CUSHING SYNDROME IN

CHILDREN

DR. MAHBUBA JAHAN SHARMIN

DR. ISMAT JAHAN SHIMI
 OBJECTIVES
History of the disease
Incidence of the disease
Definition
Distinct features of Cushing syndrome in children
Regulation of cortisol secretion
Etiologic classification of Cushing Syndrome in children
Symptoms and signs of Cushing Syndrome
Complications
Investigation protocol
Management
Follow-up
Dr Harvey Cushing first described a woman
with signs and symptoms of this disease in
1912 and in 1932 he was able to link the
adrenal overproduction of cortisol to an
abnormality in the pituitary.
CUSHING SYNDROME is rare in childhood and
adolescence. The condition is caused by
prolonged exposure to excessive glucocortioids
which can be secreted endogenously or
administered exogenously.
• Cushing Syndrome- is the result of abnormally
high blood levels of cortisol or other
glucocorticoids.

• Cushing's Disease- ACTH producing pituitary

adenoma
Cushing’s=hypercortisolism
 Incidence
Most cases of Cushing syndrome are due to
exogenous glucocorticoids. The annual
incidence of endogenous Cushing syndrome
has been estimated at 13 cases per million
individuals.
No such data is available in paediatric age
group.
 Cushing Syndrome in children-
some distinct features
Cause of Cushing Syndrome are not fundamentally
different from those in adults. However some
features are distinct.
Example includes-
 The presentation of Mc Cune Albright syndrome
with Cushing Syndrome In infancy.
 The predominance in mixed androgen and
cortisol secreting adrenocortical tumour in
early childhood.
 The increased frequency of prepubertal Cushing
disease in males compared to females.
Differences compared to adult practice include-
• The extreme rarity of ectopic ACTH syndrome.
• The frequent absence of corticotroph adenoma
on pituitary scanning in children with Cushing Disease.
• The apparent higher incidence, compared to adults, of
lateralisation of ACTH secretion demonstrated by
bilateral inferior petrosal sinus sampling(BIPSS).
• The rapid response of Cushing Disease to external beam
pituitary radiotherapy in children.
 Regulation of cortisol secretion
 Mainly regulated by ACTH from ant pituitary.
 normal diurnal rhythm of cortisol secretion is caused by varying amplitude
of ACTH pulses.

Regulation of ACTH secretion

 CRH synthesized by parvicellular division of hypothalamic paraventricular
nucleus- is the most important stimulator of ACTH secretion
 Cortisol exert a –ve feedback effect on the synthesis and secretion of ACTH,
CRH and AVP.
 ACTH inhibits its own secretion, a feedback effect mediated at the level of
hypothalamus
Then the secretion of cortisol is a result of the interaction of the
hypothalamus, pituitary, adrenal gland and other neural stimuli.
 Etiologic classification of Cushing
Syndrome in children
ACTH Dependent ACTH independent
Cushing disease(ACTH Exogenous glucocorticoid
secreting pituitary administration
adenoma) Adrenocortical tumour
Ectopic ACTH syndrome (Adenoma or carcinoma)
Primary Adrenocortical hyperplasia
-PPNAD, Carney complex/MEN
-Macronodular adrenal
hyperplasia
-McCune Albright syndrome
Ages of peak incidence in different
types of Cushing syndrome
Review of 398 children with cushing syndrome
cases from different literature Showing that-
-Cushing syndrome in infancy is usually
associated with Mc Cune Albright syndrome,
-adrenocortical tumours occur most
commonly in children under 4 years of age
and
-cushing disease is the commonest cause of
Cushing syndrome after 5 years of age.
 Pathophysiology
 Excess levels of either exogenously administered
glucocorticoids or endogenous overproduction of cortisol
causes Cushing syndrome.
 Endogenous hypercortisolism that is independent of ACTH
is usually due to a primary adrenocortical neoplasm
(adenoma/ carcinoma). Bilateral micronodular hyperplasia
and macronodular hyperplasia are rare causes.
 ACTH-secreting neoplasms cause ACTH-dependent
Cushing syndrome-- due to an anterior pituitary
tumor(Cushing disease).
ACTH depedent Cushing syndrome may also result
from ectopic prodution of ACTH, although this is
uncommon in children.
Ectopic ACTH secration in children has been
associated with
Islet cell carcinoma of pancrease,
Neuroblastoma or
Ganglioneuroblastoma,
Hemangiopericytoma
Wilms tumour and
Thymic carcinoid.
 ACTH independent Cushing syndrome

