Cushing Syndrome in Children
Introduction to Cushing Syndrome in Children
Cushing syndrome (CS) is a rare endocrine disorder characterized by excessive exposure to glucocorticoids, resulting in a constellation of clinical features. In children, CS can significantly impact growth, development, and overall health. The incidence of pediatric CS is estimated to be 0.2-5 cases per million people per year, making it a rare but important condition to recognize.
Cushing syndrome in children can be categorized into two main types:
- Exogenous Cushing syndrome: Caused by prolonged exposure to exogenous glucocorticoids, often due to medical treatment for other conditions.
- Endogenous Cushing syndrome: Results from the overproduction of cortisol by the adrenal glands, which can be further classified into ACTH-dependent and ACTH-independent causes.
The diagnosis and management of Cushing syndrome in children present unique challenges due to its rarity, the subtle nature of early symptoms, and the significant impact on growth and development. Early recognition and appropriate treatment are crucial to minimize long-term complications and ensure optimal outcomes.
Etiology of Cushing Syndrome in Children
The causes of Cushing syndrome in children can be categorized into exogenous and endogenous sources:
1. Exogenous Cushing Syndrome:
- Most common cause in children
- Prolonged use of glucocorticoid medications for various conditions:
- Asthma
- Rheumatologic disorders
- Inflammatory bowel disease
- Hematologic malignancies
2. Endogenous Cushing Syndrome:
A. ACTH-Dependent Causes (80-85% of endogenous cases):
- Cushing Disease: ACTH-secreting pituitary adenoma (most common endogenous cause in children >7 years)
- Ectopic ACTH Syndrome: Rare in children, can be caused by:
- Bronchial carcinoid tumors
- Pancreatic neuroendocrine tumors
- Thymic carcinoids
B. ACTH-Independent Causes (15-20% of endogenous cases):
- Adrenal Tumors:
- Adrenocortical adenomas
- Adrenocortical carcinomas (more common in younger children)
- Bilateral Adrenal Hyperplasia:
- Primary pigmented nodular adrenocortical disease (PPNAD)
- Macronodular adrenal hyperplasia (rare in children)
3. Genetic Causes:
- Mutations in genes involved in the cyclic AMP signaling pathway (e.g., PRKAR1A gene in Carney complex)
- Multiple Endocrine Neoplasia type 1 (MEN1)
- Familial isolated pituitary adenomas (FIPA)
Understanding the etiology is crucial for appropriate management and genetic counseling when applicable. The distribution of causes varies with age, with adrenal tumors being more common in younger children and Cushing disease predominating in older children and adolescents.
Clinical Presentation of Cushing Syndrome in Children
The clinical presentation of Cushing syndrome in children can be subtle and may overlap with other conditions. Key features include:
1. Growth and Development:
- Growth deceleration or arrest (hallmark feature)
- Excessive weight gain with central obesity
- Delayed puberty or, in some cases, precocious puberty
2. Skin Changes:
- Facial plethora (moon facies)
- Acne
- Hirsutism
- Striae (usually purple or red)
- Easy bruising
- Acanthosis nigricans
3. Musculoskeletal:
- Proximal muscle weakness
- Osteoporosis and increased risk of fractures
- Backache
4. Cardiovascular and Metabolic:
- Hypertension
- Glucose intolerance or diabetes mellitus
- Hyperlipidemia
5. Neuropsychiatric:
- Mood changes (depression, irritability, emotional lability)
- Cognitive difficulties
- Sleep disturbances
6. Other Features:
- Headaches (especially in Cushing disease)
- Increased susceptibility to infections
- Nephrolithiasis
7. Differences in Presentation by Etiology:
- ACTH-independent CS: Rapid onset, more severe virilization
- Cushing disease: Often more insidious onset
- Ectopic ACTH syndrome: May have features of the underlying tumor
The classic Cushingoid appearance may be less pronounced in children compared to adults. A high index of suspicion is needed, particularly when growth velocity decreases while weight increases. The rapidity of symptom onset can provide clues to the underlying etiology.
Diagnosis of Cushing Syndrome in Children
Diagnosing Cushing syndrome in children requires a stepwise approach:
1. Initial Screening Tests:
- 24-hour urinary free cortisol (UFC): Elevated in CS, at least 3-4 times the upper limit of normal
- Late-night salivary cortisol: Elevated in CS, loss of normal diurnal rhythm
- Overnight dexamethasone suppression test (DST): Lack of cortisol suppression in CS
- Low-dose DST (48-hour): More specific than overnight test
2. Confirmatory Tests:
- Combination of the above tests
- Midnight serum cortisol (if facilities for inpatient testing are available)
3. Determination of ACTH Dependence:
- Plasma ACTH levels:
- Elevated or normal in ACTH-dependent CS
- Suppressed in ACTH-independent CS
4. Localization Studies:
For ACTH-Dependent CS:
- MRI of the pituitary (with and without contrast)
- Bilateral inferior petrosal sinus sampling (BIPSS) if MRI is negative or inconclusive
- CRH stimulation test
- High-dose DST
For ACTH-Independent CS:
- Adrenal CT or MRI
5. Additional Investigations:
- Bone age X-ray: Often advanced in CS
- DEXA scan for bone density
- Genetic testing if hereditary syndrome suspected
6. Considerations in Pediatric Diagnosis:
- Use age- and sex-specific normal ranges for all tests
- Consider pseudo-Cushing states (e.g., obesity, depression)
- Be aware of the challenges in very young children (e.g., difficulties with 24-hour urine collection)
The diagnosis of CS in children requires careful interpretation of clinical features and laboratory results. False-positive results are common, necessitating repeated testing and a step-wise diagnostic approach. Referral to a pediatric endocrinologist is crucial for proper evaluation and management.
