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Image: “rsv1 res” by Philippe Put. License: CC BY 2.0


Definition of Cushing’s Syndrome

Cushing’s syndrome is also known as hypercortisolism. It is a condition in which the body produces excess cortisol, due to the dysfunction of the pituitary gland, adrenal gland, or disturbance anywhere in the hypothalamic–pituitary–adrenal (HPA) axis.

Cushing’s syndrome in children results in retarded growth, disrupted puberty, obesity, and various other signs and symptoms.

Introduction

Cushing’s syndrome is a pathologic culmination of chronic sustained exposure to escalated levels of glucocorticoids. They can be endogenous or exogenous in origin. Cushing’s syndrome in children is distinctly different from its adult counterpart.

A summary of the unique challenges of Cushing’s syndrome in children is as follows:

  • Reproductive function management
  • Psychologic health maintenance
  • Body composition balance
  • Bone mineral density affection
  • Final height of the child
  • Cosmetic appeal and appearance of the child
BabyCushing

Image: ‘Physical examination revealed features of Cushing’s syndrome including round facies, acne, plethora, central obesity, and poor muscle tone.’ By Elizabeth B. Fudge, Daniel von Allmen, Keith E. Volmar, & Ali S. Calikoglu. License: CC BY 3.0.

One needs to be aware of two closely related yet distinct terms when dealing with states of excess glucocorticoids circulating in the body. These are as follows:

Cushing’s disease: When the source of excess adrenocorticotropic hormone (ACTH) leading to escalated levels of circulating glucocorticoids is a pituitary tumor, more specifically an ACTH-secreting adenoma, the patient is said to have Cushing’s disease.

Cushing’s syndrome: This term refers to all the other manifestations of increased circulating glucocorticoids—both endogenously and exogenously derived.

History of Cushing’s Syndrome in Children

Cushing’s syndrome was first described in 1932 by the neurosurgeon Harvey Cushing. He was the one to expound the trans-sphenoidal surgery for pituitary adenomas and is rightfully known as the ‘father of neurosurgery’.

Epidemiology of Cushing’s Syndrome in Children

Cushing’s syndrome is rare in the pediatric population. It is observed in only 10% of the new cases per year. The most common age group afflicted are patients between 20 and 50 years of age. It is about three times more common in women than in men. But in pediatric cases, the opposite is true: It is more common in boys as compared to girls.

Etiology of Cushing’s Syndrome in Children

The use of steroids in the medical management of certain illnesses is the predominant etiology in children. It is also called iatrogenic Cushing’s syndrome. The most relevant differences between pediatric and adult Cushing’s syndrome are summarized as follows:

  • Early-age Cushing’s syndrome occurs due to a predominance of mixed androgen and cortisol-secreting adrenocortical tumors.
  • Cushing’s syndrome in infancy is caused by McCune-Albright syndrome.
  • There is an increased frequency of prepubertal Cushing’s syndrome in boys rather than girls.
  • Ectopic ACTH syndrome seldom occurs in pediatric Cushing’s syndrome.
  • It is more difficult to identify the adenoma in pituitary scans.
  • There is a potentially increased tendency to detect lateralization of ACTH secretion on bilateral inferior petrosal sinus sampling (BIPSS).
  • External beam pituitary radiotherapy proides a relative early and improved response in the pediatric population.

Etiopathogenesis of Cushing’s Syndrome in Children

A prolonged state of overexposure to glucocorticoids results in Cushing’s syndrome. This state of chaotic hormonal imbalance results from inappropriate control of the HPA axis, as is described below.

HPA axis

The hypothalamus, anterior pituitary gland, and the adrenal glands are in a state of constant negative feedback. The normal functioning of this HPA axis is vital to the precise regulation of circulating glucocorticoids. The various components of the HPA axis and their origin can be summarized as follows:

Origin Component
Hypothalamus Corticotropin-releasing hormone (CRH)
Anterior pituitary Adrenocorticotropic hormone (ACTH)
Adrenal gland Glucocorticoids such as cortisol

CRH stimulates the release of ACTH, which, in turn, downregulates the release of CRH through negative feedback. Cortisol exerts negative feedback and subsequently inhibits release of both CRH and ACTH. Regardless of the inciting factor, disruption of the normal functioning of this HPA axis results in Cushing’s syndrome.

