Could This Be Cushing Syndrome?

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Patient Presentation
A 9-year-old male came to clinic for his well child examination. His mother was slightly worried about his weight as she had noted that he seemed to be eating more and was not being as active. She said he came home from school and would play videogames mainly. He did play soccer 2 times per week and had recess and gym class at school. She herself noted that she was overweight. The family history was positive for heart disease, type 2 diabetes and obesity. The review of systems was negative including no sleep disturbances, headache, abdominal pain, joint pain, excessive tiredness, or vision complaints.

The pertinent physical exam revealed a blood pressure = 104/70 (normal for age and gender), respiratory rate of 24 per minute, weight = 46.1 kilograms (>90%, equivalent of 13 year old, which was increased from 90% the previous year), height = 138 cm (75% which was consistent from the past several years), BMI = 23.4 (97%, 110% of 95th percentile). Vision screening was 20/30 bilaterally. Skin exam showed no acanthosis nigricans, but he did have some pink-white abdominal striae. His heart, lungs, and abdomen were normal. Genitourinary exam showed that he was Tanner I for gonads and hair. His neurological and extremity exams were normal.

The diagnosis of of healthy male with obesity was made. The patient and mother were counseled regarding ways to improve his nutrition and increase his activity. “I highly recommend family walks. It gets everyone out of the house and people can laugh and talk. You have a dog too, so it would be great to walk the dog then,” he recommended. Obesity screening labs were also added to the routine lipid screening for this visit as well.

Afterwards, the medical student asked how the pediatrician didn’t think the obesity wasn’t due to something else like Cushing syndrome. “That’s always a good question. First I’ve only seen Cushing’s one time. It’s not very common and obesity is very common especially after COVID. He mainly didn’t have other problems like his height was normal, the striae were a pink-white color and not purple which I’ve seen in pictures. He didn’t look overall fat and round with thinner extremities and he had normal blood pressure, plus he didn’t complain of other problems like a headache. Cushing’s is due to elevated cortisol as you know. So it is an endocrine problem. If it is a real endocrine problem then kids usually will have two or more of their growth parameters that are abnormal. Cushing’s I know has children that are overweight and not growing. His growth was consistent but he was gaining in weight. Polycystic ovarian syndrome in girls has some overlap too with general obesity and metabolic syndrome as well as Cushing syndrome. He’s male so we don’t have to worry about PCOS. We’ll follow him up in 6 months to check on his weight. It’s always good though to think about broad differential diagnoses.”

Discussion
Cushing’s syndrome (CS) is caused by prolonged, excessive cortisol exposure which causes disruption of the hypothalamic-pituitary-axis. Normally the hypothalamus secretes corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to release ACTH (adrenocorticotropic hormone, also called corticotropin). Increased ACTH causes the adrenal gland to secrete cortisol. Increased cortisol then feeds back to down regulate the hypothalamus and anterior pituitary from releasing their respective hormones.

The most common cause of CS is exogeneous glucorticoid such as the medications prednisone or dexamethasone. Endogeneous CS is rare in the pediatric population. Endogeneous causes are due to tumors of the pituitary, adrenal gland or rarely some other type of tumors which secretes CRH or ACTH. Adrenal hyperplasia is also a potential cause.

Cushing’s disease (CD) is CS due to a pituitary adenoma secreting excess ACTH. This is even rarer than CS overall. CD has a male predisposition. The adenomas usually are sporadic but can be part of recognized genetic patterns including Multiple Endocrine Neoplasia 1 (MEN1)

Diagnosis of hypercortisolism can be done by several tests each of which have their pros and cons and multiple tests may be needed to confirm the hypercortisolism. Treatment depends on the cause and often surgery is needed to remove pituitary or adrenal masses, along with medical therapy to suppress adrenal steroidogenesis such as ketoconazole or mitotane. Other therapy to address side effects also includes treatment for hypertension, glucose management, bone fractures and psychological treatment. Even with treatment children can have long-term health problems including growth and pubertal development (adult height is often shorter than expected), metabolic problems and especially behavioral problems. Cognitive and emotional regulation has been disrupted by the CS, and therefore it can take a long time for the brain to resolve it (cerebral atrophy has been documented in pediatric patients). It is not uncommon for at least 1 year of continued academic and other problems before there may be some resolution. Complete resolution may also not occur and there is an increased risk of suicidal ideation after treatment.

Learning Point
Clinical manifestations of CS include:

  • Growth and body habitus
    • **Weight gain with simultaneous linear growth deceleration (accelerated weight gain is often not recognized)
    • **Central obesity
    • **Dorsocervical fat pads
    • **Facial plethora (Moon facies)
    • Muscle wasting and general weakness
  • Skin
    • **Striae that are violaceous
    • Hyperpigmentation
    • Skin atrophy
    • Acanthosis nigricans
    • Hirsutism with fine downy hair especially on cheeks, arms, and legs
    • Acne
    • Easy bruising
    • Fungal infections
  • Behavior/Psychological
    • **Irritability
    • Anxiety
    • Depression
    • Mood swings
    • Fatigue
    • Academic problems
  • Cardiac
    • **Hypertension
    • Hypertrophic cardiomyopathy
  • Genitourinary
    • Puberty disruption
    • Amenorrhea – primary or secondary
    • Gynecomastia
    • Virilization
  • Hematologic
    • Easy bruising
    • Hypercoagulability
  • Metabolic
    • Glucose intolerance
    • Insulin resistance / suppression
    • Osteopenia or osteoporosis
    • Bone pain or fracture
  • Neurological
    • Headaches

** are common presentations

Questions for Further Discussion
1. What is Addison’s disease?
2. What is Cushing’s triad?
3. What causes short stature? A review can be found here.
4. What clinical signs are seen in PCOS? A review can be found here.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Cushing’s Syndrome and Obesity in Children.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Ferrigno R, Hasenmajer V, Caiulo S, et al. Paediatric Cushing’s disease: Epidemiology, pathogenesis, clinical management and outcome. Rev Endocr Metab Disord. 2021;22(4):817-835. doi:10.1007/s11154-021-09626-4.

Stratakis CA. Cushing’s disease in children: unique features and update on genetics. Pituitary. 2022;25(5):764-767. doi:10.1007/s11102-022-01237-9.

Parish A, Cheung C, Ryabets-Lienhard A, Zamiara P, Kim MS. Cushing Syndrome in Childhood. Pediatric in Review. 2024:45(1);14-24.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

Published