Diagnosis and management of

adrenal disorders in childhood

Professor Maria CraigStaff Specialist

Institute of Endocrinology & Diabetes

Children's Hospital at Westmead

University of Sydney, University of NSW

Session Outline

• Adrenal physiology – the basics

• Case presentations

• Pheochromocytoma

• Cushing’s disease in an infant

• Hyponatraemia

• Diagnosis and management of PPGL

• Diagnosis and management of Cushing’s

• Diagnosis and management of adrenal

insufficiency and CAH

Fetal adrenal cortex

• Adrenal cortex is derived from mesodermal

gonadal ridge at 5-6wks gestation

• Gonadal ridge cells migrate, giving rise to

steroidogenic cells (adrenal and gonadal)

• At 7-8wks, sympathetic nerve cells (neural

crest/ectodermal origin) invade into primitive

adrenocortical cells – adrenal medulla

• During late gestation, placental oestrogen

promotes fetal cortisol production• Promotes maturation of lung, thyroid, liver, gut

• Fetal adrenal rapidly regresses at birth

Mineralocorticoid

Glucocorticoids

Androgens

CatecholaminesNeural crest origin

Mesothelium

origin

Adrenal cortical hormone synthesis

*

*

* CYP11B2 (in zona glomerulosa)

CYP11B1 (in zona fasciculata)

Adrenal Physiology 1

• Cortisol secretion regulated

by CRH and ACTH

• negative feedback on

both CRH and ACTH

• ACTH secretion also

regulated by cytokines

• CRH regulates ACTH

via production of POMC

• Cortisol secretion

• 7-9 mg/m2/day neonates

• 6-7 mg/m2/day children

• 100-150 mg/m2/day stress

Renin-angiotensin-aldosterone axis

Angiotensinogen Angiotensin I Angiotensin II and III

(liver)

Aldosterone secretion

Potassium ACTH

Renin (kidney) ACE (lung)

+

+ (+)

Aldosterone secretion rate

50 ug/m2/day - adults and older children

> 300 ug/m2/day neonates and young infants

Adrenal Physiology 2

Mineralocorticoid secretion regulated mainly

by RAAS, potassium and ACTH (minor)

Actions of glucocorticoids

• Glucocorticoids influence the regulation of

about 20% of the human genome !

• Intermediary metabolism • Maintenance of plasma glucose

• Lipolysis

• Cardiovascular function• Permissive effects on inotropic, chronotropic &

pressor effects of hormones

• Maintenance of muscle work capacity• muscle enzyme induction

Actions of glucocorticoids 2

• Growth and development

• Induction of fetal enzymes, surfactant

• Immunoregulatory and antiinflammatory actions• Induction of lymphocyte apoptosis

• Renal function

• GFR, sodium and water excretion

• Central nervous system / behaviour

• Bone and connective tissue

• Increase bone resorption and reduce bone formation

• Calcium balance

• Decrease intestinal ca absorption

Actions of mineralocorticoids

• Aldosterone promotes active sodium

resorption and potassium excretion in its

major target tissues

• Target tissues - kidney, colon, salivary glands

• Others: liver, pituitary, brain, mononuclear cells

• Effects via high affinity type I glucocorticoid

(mineralocorticoid) receptors

• Glucocorticoids also act weakly via these

receptors

Adrenal disorders in children

• Adrenal insufficiency

• 72% CAH, 6% other genetic, 13% Addison’s

• CAH： 1 in 15,000-20,000

• Adrenal insufficiency: 1 in 16,000

• Congenital adrenal hypoplasia

• 1 in 12,500 (Japan), less frequent elsewhere

• Phaeochromocytoma: 1 in 100,000

• Adrenal tumor: 1 in 1,000,000

Case 1 - Phaeochromocytoma

Pimonsri Hantanasiriskul

Bangkok, Thailand

PPGL: chromaffin cell tumours

• Pheochromocytoma (80%) - arises from

adrenomedullary chromaffin cells

• 1.7% of children with hypertension

• 5% of incidentally discovered adrenal masses

• Rarely biochemically silent but 1/3 of cases

normotensive and asymptomatic

• Paraganglioma (20%) - from extra-adrenal

chromaffin cells in sympathetic paravertebral

ganglia of thorax, abdomen and pelvis

• At least 1/3 of patients with PPGLs have disease-

causing germline mutations

Phaeochromocytoma: 5 Ps

• Pressure (HTN) ~90%

• Pain (Headache) ~80%

• Perspiration ~71%

• Palpitation ~64%

• Pallor ~42%

• Lack of the first 3 Ps exclude diagnosis of

phaeo

Clinical importance of PPGL

• Catecholamine hypersecretion - high

cardiovascular morbidity and mortality

• Enlargement over time – mass effect

• Earlier diagnosis and treatment in relatives if

familial disease

• Detection of malignant disease

• Metastases in nonchromaffin tissue: 10-17%

• SDHB mutations 40%

PPGL diagnosis

• Initial testing: plasma free metanephrines or

24-hr urinary fractionated metanephrines• Use liquid chromatography with mass spectrometric or

