrophy, deepening of the voice, and high serum androgen (eg, testosterone, other androgens) levels
  • In patients with an androgen-secreting tumor, serum testosterone is not suppressed by dexamethasone
Congenital adrenal hyperplasia
  • Congenital adrenal hyperplasia is a rare genetic condition resulting from 21-hydroxylase deficiency
  • The late-onset form presents at or around menarche Patients have features of androgenization and subfertility
  • Affects approximately 1% of hirsute patients More common in Ashkenazi Jews (19%), inhabitants of the former Yugoslavia (12%), and Italians (6%)
  • Associated with high levels of 17-hydroxyprogesterone
  • A short adrenocorticotropic hormone stimulation test with measurement of serum17-hydroxyprogesterone confirms the diagnosis Assays of a variety of androgenic hormones help define other rare adrenal enzyme deficiencies, which present similarly to 21-hydroxylase deficiency
Anabolic steroid abuse
  • Anabolic steroids are synthetic hormones that imitate the actions of testosterone by increasing muscle bulk and strength
  • Should be considered if the patient is a serious sportswoman or bodybuilder
  • Features include virilization (including acne and hirsutism), often increased muscle bulk in male pattern, oligomenorrhea or amenorrhea, clitoromegaly, gastritis, hepatic enlargement, alopecia, and aggression
  • Altered liver function test results are seen
Hirsutism
  • Hirsutism is excessive facial and body hair, usually coarse and in a male pattern of distribution
  • Approximately 10% of women report unwanted facial hair
  • There is often a family history and typically some Mediterranean or Middle Eastern ancestry
  • May also result from use of certain medications, both androgens, and others including danazol, glucocorticoids, cyclosporine, and phenytoin
  • Menstrual history is normal
  • When the cause is genetic, the excessive hair, especially on the face (upper lip), is present throughout adulthood, and there is no virilization
  • When secondary to medications, the excessive hair is of new onset, and other features of virilization, such as acne and deepened voice, may be present

Less common differentials

Cushing's syndrome must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, and adrenal medullary tumors:

Differential Diagnosis Clinical picture Imagings Laboratory tests
Adrenocortical carcinoma
Adrenal adenoma
Cushing's syndrome
  • Imaging may show mass if presents
Pheochromocytoma
Adrenal metastasis

References

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