Cushing disease

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Cushing disease is caused by high levels of a hormone called cortisol, which leads to a wide variety of signs and symptoms. Cortisol has many functions, which include helping the body respond to stress. Cushing disease is a type of Cushing syndrome. As with Cushing disease, Cushing syndrome is caused by high levels of cortisol in the body. Because both conditions result from elevated cortisol levels, the signs and symptoms seen in people with Cushing disease are similar to those seen in people with Cushing syndrome.

People with Cushing disease may have rapid and unusual weight gain, particularly around the abdomen and face. Affected individuals may bruise easily and have purple stretch marks (striae) on the thighs and abdomen. Individuals with Cushing disease may also develop a hump on their upper back caused by changes in the amount and distribution of body fat.

Additional signs and symptoms of Cushing disease can include muscle weakness, fatigue, irregular menstruation, and thin and brittle bones that are prone to fracture (osteoporosis). Women with Cushing disease often have excessive hair growth (hirsutism) on the face, chest, and abdomen. People with Cushing disease are at increased risk of developing high blood pressure (hypertension) and diabetes. Affected individuals may also have a weakened immune system and an increased risk of infections.

Cushing disease can affect a person's thinking and mood. Affected individuals often report anxiety, irritability, and depression. This condition can also affect learning, concentration, and memory, leading to "brain fog."

People with Cushing disease are at an increased risk of developing life-threatening complications, which can include infections, heart disease, or stroke.

Cushing disease typically occurs alone (isolated). In rare cases, it may also be a feature of genetic syndromes that affect other parts of the body, such as multiple endocrine neoplasia 1 (MEN1) and familial isolated pituitary adenoma (FIPA).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Cortisol protects the body from stress, maintains blood glucose (also called blood sugar) levels, and turns off (suppresses) inflammation. Cortisol is produced by the adrenal glands, which are small glands located at the top of each kidney. Normally, the production of cortisol is triggered by the release of a hormone called adrenocorticotropic hormone (ACTH) from the pituitary gland, which is located at the base of the brain.

In people with Cushing disease, noncancerous (benign) pituitary gland tumors (also called adenomas) release too much ACTH. The extra ACTH causes the adrenal glands to release too much cortisol, which leads to the signs and symptoms of Cushing disease.

The cause of Cushing disease is often unknown. However, genetic changes in certain genes cause Cushing disease in up to 70 percent of affected individuals. Genetic changes that cause disease are called pathogenic variants. The pathogenic variants that cause Cushing disease are typically somatic, which means they are acquired during a person's lifetime and are present only in certain cells. The genes that are associated with Cushing disease often play a role in regulating the activity of hormones.

In some people with Cushing disease, pituitary adenomas contain cells that have a pathogenic variant in the USP8 gene. Pathogenic variants in the USP8 gene are the most common genetic cause of Cushing disease.

The USP8 gene provides instructions for making an enzyme that helps regulate the breakdown (metabolism) of certain proteins, including proteins that are involved in important cell signaling pathways. The pathogenic variants in the USP8 gene that are associated with Cushing disease cause cells in the pituitary adenoma to produce a version of the protein that does not switch off properly. As a result, certain signaling proteins become overactive, causing cells within the adenoma to release too much ACTH.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Isolated Cushing disease is typically sporadic, which means it occurs in people with no family history of the disorder.

When Cushing disease occurs as part of a genetic syndrome, it follows the inheritance pattern of that syndrome.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Cushing disease affects up to 2.4 in 1,000,000 people each year. The condition affects females more often than males. Cushing disease typically occurs between the ages of 20 and 50. However, children may also be affected.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Increased circulating cortisol level · Very frequent (99-80%)

Overproduction of the hormone of cortisol by the adrenal cortex, resulting in a characteristic combination of clinical symptoms termed Cushing syndrome, with truncal obesity, a round, full face, striae atrophicae and acne, muscle weakness, and other features.

Increased urinary cortisol level · Very frequent (99-80%)

Abnormally increased concentration of cortisol in the urine.

Pituitary corticotropic cell adenoma · Very frequent (99-80%)

A type of pituitary adenoma that produces adrenocorticotropic hormone (ACTH).

Paradoxical increased cortisol secretion on dexamethasone suppression test · Very frequent (99-80%)

Abdominal obesity · Frequent (79-30%)

Excessive fat around the stomach and abdomen.

Abnormality of the cardiovascular system · Frequent (79-30%)

Any abnormality of the cardiovascular system.

Acne · Frequent (79-30%)

A skin condition in which there is an increase in sebum secretion by the pilosebaceous apparatus associated with open comedones (blackheads), closed comedones (whiteheads), and pustular nodules (papules, pustules, and cysts).

Adrenal hyperplasia · Frequent (79-30%)

Enlargement of the adrenal gland.

Other findings in the same source

From: Orphanet

Additional reported features include Amenorrhea (Frequent (79-30%)); Atypical behavior (Frequent (79-30%)); Bruising susceptibility (Frequent (79-30%)); Capillary fragility (Frequent (79-30%)); Decreased eosinophil count (Frequent (79-30%)); Diabetes mellitus (Frequent (79-30%)); Dorsocervical fat pad (Frequent (79-30%)); Emotional lability (Frequent (79-30%)); Fatiguable weakness of proximal limb muscles (Frequent (79-30%)); Hirsutism (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Cushing disease is Endocrinology, with a endocrinologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which hormone or metabolic finding is important in this case?
• How should test timing and current medicines be taken into account?
• What follow-up would show whether the care plan is working?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Cushing disease. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.