common adrenal disorders in children

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Common Adrenal Disorders in Children

Dr Sarar Mohamed FRCPCH (UK), MRCP (UK), CCST (Ire), CPT (Ire),

DCH (Ire), MDConsultant Paediatric Endocrinologist & Metabolist

Associate Professor of PediatricsKing Saud University

.Agenda

• Physiology of adrenal• Causes of adrenal insufficiency• Addison Disease• Adrenal crisis• Congenital adrenal hyperplasia• Cushing Syndrome

Aldosterone

• Mineralocorticoid

• Regulates concentration of Na+ and K+.– Kidney conserves Na+.– Kidney excretes K+.– Therefore, decreased aldosterone will lead to hyperkalemia and

hypornatremia.

• Responds to changes in composition of plasma.

• Regulated by renin-angiotensin system of kidney

Regulation of adrenal gland secretion

ACTH

CortisolCortisol

Aldosterone is regulated by the renin angiotensin system while cortisol is regulated by the hypothalamic pituitary axis.

Random cortisol measurement is not useful, ACTH stimulating test to stimulate the adrenals must be done to measure it. If it’s still low after stimulation, then it suggests adrenal insuffeciency.

Pattern of cortisole level during the day

Adrenal Dysfunction

Decrease function

• Adrenal insufficiency• Low cortisol, aldestrone

Eg Addison disease

Increase function

• Cushing syndrome

High Cortisol • Hyperaldosteronism

High aldestrone• Pheochromocytoma

High catecholamine

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Causes of Adrenal insufficiency

1. Congenital adrenal hyperplasia

2. Addison disease most common cause and it’s acquired.

3. Infection (TB, sepsis)

4. Adrenoleukodystrophy very rare.

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Addison disease

1. Autoimmune

2. Isolated or associated with other autoimmune disease

3. Presents with tiredness, weight loss, skin pigmentation

4. Hypotension, hyponatremia, hyperkalemia

5. Aldestrone & cortisol low, high ACTH, high renin

6. Low sodium , high potasium

7. ACTH stimulation test: diagnostic test by giving synthetic ACTH (IV or IM) and measuring the serum cortisol at 30 and 60 minutes. In normal individuals the baseline cortisol should be doubled after the test whereas in adrenal insufficiency, the baseline (which is low) is only increased to 25% after the test.

8. Adrenal antibodies

9. Treatment : cortisol + aldosterone

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Hyperpigmentation

A Color Atlas of Endocrinology p97

Addisonian crisis

• Life threatening complication• Severe vomiting and diarrhoea followed by

dehydration• Low blood pressure and shock• Hypoglycemia• Loss of consciousness• Treatment: IV fluids + IV hydrocortisone

Adrenal insufficiency with echomosis is suggestive of meningeococcal septicemia.

Congenital Adrenal Hyperplasia• Family of inherited disorders of adrenal synthesis

• Autosomal Recessive (M=F)

• Each disorder results from a deficiency of one of the five enzymes necessary for steroid synthesis

• 21-hydroxylase is the commonest form(90–95% of CAH cases)

Steroid biosynthetic enzymes

1) Cholesterol side chain cleavage= desmolase)

2) 3-Hydoxysteroid dehydrogenase

3) 17 hydroxylase 4) 21-Hydroxylase

5) 11-Hydroxylase

Minerlocorticoid Glucocoticiod Sex Steroid

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

3 B HSD

21 OH

11 OH

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

3 B HSD

Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

CholesterolDesmolase

3 B HSD

21 OH

11 OH

18 OH

17 a OH

17 a OH

17,20 lyase

•Desmolase is the first step in the pathway and if deficient all three pathways will be stopped. Only female genitalia because no androgens at all.

•3BHSD deficiency: all 3 enzymes will be absent but will also present with ambiguous genitalia because of high levels of DHEA

•17aOH: cortisol and androgens are deficient and males will present with ambiguous genitalia. Aldosterone is present; therefore, they will not develop adrenal crisis and will have hypertension due to the excess aldosterone levels.