The-HPA-Axis

The HPA axis. Image created by Lecturio.

Classification of Cushing’s Syndrome in Children

Cushing’s syndrome in children can be classified based on either etiology or according to the age at manifestation. Based on etiology, the classification is as follows:

ACTH dependent ACTH independent
Pituitary adenoma (most common): Cushing’s disease Exogenous steroid
Ectopic ACTH syndrome (extremely rare) Adrenocortical tumor (adenoma or carcinoma)
Carcinoid tumors: bronchial, renal, thymic, or duodenal Primary adrenocortical hyperplasia (associated with multiple endocrine neoplasia (MEN) syndrome: macronodular adrenal hyperplasia, McCune-Albright syndrome, primary pigmented nodular adrenocortical disease (PPNAD), Carney complex)

Based on the age of onset, different subsets of Cushing’s syndrome can be segregated as follows:

Age of onset Feature
Infancy It is usually associated with McCune-Albright syndrome.
Children under 4 years Adrenocortical tumor is the most common etiology.
Children more than 5 years of age Cushing’s disease secondary to pituitary adenomas is the most frequently encountered feature.

There are a few distinct syndromes associated with pediatric Cushing’s syndrome; they are discussed in the following section.

McCune-Albright syndrome

Secondary to GNAS1 gene mutation, this sporadic disease is an aggregation of characteristic features such as peripheral precocious puberty, polyostotic fibrous dysplasia, and cafe-au-lait pigmentation. Cushing’s syndrome in infancy is most likely associated with this condition. It is an aggressive culmination of nodular adrenal hyperplasia.

Primary pigmented nodular adrenocortical disease (PPNAD)

This condition derives its name from the characteristic histologic appearance of the affected adrenal glands. Multiple pigmented adrenocortical nodules are seen, thus justifying the other name for this disease, ‘micronodular adrenal disease’.

PPNAD is associated with Carney’s complex and Cushing’s syndrome is the most common manifestation of Carney’s complex in the pediatric population. Carney’s complex comprises cardiac myxomas, lentigines, and various endocrine and non-endocrine tumors.

Cyclical or periodic Cushing’s syndrome

The patients with Carney’s complex and PPNAD often have intermittent remissions, thus leading to the concept of ‘cyclical’ Cushing’s syndrome in these patients.

Atypical Cushing’s syndrome

This term is uniquely related to PPNAD. It is characterized by muscle and skin wasting, short stature, and osteoporosis.

Clinical Presentation of Cushing’s Syndrome in Children

Pediatric patients with Cushing’s syndrome have typical, characteristic stark features and a distinct stereotype appearance, thus making Cushing’s syndrome a potential clinical diagnosis. Subtle features are seldom seen. The most common characteristics are as follows:

Feature Frequency
Fatigue 60%
Hirsutism 60%
Striae 51%
Emotional lability 51%
Hypertension 45%

A detailed list of all significant Cushingoid signs and symptoms is summarized below for easy memorization and recall:

Sign Symptom
  • Moon facies
  • Violaceous striae
  • Plethora (redness)
  • Deregulated pubertal development
  • Short stature
  • Auxology: decrement in height standard deviation score (SDS) in association with increased basal metabolic index (BMI) SDS
  • Buffalo hump (dorsocervical fat pad)
  • Myopathy
  • Lentigines (Carney’s complex)
  • Freckles
  • Virilization
  • Osteoporosis
  • Poor growth
  • Irritability
  • Fatigue
  • Acne
  • Headache
  • Emotional lability
  • Weight gain
  • Lethargy
  • Hirsutism
  • Easy bruisability
  • Family history

Diagnosis of Cushing’s Syndrome in Children

Cushing’s syndrome is potentially a clinical diagnosis. There are two tiers of investigations when it comes to pediatric Cushing’s syndrome. The first is to reinstate the clinical diagnosis, and the next is to determine the etiology. The biochemical definition of Cushing’s syndrome is the disruption of the normal feedback mechanism of the HPA axis and the deregulated circadian rhythm of glucocorticoid circulation and secretion. A combination of two or more tests typically yields high sensitivity and specificity.

