Adrenal disorders in

children
Muhammad Faizi
Clinical Lecturer of Pediatric Endocrine Division
S c h o o l o f M e d i c i n e A i r l a n g g a U n i v e r s i t y – D r. S o e t o m o H o s p i t a l S u r a b a y a .

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Introduction
Adrenal
§  Medulla à Epinephrine & norepinephrine.
§  Cortex à Glucocorticosteroids, mineralocorticoids, and androgenic
steroids.
Ø  Glucocorticoids and mineralocorticoids à essential for
maintaining metabolic homeostasis.
§  Deficiency à life-threatening.
§  Excess à severe & permanent consequence.
à It is critically important to recognize disordered adrenal function.

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Adrenal gland physiology
§  Adrenal cortex
§  Outer: Glomerolusa à mineralocorticoid
§  Middle: Fasciculata à cortisol
§  Inner: Reticularis à sex steroid
§  Fasciculata à principle component of H-P-A axis
§  Glucocorticoid secretion is regulated by ACTH
§  ê Cortisol à activate the axis àéACTH
§  é Cortisol à downregulate the axis of H-P-A
§  Glomerolusa à Aldosteron (independent controlled through RA-system)
§  ê BP & ê i.v volume à é renin à activate RA-system

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Adrenal gland physiology

Regulation of adrenal hormones

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Functions of adrenal hormones
§  Cortisol:
§  Cardiovascular stability à ésensitivity of vasculature to epinephrine and
norepinephrine
§  Metabolism à égluconeogenesis
§  Fluid electrolyte balance à Na+ retention & K+ excretion
§  Inhibit bone formation
§  Potent anti-inflammatory agent
§  Aldosterone:
§  Act on distal tubules and collecting ducts of kidney à é Na+ and water
conservation, secrete K+ à é blood pressure
§  Adrenal androgen:
§  Pubarche and 2nd sexual development

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 Functions of adrenal hormones

Action of cortisol

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Adrenal Insufficiency

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 Etiology and pathogenesis
§  Primary:
§  Autoimmune adrenalitis (Addison’s disease), TB
§  CAH: enzyme defect à cortisol deficiency à éprecursor hormones
à loss of – feedback à éACTH
§  Secondary:
§  Defect in pituitary or hypothalamic à congenital, acquired
§  Atrophy of fasciculate zone à þmineralocorticoid secretion
§  Iatrogenic:
o  Long-term effects of glucocorticoid administrations à HPA-axis
suppression

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Clinical presentation
§  Vague, often unrecognized
§  Fatigue, malaise, poor weight gain and growth, and
anorexia
§  Physical stress à adrenal crisis
§  Shock like syndrome (tachycardia, hypotension,
dehydration, and acute abdominal pain)
§  Hypoglycemia, hypercalcemia, acidosis, eosinophilia,
éBUN & SC

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Clinical presentation
§  Primary:
§  éACTH, hyperpigmentation of skin and bucal
§  Hyperplasia of pituitary corticotrophic cell
§  Hyponatremia, hyperkalemia
§  Secondary:
§  êACTH
§  Normal kalium

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Clinical presentation
§  Signs and symptoms related to etiology of primary
A.I
§  Evidence of A.I.D (thyroiditis, vitiligo, T1DM) à Addison's
disease
§  Hypoparathyroidism and mucocutaneus candidiasis à
autoimmune polyendocrinopathy syndrome
§  Neuromuscular dysfunction à Adrenoleukodystrophy
§  Weight loss, fever, pulmonary dysfunction à TB
§  Central adrenal insufficiency à midline facial defect

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Clinical presentation
§  Signs and symptoms related to etiology of Central
A.I
§  Midline facial defect à structural defect of pituitary
§  Poor growth and progression of puberty à multiple
pituitary hormones deficiency

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Evaluation and management
§  Lab study:
§  Screening:
o  Basal cortisol at 8 am (N>12 μg/dL)
§  Primary A.I:
o  éACTH, êCortisol, hyponatremia, hyperkalemia
o  éPRA, êAldosterone, hyponatremia or shock à
mineralocorticoid deficiency
§  If the test equivocal or no clinical crisis à stimulation
test
o  ACTH test for primary A.I or CRH test for 2nd-ry A.I

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Evaluation and management
§  Others test:
§  Adrenoleukodystrophy à very long chain fatty acid
§  Addison’s disease à adrenal antibodies
§  Other syndrome à genetic testing
§  PPD à TB
§  HIV testing à AIDS
§  Pituitary imaging, pituitary deficiency (GH, TSH,
gonadotropin) à 2nd-ry A.I

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Treatment and prognosis
§  Appropriate replacement of cortisol and
aldosterone
§  To resemble endogenous cortisol production rate (6-8
mg/m2/day)
o  Hydrocortisone p.o 10-15 mg/m2/day or its equivalent
o  Hydrocortisone i.m or i.v 100 mg/m2 and then 100 mg/m2/
day divided every 6 hours (in critical illness)
§  Fludrocortisone 0.1-0.2 mg/24 hours

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Potency of Various Therapeutic Steroids (Set Relative to the Potency of Cortisol)

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Cushing’s syndrome

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Etiology and pathogenesis
§  Cushing’s disease
§  Glucocorticoid excess caused by oversecretion ACTH
from pituitary corticotrope adenoma
§  Cushing’s syndrome
§  Glucocorticoid excess of nonpituitary cause including
ectopic ACTH production, adrenal disease, and
exogenous glucocorticoid use