electrochemical detection methods

• Draw blood with the patient in the supine position,

having been recumbent for 30 mins

• False +ve: acetaminophen, labetalol, sotalol, stress

• Imaging if biochemical evidence of PPGL

• CT with contrast rather than MRI - excellent

spatial resolution for thorax, abdomen & pelvis

PPGL Management

• Surgery is first line therapy

• Perioperative pharmacological blockade

• α blockade: Prazosin (usually 10-30 mg TID)

• β blockade: Atenolol (β1) (12.5-25 mg BID) after

at least 1 week of alpha blockade

• Ca channel blockers (start with 5 mg OD)

• High sodium diet and fluid intake

• Duration: 7 to 14 days to allow adequate time to

normalize blood pressure and heart rate

PPGL follow up

• Post op: monitor BP, HR and BGLs

• Biochemical testing 2–4 wk after surgery to

document successful tumour removal

• Lifelong annual biochemical testing to

assess for recurrent or metastatic disease

• High likelihood of hereditary disease if

• positive family history, syndromic features,

multifocal, bilateral or metastatic disease

• even if none of these, mutation rate ~12%

Genetic testing

• Most common mutations

• SDHB 10.3%, SDHD 8.9%, VHL 7.3%,

RET 6.3%, NF1 3.3%

• Clinical feature-driven decisional algorithm

• Genes tested prioritized according to a

syndromic or metastatic presentation

• If paraganglioma – test for SDH mutation

• If metastatic disease – test for SDHB mutations

Lenders et al, JCEM 99: 1915–1942, 2014)

Summary

• Look for associated features

• Look for familial disease

• Look for location, biochemistry and

immunohistochemistry to prioritize genetic

screening in sporadic patients

• clinical feature-driven diagnostic algorithm

• Indefinite monitoring

Case 2

Cushing’s disease in an infant

Mya Sandar Thein

Myanmar

Hypercortisolism

• Physiologic States

1. Stress

2. Pregnancy

3. Chronic strenuous exercise

• Pathophysiologic States

1. Cushing syndrome

2. Psychiatric states

• Depression

• Alcoholism

• Anorexia nervosa

• Anxiety disorders

3. Malnutrition

4. Glucocorticoid resistance

Cushing’s syndrome in childhood

• 1-5 per million population per year

• 10% are paediatric cases

• Median age at diagnosis ~ 9 years*

• Median time between symptoms and

diagnosis 1 year

• F>M• * Güemes M et al, Eur J Peds 2016

• In adults

• Cushing’ s disease > adrenal Cushing’s

Aetiology of Cushing’s

• >7 years old: 85% ACTH dependent • Of these, 80% pituitary dependent, 20% ectopic ACTH

• 15% ACTH independent

• Adenoma 30%, carcinoma 70%

• <7 years old: adrenal tumors (esp infants)

• UK series (all ages)

• 50% pituitary dependent CS

• 36% adrenal dependent CS

• 7% (2 cases) – ectopic ACTH

• Güemes M et al, Eur J Peds 2016

Aetiology of Cushing’s syndrome

Data courtesy of Nalini Shah

Mechanisms of clinical signs

• Excess glucocorticoids

• Excess mineralocorticoids

• Excess adrenal androgens

Clinical symptoms & signs

• Weight gain 77%,

• Hirsutism 57%

• Acne 50%

• Hypertension 50%

• Poor school performance 43%

• Fatigue or weakness 40%

• Growth retardation 37%

• Striae 25%

• Median BMI +2.1 SDS (-6.5 to +4.6)

• Güemes M et al, Eur J Peds 2016

Evaluation of Cushing’s syndrome

1. Establish diagnosis

2. Differentiate causes

Diagnosis of Cushing’s syndrome

• Drug history to exclude iatrogenic CS

• Testing recommended for specific groups

• Patients with unusual features for age (eg

osteoporosis, hypertension)

• Patients with multiple and progressive features

• Children with decreasing height percentile and

increasing weight

• Patients with adrenal incidentaloma compatible

with adenoma

Diagnostic

work up

in Cushing’s

Syndrome

Localisation of endogenous

hypercortisolism

• Clinical assessment

• ACTH : basal, midnight

• Imaging : MRI

Pituitary Adenoma vs.