•21aOH: is the commonest cause of CAH, both cortisol and aldosterone will be missing, the pathway will be shifted to the production of androgens which will be manifested as ambiguous genitalia in females and hyper-pigmentation and virilization in males.

•11aOH: both cortisol and aldosterone will be deficient, but there will be accumulation of the Desoxycorticosterone which has an aldosterone like activity, therefore they will present hypertension, hypernatremia and hypokalemia), but it similar to 21OH in that they both present with ambiguous genitalia and low cortisol levels.

•Hypertension is only present in 11 And 17 OH deficiency.

Congenital Adrenal Hyperplasia

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Congenital Adrenal Hyperplasia

21-OH CAH: Clinical phenotypes

1. “Classic, severe” salt-wasting (SW) form: it is the life-threatening form.

2. “Classic, less severe” simple-virilizing (SV)

3. “Mild, non-classic” forms

Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

CholesterolDesmolase

3 B HSD

21 OH

11 OH

18 OH

Desmolase

3 B HSD3 B HSD

21 OH

11 OH

17 a OH

17 a OH

Treatment

Hydrocortisone

Fludrocortisone

For life

21-OH CAH:

90 % of CAH

50-70 % salt wasting

Female =

ambiguous, Hyperpig

Male =

Virlization and hyperpigmentation

Salt wasting form

• Salt wasting form

– Adrenal crisis in the 1st-4th weeks of life, peaking at 3rd – Poor feeding, vomiting, diarrhea, FTT

• Dehydration• Shock • Electrolytes imbalance

– Hyponatremia – Hyperkalaemia

• Hypoglycemia• Hyperpigementations

– If untreated circulatory collapse shock death– Permanent brain injury due to shock and hypoglycemia lower IQ

Simple virilizing form 21-OH CAH

• Simple virilizing form

– No adrenal-insufficiency symptoms unless subjected to severe stress but exhibit virilization

– Girls present with ambiguous genitalia at birth

– Males usually not diagnosed until later (virilization, precocious, growth acceleration)

– Advanced skeletal age diagnosed late short adult stature

Prader Classification of Virilization

• Type 1: increase in the size of the clitoris.• Type 2: more increase in the size of the clitoris.• Type 3: one opening, the vagina and clitoris opens in the same

opening.• Type 4: one opening and more increase in the size, starts

looking as a penis.• Type 5: looks like male genitalia with no testis.

Newborn Screening

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Prader 1

.Prader 2

Prader 3

• .

Prader4

Prader5

Nonclassical CAH

Residual enzyme activity.Non-salt losing CAHPresents late in childhood with

precocious pubic hair and/or clitoromegaly and accelerated growth.

Present in adolescence or adulthood with varying virilizing symptoms ranging from oligomenorrhea to hirusutism and infertility.

Non classicCAH .

Diagnosis of CAH

Serum electrolytes & glucose Low Na & high K Fasting hypoglycemia Elevated serum urea due to associated dehydration

Elevated plasma Renin & ACTH levels Low Cortisol High 17 – OHP High androgens especially testosterone level Low Aldosterone Urinary steroid profile Chromosomal study and US of external genitalia if

they present with ambiguous genitalia. Pelvic US

Management

• Hydrocortisone

• Fludrocortisone 0.05 - 0.2 mg/day

• Triple dose of hydrocortisone and mineralcorticoids during stress or very sick.

• During adrenal crisis intravenous hydrocortisone and IV fluid

• Surgery for female external genitalia can be done in the 1st year of life.