Treatment of Cushing Syndrome in Children
The treatment of Cushing syndrome in children depends on the underlying etiology and aims to normalize cortisol levels while minimizing complications:
1. Exogenous Cushing Syndrome:
- Gradual tapering of exogenous glucocorticoids under medical supervision
- Use of alternate-day therapy or lower doses when possible
- Consider steroid-sparing agents for the underlying condition
2. Endogenous Cushing Syndrome:
A. ACTH-Dependent Cushing Syndrome (Cushing Disease):
- First-line treatment: Transsphenoidal surgery (TSS) to remove the pituitary adenoma
- Second-line options:
- Repeat TSS
- Pituitary radiation therapy
- Bilateral adrenalectomy
- Medical therapy: May be used as bridging treatment or in cases where surgery is contraindicated
- Ketoconazole
- Metyrapone
- Mitotane
- Etomidate (in severe cases requiring ICU management)
B. ACTH-Independent Cushing Syndrome:
- Adrenal adenoma: Laparoscopic adrenalectomy
- Adrenocortical carcinoma: Open adrenalectomy with potential adjuvant therapy (e.g., mitotane)
- Bilateral adrenal hyperplasia: Bilateral adrenalectomy
3. Management of Complications:
- Hypertension: Antihypertensive medications
- Diabetes: Insulin or oral hypoglycemic agents
- Osteoporosis: Calcium and vitamin D supplementation, bisphosphonates in severe cases
- Growth hormone therapy: Consider after resolution of hypercortisolism if growth remains impaired
4. Perioperative Management:
- Stress-dose glucocorticoids during and after surgery
- Careful monitoring for adrenal insufficiency
- Gradual tapering of glucocorticoid replacement
5. Long-term Follow-up:
- Regular monitoring of cortisol levels
- Assessment of growth and pubertal development
- Screening for recurrence
- Management of persistent comorbidities
Treatment of Cushing syndrome in children requires a multidisciplinary approach involving pediatric endocrinologists, neurosurgeons, and other specialists. The goal is to achieve cure while minimizing treatment-related morbidity and ensuring optimal growth and development.
Prognosis and Follow-up of Cushing Syndrome in Children
The prognosis for children with Cushing syndrome varies depending on the etiology, duration of disease, severity of hypercortisolism, and effectiveness of treatment. With appropriate management, many children can achieve good outcomes, but long-term follow-up is essential.
Prognosis:
- Mortality is rare with modern treatment but morbidity can be significant
- Exogenous CS generally has a good prognosis once glucocorticoids are tapered
- Cushing disease has a remission rate of 60-98% with transsphenoidal surgery
- Adrenal tumors have variable prognosis:
- Benign adenomas: Excellent prognosis after surgery
- Adrenocortical carcinoma: Generally poor prognosis, depends on stage at diagnosis
Follow-up Care:
- Immediate Post-treatment Period:
- Monitor for adrenal insufficiency
- Glucocorticoid replacement therapy as needed
- Assess for resolution of clinical features
- Long-term Monitoring:
- Regular clinic visits (every 3-6 months initially, then annually)
- Monitoring of growth velocity and pubertal development
- Annual bone age assessment
- Screening for recurrence:
- 24-hour UFC or late-night salivary cortisol
- Low-dose dexamethasone suppression test
- Endocrine Function Assessment:
- Evaluation of pituitary function in cases of Cushing disease
- Monitoring of adrenal function in cases of adrenalectomy
- Assessment of gonadal function and fertility in adolescents
- Metabolic and Cardiovascular Follow-up:
- Regular blood pressure monitoring
- Lipid profile and glucose tolerance tests
- Echocardiogram if there's a history of hypertension
- Bone Health:
- DEXA scans to monitor bone mineral density
- Calcium and vitamin D supplementation as needed
- Psychological Support:
- Assessment for depression, anxiety, and cognitive issues
- Psychosocial support and counseling
Long-term Considerations:
- Growth and Final Height: Many children experience catch-up growth after successful treatment, but some may not achieve their full height potential
- Body Composition: Gradual normalization of weight and fat distribution, but may require dietary and exercise interventions
- Cognitive Function: Improvement in cognitive abilities and school performance, but some deficits may persist
- Fertility: Generally preserved, but may require hormonal evaluation and support
- Risk of Recurrence: Lifelong monitoring recommended, especially for Cushing disease
Transition to Adult Care:
- Planned transition to adult endocrinology care
- Education on long-term health implications and self-management
- Genetic counseling for familial forms of CS
The long-term prognosis for children with Cushing syndrome has improved significantly with advances in diagnosis and treatment. However, these patients require lifelong monitoring and a multidisciplinary approach to care to ensure the best possible outcomes and quality of life.
