History and exam

Key diagnostic factors

common

facial plethora

Many patients with Cushing syndrome have plethora.[23][62]

supraclavicular fullness

Increased subcutaneous fat in the supraclavicular fossa is commonly seen in patients. It is much less commonly seen in patients with obesity from other causes.

violaceous striae

Worsening or significant violaceous striae are commonly associated with hypercortisolism in younger individuals.[23][62]

absence of pregnancy

Pregnancy should be excluded as a potential physiologic cause of hypercortisolism.

menstrual irregularities

Women with hypercortisolism generally have irregular menses or amenorrhea.

absence of malnutrition

Malnutrition should be excluded as a potential physiologic cause of hypercortisolism.

absence of alcoholism

Alcoholism should be excluded as a potential physiologic cause of hypercortisolism.

absence of physiologic stress

States of physiologic stress should be excluded as a potential cause of hypercortisolism.

linear growth deceleration in children

Almost all children (>95%) show decreasing linear growth velocity.[63] Decreasing linear growth with accompanying weight gain in children is suggestive of Cushing syndrome.[1]

Other diagnostic factors

common

female sex

Cushing syndrome has a female-to-male predominance of 3:1.[1]

hypertension

Among patients with hypertension, 0.5% to 1% have Cushing syndrome.[12][13] However, hypertension is common, and most patients with hypertension do not have hypercortisolism.

glucose intolerance or diabetes mellitus

Up to 70% of Cushing syndrome patients have impairment of glucose metabolism (glucose intolerance, diabetes).[55] Patients with diabetes may have poorly controlled blood sugars. Poorly controlled diabetes is common, and only 2% to 3% of patients with poorly controlled diabetes have Cushing syndrome.[8][56]

premature osteoporosis or unexplained fractures

Low bone density in younger men should raise suspicion.

In patients with Cushing syndrome, osteoporosis occurs in over 50% and skeletal fractures in up to 76%.[57] As many as 11% of patients with osteoporosis and vertebral fractures have unsuspected hypercortisolism.[15]

weight gain and central obesity

Nearly all patients gain weight. The degree of weight gain is based on the severity and duration of hypercortisolism. The increasing prevalence of obesity in the general population has made weight gain a very nonspecific finding. It has also made the decision about which patients to test more difficult.

acne

Many patients have increased frequency of acne on the face, back, and chest.

psychiatric symptoms

Mood changes are common and occur in 70% of patients with Cushing syndrome. Depression is the most common, but other psychiatric symptoms, such as anxiety and even psychosis, can also occur.[58][59] These symptoms improve or resolve with effective treatment of the hypercortisolism.

decreased libido

Occurs in up to 90% of patients, and true gonadal dysfunction is common.[57] Men generally complain of decreased libido initially. As the hypercortisolism persists, erectile dysfunction may develop.

easy bruisability

Cushing syndrome patients have thinning of the skin and subcutaneous tissues with subsequent easy bruising.[23][57] Bruising without obvious trauma is a relatively specific physical finding.

weakness

Muscle weakness is very common, with proximal weakness being most prominent.[1][23][57]

facial rounding

Rounding of the face occurs in most if not all people who are obese, giving this finding a low specificity for the diagnosis of Cushing syndrome. However, 90% of patients with Cushing syndrome develop this.

dorsocervical fat pads

Increased subcutaneous fat on the back of the neck is commonly seen in Cushing syndrome, but also in patients with obesity from other causes.

uncommon

unexplained nephrolithiasis

Some patients develop renal stones. Episodes of recurrent renal stones without other explanation should raise suspicion.

venothrombolic event

Cushing syndrome creates a hypercoagulable state and is associated with an increased risk of venous thromboembolic disease.[1] Patients with Cushing syndrome have a 10-fold increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism).[60][61]

hirsutism

Rapid onset of virilization may be a sign of adrenal carcinoma, which is associated with a 50% to 60% chance of Cushing syndrome.[10]

Risk factors

strong

exogenous corticosteroid use

Patients who use any dose of exogenous glucocorticoid greater than the normal daily production by the adrenals are at risk for developing Cushing syndrome.[20] The exact dose and the duration needed to manifest Cushing syndrome varies among patients. Diagnosis of exogenous Cushing syndrome is obvious in the setting of treatment with high-dose glucocorticoids, with increased risk associated with higher daily and cumulative doses.[21] However, suspicion and detailed questioning may be required to determine glucocorticoid delivery via alternative routes (e.g., intra-articular, inhaled, topical therapy).[20]

pituitary adenoma

About 70% to 80% of patients with Cushing syndrome have adrenocorticotropic hormone-secreting pituitary adenomas (Cushing disease).[8] However, up to 10% of the population has incidental pituitary lesions consistent with microadenomas.[22] The vast majority of these adenomas are nonsecretory and do not cause Cushing disease.

adrenal adenoma

About 15% of patients with Cushing syndrome have adrenal adenomas that overproduce cortisol.[8] A significant proportion of patients with adrenal adenoma may have excess and inappropriate secretion of cortisol leading to mild cortisol excess, also known as subclinical Cushing syndrome.[8][14]

adrenal carcinoma

A very rare disease. When it does occur, it can cause adrenal overproduction of cortisol resulting in adrenocorticotropic hormone-independent Cushing syndrome. About 50% to 60% of adrenal carcinomas present with Cushing syndrome, but only 1% of Cushing syndrome cases are caused by adrenal carcinoma.[10] Mixed Cushing and virilizing syndromes are observed in the majority of patients, and cases may present with rapid onset of virilization in women: for example, hirsutism, voice deepening, and clitoral enlargement.[10]

weak

neuroendocrine tumors

A small proportion of patients with Cushing syndrome have ectopic adrenocorticotropic hormone (ACTH) secretion. Neuroendocrine tumors, especially of bronchial and thymic origin, are the most commonly reported to secrete excessive ACTH and cause ectopic ACTH syndrome.

thoracic or bronchogenic carcinoma

These malignancies, especially small cell lung cancer, may produce adrenocorticotropic hormone (ACTH) and cause the ectopic ACTH syndrome.

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