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Clinical presentation
§  Weight gain, growth failure, fatigue, hypertension,
glucose intolerance, and delayed puberty
§  Osteopenia, acne, plethora, hirsutism, ‘buffalo
hump’, strie
§  Hyperandrogenism and virilization can indicate
adrenal carcinoma

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Ilustrasi kasus
 Wanita, 3 tahun, berat badan cepat naik dalam 7 bulan.
 Nafsu makan meningkat
 BB 17 kg
 TB 85 Cm
 Tensi 140/90 mmHg

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Ilustrasi kasus

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Ilustrasi kasus

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Ilustrasi kasus
TB= 85 cm
BB= 17 Kg

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Ilustrasi kasus
 Hb: 13, g/dL
 Leko: 6.700/mm3
 GDA: 87 mg/dL
 Profil lemak: DBN
 Kortisol AM: 421 nmol/L (50-250)
 Na: 153 meq/L
 K: 3.1 meq/L

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Evaluation and management
§  Loss of diurnal rhythm of cortisol secretion
§  A 24 hours urine collection and measurement of free cortisol
(N <40-50 μg )
§  Salivary cortisol at 11 pm (N <4.2 nmol/L)
§  Dexamethasone suppression test
o  1 mg of DXM at 11 pm orally à serum cortisol before 9 am (N <1.8
μg/dL)
o  ACTH measurement and high dose DXM suppression test need to
distinguish ACTH-dependent or independent

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Evaluation and management
§  Inferior petrosal sinuses blood sampling for ACTH test à
Cushing’s disease
§  Pituitary MRI with gadolinium can be used to visualize
small adenomas.
§  Abdominal USG or CT to identify adrenal mass.

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Evaluation and management

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 Cushing Syndrome
Established
Evaluation and management
Measure Plasma ACTH Level

ACTH Level Low ACTH Level Normal or Elevated

Normal Negative Feedback Abnormal Negative Feedback

ACTH – Independent Cushing ACTH – Dependent

MRI of Pituitary
Syndrome Cushing Syndrome

Adrenal CT * Normal or Equivocal Clearly Abnormal

Results Results

Bilateral Petrosal Sinus Sampling for ACTH with CRH Administration

No Pituitary Gradient for Significant Pituitary Gradient

ACTH for ACTH

Occult Ectopic Cushing

ACTH Disease
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Congenital adrenal hyperplasia

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Etiology and pathogenesis
§  Group disorders characterized by:
§  Defective of adrenal steroid synthesis
§  é androgenic steroid intermediates
§  ê cortisol and mineralocorticoid (variably)
§  Mostly caused by homozygous mutation of the
CYP21 gene

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 Cholesterol
CYP11A1
StAR
CYP17
Adrenal
& Gonadal
CYP17
Pregnenolone 17-OH pregnenolone Dehydroepiandosterone

HSD3B2 HSD3B2 HSD3B2
CYP17
Progesterone 17-OH progesterone Androstenedione

CYP21 CYP21 CYP19 HSD17B3

DOC 11-Deoxycortisol Estrone Testosterone

CYP11B2 CYP11B1 HSD17B1

Corticosterone Cortisol Estradiol
Testis

CYP11B2

18-OH corticosterone Adrenal Cortex Ovary

CYP11B2

Aldosterone STEROIDOGENESIS
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Clinical presentation
§  Classic
§  Salt wasting (mostly caused by 21-hydroxylase deficiency)
o  adrenal crisis during 2nd weeks of life
§  Simple virilizing
o  varying degrees of virilization in 46 XX female
o  premature pubarche
o  penile enlargement in boys
§  Non classic
§  Late onset
§  PCOS in women
§  Less common: associated with hypertension (11-β-hydroxylase deficiency (CYP11
gene)

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 Prader scale
  I: clitoromegaly without labial fusion.
  II: clitoromegaly and posterior labial fusion.
  III: greater degree of clitoromegaly, single perineal urogenital orifice, and
almost complete labial fusion.
  IV: increasingly phallic clitoris, urethra-like urogenital sinus at base of clitoris,
and complete labial fusion.
  V: penile clitoris, urethral meatus at tip of phallus, and scrotum-like labia
(appear like males without palpable gonads).

Speiser and White. Endocrine Reviews, 2000; 21(3): 245-91.

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Prader scale

Speiser and White. Endocrine Reviews, 2000; 21(3): 245-91.

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Differential diagnosis
§  Infant with shock
§  sepsis, primary adrenal insufficiency, cardiac or metabolic
disease
§  Ambiguous genitalia
§  in utero sex hormones exposure, androgenic enzyme
inhibitors, gonadal steroid synthesis defects, isolated or
syndromic malformation of genital
§  Virilization
§  precocious pubarche/puberty, PCOS, virilizing tumors,
exogenous androgen exposures

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Evaluation and management
§  Newborn screening
§  Blood spot à 17 OHP
§  Adrenal steroid precursor
§  17 OHP, 17-hydroxypregnenolone, androstenedione,
dehydroepiandrosterone, deoxycortisol, deoxycorticosterone, and
testosterone
§  ACTH stimulation test
§  Genetic analysis of CYP21 or CYP11
§  Abdominal imaging to rule out adrenal tumor or source of
androgen

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Evaluation and management
§  Adrenal crisis à special protocol
§  Glucocorticoid
§  prevent to adrenal crisis
§  êoverproduction of adrenal steroid intermediates
§  êadrenal androgen
§  prevent accelerated skeletal maturation
§  Mineralocorticoid
§  prevent salt wasting

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Thank you

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