Primary pigmented nodular adrenocortical

disease(PPNAD)
- Usually present before 20 years of age
- Occurs as a isolated event or as a component of
Carneys complex(autosomal dominant disease)
- Adrenal glands are small, have multiple, small(,4 mm),
pigmented nodule.
McCune Albright syndrome
- Symptoms begins in infancy and early childhood
- Nodular hyperplasia and adenoma formation
Multiple endocrine neoplasia
 Clinical features
SYMPTOMS
Rounded face
Reddened cheek
Acne
Headache
Excess hair growth(fine hair on cheeks,arms,legs)
Purplish pink stretch mark(more prominent in older
children)
Darkened skin around neck and armpit areas
Easy bruising
Development of pubic hair at younger age than usual
Irregular or absent menstrual period
symptoms that are less commonly seen in
children:
Sleep disturbance
Mental changes
Muscle weakness
SIGNS
General- Truncal obesity
- Reduction in height associated with increased BMI
- Abnormal pubertal development
Face- rounded moon facies
Facial plethora
Buffalo hump
Supraclavicular pad fat
Skin- violaceous Striae- abdomen, buttocks, lower
back, upper thighs, upper arms, and breasts.
Pigmentation
Hirsutism
Acne
Acanthosis nigricans
Perpura
CVS- Hypertension
Musculoskeletal- proximal muscle weakness
Neurological-
– emotional liability, fatigue, and depression.
- Visual-field defects
in adrenal crisis- hypotension, abdominal pain,
vomiting, and mental confusion (secondary to
low serum sodium or hypotension).
Child with Cushing Syndrome
Clinical features of Cushing syndrome
 Complications of Cushing's if
Untreated
Diabetes
HTN
Psychosis
Osteoporotic fractures and avascular necrosis
Infections
Nephrolithiasis
APPROACH TO A PATIENT
WITH
CUSHING SYNDROME
 OBJECTIVES
Screening test to confirm Cushing syndrome
Steps to demonstrate aetiology of Cushing
Syndrome.
Algorithm
Treatment
Follow-up
 Clinical suspicion

Assessment of circadian rhythm,

Overnight dexamethasone
suppression test,
24 hour urinary free cortisol

Normal Equivocal
Abnormal
Cushing syndrome Suspecting
Cushing
excluded pseudocushing
Syndrome
syndrome

CRH test
 Screening test
Overnight(single dose) dexamethasone suppression
test
- 25-30μgm/kg(max 2 mg) Dexamethasone orally at
11 pm, Serum cortisol is measured next morning at 8
am.
-Normal value is <5micrograms/dL
Or
24 hour urinary free cortisol
- This is the most effective diagnostic tool.
- Values > 3-4 times the upper limit of normal are
highly suggestive of Cushing Syndrome.
 Other Test That May be helpful
• Midnight serum cortisol
In the normal sleeping child the midnight serum
cortisol level should be <50nmol/l.
• Midnight saliva cortisol
-Simple and convenient
-Level <1.3ng/ml(RIA) or <1.5ng/ml(competitive
protein binding assay) exclude cushing syndrome.
• Glucose tolerance test
• Serum electrolyte
 False Positives 24 hour UFC
• Severe depression
• Severe stress
• Medication with
Phenytoin/phenobarbitone/rifampicin
• Estrogen (pregnancy or OCP)
• obesity
• Chronic exercise
 Biochemically confirmed
cushing syndrome

Serum ACTH, CRH test, two step

dexamethasone suppression test

ACTH independent ACTH dependent

High dose dexamethasone

suppression test
Adrenal ,CRH,BIPSS
scanning

Pituitary Ectopic cushing

cushing
For demonstration of cause of CD
Plasma ACTH level(normal range 10-50ngm/l)
If undetectable (<10ngm/l)
- Adrenocortical tumour
- nodular adrenal hyperplasia
If detectable
-Cushing disease
- Ectopic ACTH Syndrome
Plasma ACTH level may be normal in pituitary adenoma.
 (Corticotropin releasing hormone)CRH
test: After administration of IV CRH
• Patient with ACTH dependent Cushing syndrome have
an exaggerated ACTH and Cortisol response.
• Patient with adrenal tumour show no increase in ACTH
and cortisol level.
If abnormality found in screening test, two step
dexamethasone suppression test
• Dexamethasone 30-120μgm/kg/day, 6 hrly x 48
hours
• Blood is taken for serum cortisol at 0 hr, 24 hr and
48 hr. Normal individual will suppress [Link]
level to < 50nmol/l by 48hrs.
• Children with pituitary cushing disease, the larger
dose, but not the smaller dose suppresses S.
cortisol.
• Typically pt with ACTH independent Cushing
syndrome do not show suppressed cortisol levels
with dexamethasone.
High dose dexamethasone suppression
test:

NOT ROUTINELY PERFORMED

Genetic analysis in Cushing syndrome
patients.
May be helpful in certain situation.
Analysis of the PRKAR1A gene to help in the
diagnosis of PPNAD. However, genetic
mutations only account for a proportion of
cases and negative testing does not exclude
the condition.
 Imaging modalities
Adrenal imaging
 Adrenal CT or MRI is essential to differentiate
between an adrenocortical tumour and
primary nodular adrenal hyperplasia.
 CT detects virtually all adrenal tumour larger
than 1.5 cm in diameter.
 In cases of PPNAD, the adrenals are usually
normal sizes, although occasionally
adrenocortical nodules (< 6 mmin size) are
visible on imaging .
Adrenal Nodule in CT scan abdomen
Adrenal Tumour in CT scan abdomen
Pituitary imaging
MRI imaging of the pituitary gland should be
performed in ACTH dependent Cushing
Syndrome.
Most Cushing Disease in children is caused by a
microadenoma less than 5 mm in diameter.
Often these lesions are too small to detect ; the
addition of godolinium contrast increases the
sensitivity of detection.
MRI brain showing pituitary
macroadenoma
Further Imaging
CT scan chest to exclude carcinoid tumour of
bronchial origin.
 Bilateral Inferior Petrosal Sinus
Sampling(BIPSS)
• BIPSS used to measure conc. of ACTH before and
after CRH administration to localize the tumour
when a pituitary adenoma is not visualized.
• Only when Serum Cortisol is above normal
• Pituitary Cushing disease if IPS/PV(ACTH)
Basal > 2
After CRH> 3
• False –ve in anomalous vein anatomy
• False +ve when Serum cortisol is normal
• Complication: brain stem infarct, DVT, Groin
heamatoma.
PETROSAL VENOUS SAMPLING
• If Inferior petrosal sinus sampling not
diagnostic of Cushing Syndrome-
Chest and abdomen CT
Octreotide scan
Clinical suspicion Detailed history and examination, Review of past
photograph, Auxological assessment

•Serum Cortisol circadian rhythm,

•24 hrs urinary free cortisol,
•single dose Dexamethasone suppression test

Cushing Syndrome confirmed

Basal plasma ACTH measurement

ACTH dependent CRH Test ACTH independent

Adrenal MRI/CT
Pituitary MRI

Chest CT +/- Genetic analysis

BIPSS
McCue Albright syndrome
Ectopic ACTH Adrenocortical tumour
Cushing disease
syndrome Bilat nodular hyperplasia
PPNAD/Carney complex,AIMAH
 Treatment
Mainly surgical

• Cushing’s Disease: Transphenoidal microsurgery of

pituitary adenoma. Relapses are treated with re-
operation or pituitary irradiation.
• Benign cortical adenoma: Unilateral adrenalectomy. If
adenoma is bilateral option is subtotal adrenalectomy.
• Adrenocortical carcinoma: Frequently metastsize even
after removal of primary lesion. Rarely the tumours are
bilateral and require total adrenalectomy.
• Ectopic ACTH: resection if possible
• Bilateral adrenal hyperplasia: may need
adrenalectomies (lifelong glucocorticoid and
mineralcorticoid replacement)
 Peri-operative management:
Corticosteroi replacement therapy
• Patient undergoing adrenalectomy requires adequate
preoperative and postoperative corticosteroid
replacement therapy.
• Corticosteroid producing tumour usually lead to
atrophy of the normal adrenal tissue. Replacement
with cortisol (10 mg/m2/day in 3 div doses after the
immediate post-operative period) is required until
recovery of hypothalamic-pituitary-adrenal axis.
 Complication
• Post operative complications include sepsis,
pancreatitis, thrombosis, poor wound healing,
sudden collapse.
• Substantial catch up growth, pubertal
progress, and increased bone density occur
but bone density remains abnormal and adult
height is often compromised.
 ‘Medical’ Adrenalectomy
Medications that inhibit adrenal steroidogenesis
• Ketoconazole
• metyrapone (exacerbates female virilization)
• Mitotane
• Aminoglutethimide
• Ocreotide .
These agents have been used preoperatively to
normalize circulating cortisol levels and reduce
perioperative morbidity and mortaliy.
 Follow up after surgery
Close followup is essential by taking relevant history,
physical examination and biochemical hormone
assay / imaging investigations.
 One year after surgical cure of Cushing Syndrome
most children has lost wt and body mass, height and
growth velocity had increased.
 Temporary or permanent dysfunction of pituitary
gland for example hypothyroidism, adrenal
insufficiency, GH insufficiency, pubertal delay can
occur with surgical removal of pituitary adenoma.
 After transsphenoidal pituitary microsurgery daily
cortisol replacement for a period of 6-18 months is
necessary until HPA axis recovers.
 Cont..
 Children who undergo bilateral
adrenalectomy will require daily hormone
replacement (hydrocortisone and
fludrocortisone) for the rest of their life.
 Children with an adrenal tumor require single
adrenalectomy need to take daily
hydocortisone replacement until the HP axis
recover.
 Most children who are recovering from
Cushing Syndrome are able to resume normal
physical activities within several weeks to
months.
THANK YOU
 THANK
YOU

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