What are the clinical signs of Cushing disease (ACTH‑producing pituitary adenoma)?

Clinical Signs of Cushing Disease

Cushing disease (ACTH-producing pituitary adenoma) presents with a characteristic constellation of physical findings dominated by central obesity with specific fat redistribution, wide violaceous striae, proximal muscle weakness, and in children, the pathognomonic combination of declining height velocity with increasing weight. 1

Cardinal Physical Findings

Fat Distribution Abnormalities

• Central obesity with characteristic fat redistribution to the face (moon facies), supraclavicular fossae, and dorsocervicular region (buffalo hump) is the key discriminator of true Cushing's syndrome from simple obesity 1
• Moon face and increased fat around the neck are present in virtually all patients at presentation 2, 3
• Facial plethora (reddish appearance) accompanies the moon facies 2

Skin Manifestations

• Wide violaceous (purple) striae ≥1 cm on the abdomen, thighs, or arms are highly specific physical findings of hypercortisolism 1
• Thin, fragile skin that bruises easily after minor trauma is typical 1
• Hirsutism is frequently present, particularly in women 1

Musculoskeletal Signs

• Proximal muscle weakness affecting hip flexors and shoulder girdle (e.g., difficulty rising from a chair without using arms) is a common manifestation 1
• Signs of protein wasting are evident 4

Pediatric-Specific Presentation

In prepubertal children, a pattern of declining height velocity combined with increasing weight (height SDS below the mean while BMI SDS is above the mean) is highly sensitive and specific for Cushing's syndrome and reliably separates it from simple obesity 1, 5

• Growth failure with weight gain is the hallmark presentation in prepubertal children, with inexplicable weight gain combined with either decreased height standard deviation score or decreased height velocity 5
• This growth pattern is not reliable for diagnosing Cushing's in post-pubertal adolescents 1
• The interval between symptom onset and diagnosis typically ranges from 2.5 to 5 years in children 3
• Male predominance (71%) is observed in prepubertal children, contrasting with 79% female predominance in adults 5

Cardiovascular and Metabolic Signs

• Hypertension occurs in 70–90% of patients with Cushing's syndrome 1
• Hyperglycemia or impaired glucose tolerance is present in the majority of cases 1
• Severe insulin resistance may be the primary presenting symptom in patients with type 2 diabetes 6

Biochemical Abnormalities

• Hypokalemia with metabolic alkalosis is especially marked in ectopic ACTH secretion but can occur in pituitary disease 1
• Loss of normal serum cortisol circadian rhythm is characteristic 3

Reproductive and Endocrine Signs

• In women, menstrual irregularities (amenorrhea) frequently accompany hypercortisolism 1
• Gonadal dysfunction occurs in both sexes 6

Common Diagnostic Pitfalls

Clinical abnormality is often undetected for long periods because the signs develop insidiously and may be attributed to other causes such as simple obesity, depression, or metabolic syndrome 3, 4

• The average diagnostic delay is 3 years from initial symptoms to diagnosis, resulting in increased morbidity and mortality from cardiovascular events 1
• Signs such as obesity, moon face, and hirsutism are non-specific and can occur in other conditions, requiring biochemical confirmation 4
• In children, growth failure may be misattributed to constitutional delay or familial short stature unless the characteristic pattern of declining height with increasing weight is recognized 5

Associated Complications at Presentation

• Osteoporosis is common due to cortisol's catabolic effects on bone 3, 4
• Immunosuppression increases susceptibility to infections 6, 4
• Psychiatric complications including depression and cognitive changes are frequent 4
• Metabolic syndrome features (hypertension, diabetes, dyslipidemia) are present in >80% of patients 1