• Antenatal diagnosis and treatment

Newborn screening for CAH

• Neonatal screening by filter paper on 3rd day of life• 17 Hydroxyprogestrone blood level (17 OHP)

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Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

CholesterolDesmolase

3 B HSD

21 OH

11 OH

18 OH

Desmolase

3 B HSD 3 B HSD

21 OH

11 OH

17 a OH

17 a OH

11 Hydroxylase Deficiency:

5 % of CAH

HTN

Female =

ambiguous, Hyperpig

Male =

virlization

Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

CholesterolDesmolase

3 B HSD

21 OH

11 OH

18 OH

Desmolase

3 B HSD 3 B HSD

21 OH

11 OH

17 a OH

17 a OH

17 Hydroxylase Deficiency: (adrenal crisis doesn’t occur)

HTN

Hypokalemic alkalosis

Female =

Normal

Male =

Ambiguous

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Pregnenlolone

Progesterone

Desoxycorticosterone

Corticosterone

18 OH Corticosterone

Aldosterone

17 OH Pregnenlolone

17 OH Progesterone

11 Desoxycortisol

Cortisol

DeHydroEpiAndrosterone

Androstendione

Testosterone Estradiol

CholesterolDesmolase

3 B HSD

21 OH

11 OH

18 OH

Desmolase

3 B HSD 3 B HSD

21 OH

11 OH

17 a OH

17 a OHSurvival is rare due to more proximal enzyme bloke

3 B Hydroxy steroid DH Deficiency:. Weak Androgen; therefore, ambiguous genitalia in females only.

Congenital Lipoid Adrenal Hypoplasia

• Inability to convert cholesterol to pregnenolone thus all 3 classes of steroids are absent (1st step is inhibited due to the absence of desmolase)

• Clinical Manifestations:

– Salt-losing crisis

– XX and XY have female genitalia

– Massive cholesterol accumulation in adrenal cortex

– Absent puberty in males

– Females may have puberty

Harvey Williams Cushing (1869-1939)

Definitions

• Cushing’s Syndrome– Excess cortisol in the blood

• Cushing’s Disease most common– Excess cortisol in the blood due to an ACTH secreting pituitary

tumour, due to pituitary adenoma.

ACTH

ADRENAL CORTEX

PITUITARY

HYPOTHALAMUS

CRH

CORTISOL

Cushing’s syndrome

• Cushing’s Syndrome– Results from increased adrenocortical secretion of

cortisol– Causes include:

• ACTH-secreting tumor of the pituitary (Cushing’s disease)

• excess secretion of cortisol by a neoplasm within the adrenal cortex

• ectopic secretion of ACTH by a malignant growth outside the adrenal gland

• excessive or prolonged administration of steroids

• Cushing’s Syndrome– Characterized by:

• truncal obesity• moon face• buffalo hump• acne, hirsutism• abdominal striae• hypertension• psychiatric disturbances• osteoporosis• Amenorrhea• Diabetes

Cushing’s syndrome

www.saadmedical.com

Establishing the Cause

• Serum ACTH, cortisol and urine free cortisol (urine free cortisol is so sensitive, if high you do the suppression test)

• Dexamethasone Suppression testing• Localisation of the ACTH source

– Imaging (MRI) for pit pathologies– CT scan for adrenal pathologies.

Treatment of Cushing’s syndrome

• Treatment of underline cause• Surgery for neoplasia

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Data interpretation

A 2 week old infant presents to hospital with 1 week history of persistent vomiting and lethargy. On examination the infant is 10% dehydrated and unwell. He has normal male genitalia and both gonads are palpable blood results are:

Sodium 115 mmol/L

Glucose 3.8 mmol/L; hypoglycemic <2.7mmol/L

Potassium 7.2 mmol?L

What two investigations would be most likely to confirm the diagnosis?

How do you treat?

• This case could be CAH or hyponatremic dehydration, so now we added the presence of hyperpigmentation to the scenario to confirm CAH.

• The most important 2 investigations are: A. 17 hydroxyprogesterone as a screening test, it will be high (blockage of 21OH will lead to its accumulation of substrate before. B. ACTH stimulation test to confirm the diagnosis.

• DNA study (CYP21) for 21 OH deficiency is done at the end.• Treatment: I.V fluid and I.V hydrocortisone for the treatment of

the crisis, and replacement of cortisol and aldosterone for life.• Not addisons because it doesn’t present in the first few

months of life.

Newborn Screening