Investigations thus relevant in Cushing’s syndrome can be summarized as follows:

Investigation Explanation
Urinary free cortisol assessment This highly sensitive test is the first one to be performed. Three consecutive 24-hour urine samples are collected and free cortisol levels are assessed.
Serum cortisol measurement Serum cortisol levels fluctuate in accordance with the circadian rhythm. Midnight serum cortisol more than 50 nmol/L is one of the best discriminating tests.
Low-dose dexamethasone suppression test (LDDST) In accordance with the NIH recommendations, 0.5 mg of dexamethasone is administered every 6 hours for 24 hours in children less than 40 kg. For those over 40 kg, 30 ug/kg/day of dexamethasone is typically used. Serum cortisol assessment is performed at 0, 24, and 48 hours. Cushing’s syndrome is characterized by an inability to suppress cortisol secretion secondary to the loss of the negative feedback mechanism. Consequently, one encounters increased cortisol levels after 48 hours. The typical cutoff used is 50 nmol/L. LDDST plays a critical role in differentiating between patients with Cushing’s disease and Cushing’s syndrome.
Midnight salivary cortisol measurement This screening test is suitable for children because of its non-invasive nature.
Plasma ACTH level assessment It is of crucial importance to differentiate ACTH-dependent Cushing’s syndrome from ACTH-independent cases. Plasma ACTH levels are typically examined at about 0900 hours.
CRH test The CRH test is used selectively to differentiate between Cushing’s disease and ectopic ACTH secretion. The overwhelming response to CRH in the form of increased cortisol levels by more than 20% is recorded in patients with Cushing’s disease.
High-dose dexamethasone suppression test (HDDST) The HDDST is falling out of favor recently. Dexamethasone is administered at a rate of 2 mg/6 hr (80 mcg/kg/d) for about eight times in 48 hr and then serum cortisol level analysis is carried out.
Radiologic investigations:

CECT abdomen SOS chest

MRI adrenal

MRI brain-pituitary protocol

A CECT of the abdomen is required in patients with adrenal etiology such as tumors and nodular hyperplasia. HRCT may be rarely required in cases such as carcinoid syndrome.
Adrenal CT and MRI protocols help differentiate between primary adrenal nodular hyperplasia and adrenocortical tumors.
A pituitary microadenoma less than 5 mm is the frequent etiology of pediatric Cushing’s syndrome. The same requires an MRI of the brain to locate the adenoma.
Genetic analysis Genetic analysis is helpful in establishing the diagnosis of Carney’s complex and associated PPNAD. PRKAR1A gene mutations are assessed.
BIPSS This investigation is used as a last resort to establish lateralization of ACTH secretion. It is an invasive test and not without complications.

Complications of Cushing’s Syndrome in Children

The majority of complications are correlated with the direct or indirect effects of excessive glucocorticoids. Long-term exposure to cortisol leads to many complications and cardiovascular disease is the most important out of those. Cushing’s syndrome is often associated with cardiovascular risk factors.

Some important complications are as follows:

Hypertension: This may result from various disturbed mechanisms regulating plasma volume and peripheral vessel resistance or from direct cardiomyopathy due to the excessive levels of cortisol.

Impaired glucose tolerance/diabetes: Excessive glucocorticoids stimulate gluconeogenesis (glucose production) in the liver, along with the inhibition of insulin sensitivity, resulting in high levels of blood glucose.

Hyperlipidemia: High levels of cortisol result in exaggerated fat metabolism. Therefore, there is a rise in free fatty acids in the blood. There is also an increased synthesis of cholesterol and triglycerides, resulting in total hyperlipidemia.

Hypokalemia: Cortisol is supposed to have some mineralocorticoid activity that results in the disturbance of potassium metabolism.

All these factors, in turn, predispose the patient to cardiovascular disease.

Management of Cushing’s Syndrome in Children

The management of Cushing’s syndrome in the pediatric population is best achieved in the hands of a multidisciplinary team. The etiology responsible determines the mode of the management. The multi-pronged attack often comprises surgical, medical, and radiologic modalities of treatment. This is summarized in the following section.

Surgical management

Surgical excision in the form of trans-sphenoidal surgery (TSS) microadenoma excision is the primary mode of treatment for Cushing’s disease secondary to pituitary adenoma. Adrenalectomy is performed only if trans-sphenoidal surgery is impossible.

The management of PPNAD and primary adrenal pathologies is often surgical. Optimum glucocorticoid replacement in the perioperative period is essential. Cure rates as high as 72% are achieved.

Medical management

Medical therapy is often used temporarily until the patient is optimized for surgical management. Adrenal blocking agents such as metyrapone and ketoconazole are frequently used. Mitotane is instrumental in the treatment of metastatic adrenocortical carcinoma.

Radiotherapy

This is used in the treatment of Cushing’s disease as a second-tier modality when trans-sphenoidal surgery fails to achieve remission. It is more successful in children than in adults.

For patients with ectopic ACTH or a suspected tumor, imaging and chemotherapy/surgical excision are necessary.

There are a few specific complications of trans-sphenoidal surgery for Cushing’s disease in the pediatric population, which are summarized as follows:

  • Post-operative short stature, subnormal growth, and hypopituitarism
  • Post-operative obesity
  • Cognitive aberrations
  • Psychologic disturbances

The best treatment modality is not without complications. Therefore, a multidisciplinary dedicated team comprising pediatricians, surgeons, and endocrinologists is vital to the management of Cushing’s syndrome in the pediatric population.

Prognosis of Cushing’s Syndrome in Children

  • Untreated cases of Cushing’s syndrome have a survival rate of 50% at 5 years.
  • With therapy for cortisol normalization, the mortality rate is the same as the general population.
  • Outcomes of surgery depend on the size of the tumor.

Summary

Secondary to chronic sustained abnormal exposure to increased glucocorticoids, Cushing’s syndrome in the pediatric population is a rare diagnosis. The most common etiology is Cushing’s disease secondary to an ACTH-secreting adenoma.

Children are not little people. The issues encountered in handling pediatric Cushing’s syndrome are quite specific and need a dedicated multidisciplinary team for optimal work-up, management, and follow-up.

Cushing’s syndrome is the ultimate culmination of the aberrant HPA axis and the loss of normal negative feedback.

Patients with Cushing’s syndrome can be classified based on etiology or based on the stratification of etiology according to the patient’s age.

A few syndromic diseases associated with pediatric Cushing’s syndrome are McCune-Albright syndrome and PPNAD. Cushing’s syndrome is the most common manifestation of Carney’s complex in the pediatric population. The latter includes cardiac myxomas, lentigines, and complex endocrine and non-endocrine tumors.

Cushing’s syndrome is a clinical diagnosis with stark characteristic signs and symptoms. Fatigue and hirsutism are most frequently encountered in the pediatric population.

Diagnosis is based on clinical suspicion further reinforced by several blood tests, which when used together supplement each other to ultimately yield high sensitivity and specificity.

Urinary cortisol level, low-dose dexamethasone suppression test, ACTH level assessment, and imaging studies as needed commonly comprise the diagnostic armamentarium for Cushing’s syndrome. Other tests such as CRH measurement and the high-dose dexamethasone suppression test are seldom used.

The management of Cushing’s syndrome is surgical or medical, or is based on the usage of radiotherapy according to the etiology. Trans-sphenoidal excision of pituitary adenoma is an established procedure for Cushing’s disease. Hypopituitarism is a potential complication.

Medical therapy is often a temporary solution before surgical management. Radiotherapy is typically reserved for patients with Cushing’s disease who have failed trans-sphenoidal surgical management. Ultimately, it requires a dedicated multidisciplinary team to optimally manage Cushing’s syndrome in pediatric patients.

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