Ectopic ACTH Secreting Tumour

• False positive (1-3%)

• Normal corticotrophs not fully suppressed in

adrenal disorder

• False negative (6 – 9%)

• Technical factors

• Anatomical variation

• Anomalous venous drainage

• Hypo plastic IPS

• Ectopic tumour in CD

Treatment of Cushing’s syndrome

• Principles:

• Normalize cortisol levels or action at its receptors

to eliminate symptoms and signs of cortisol

• do not treat based on biochemistry alone

• Treat comorbidities

• Multidisciplinary team approach

• Provide educational materials

• Surgery for CD, ectopic and adrenal causes

• 1-2 weeks post op assess for pit hormone def

• 1-3 months post op – MRI

Treatment of Cushing’s disease

• Successful management

• Localisation is essential

• Treatment of choice

• Trans-sphenoid surgery

• For failed surgery or persistent/recurrent CD

• radiotherapy

• bilateral adrenalectomy

• medical management

Nieman L et al, JCEM 2015,

100(8):2807–2831

Is there a role for biopsy in

adrenal disease?

• NO, because needle biopsy

• Cannot distinguish a functional cortical

adenoma from a non-functional adenoma

• Cannot reliably distinguish adrenocortical

carcinoma from benign adenoma

• Unfavourable to violate an adrenal cortical

carcinoma with needle biopsy

• Biopsy of an unknown and/or untreated

phaeochromocytoma may result in

haemorrhage and hypertensive crisis

= potentially fatal

Case 3 - Hyponatraemia

Lisa Power

Auckland, New Zealand

Primary Adrenal Insufficiency

ADRENAL PATHOLOGY

1. Autoimmune (Addison’s disease, most common ~80%)

2. Congenital

• Congenital adrenal hyperplasia

• Congenital adrenal hypoplasia (DAX-1, SF-1, IMAGe syn)

• Adrenoleukodystrophy, adrenomyeloneuropathy

• ACTH resistance (FGD: MC2R, MRAP, NNT, TXNRD2, NNT)

• Resistance: glucocorticoid/mineralocorticoid receptor

3. Infection / destruction / haemorrhage / infiltration

• TB, fungal, CMV, meningococcus, anticoagulants, Trauma, emboli, tumour, Sarcoid, Amyloid, Hemochromatosis

4. Surgical – adrenalectomy

5. Adrenal suppressive or antagonist drugs

• Ketoconazole, cyproterone, steroid withdrawal, T4

AAA syndrome

• Alacrima-Achalasia-Adrenal Insufficiency

• AAAA syndrome + autonomic disturbance

• Mutations in ADRACALIN (AAAS) gene (12q13)

• Encodes ALADIN protein of nuclear pore complexes

• Progressive loss of cholinergic function, or melanocortin

receptor signalling

• Alacrimia earliest & most consistent feature

• Crying without tears

• Recurrent vomiting, dysphagia, failure to thrive

• Neurological manifestations at later age

APECED / APS-1: spectrum of illness

• Uncommon – approx 1 per 100,000• 1/9,000 Iranian Jews, 1/10,000,000 Japanese

• 21q22.3 (AIRE – autoimmune regulator)

• High phenotypic variability, even within families• Chronic mucocutaneous candidiasis (~97%)

• Hypoparathyroidism (~96%)

• Addison’s disease (78%)

• Hypothyroidism

• Type 1 diabetes

• Primary gonadal failure

• Chronic active hepatitis

• Pernicious anaemia

Secondary Adrenal Insufficiency

HYPOTHALAMIC - PITUITARY PATHOLOGY

1. HPA axis suppression

• Exogenous or endogenous glucocorticoids

2. Pituitary or hypothalamic disorders

• aplasia, hypoplasia

• Note: 44% of adults with childhood GHD - ACTH deficient

• tumours, surgery, radiation

• autoimmune

• infection

• haemorrhage

• infiltration

AI – metabolic consequences

PRIMARY (ie adrenal pathology)

• Glucocorticoid AND mineralocorticoid deficiency

• Hypotension Acidosis Hyperpigmentation

• Hyponatraemia Renal salt loss Failure to thrive

• Hypoglycaemia Hyperkalaemia (Hypocalcaemia)

SECONDARY OR TERTIARY (ie pituitary or hypothalamic)

• Glucocorticoid deficiency only

• Signs of AI may be non-specific in neonates: • respiratory distress, prolonged cholestatic jaundice, lethargy, FTT,

recurrent vomiting, poor feeding, sepsis

• + hypoglycaemia, seizures

Diagnosis of AI

Diagnostic approach to PAI

Bornstein et al, JCEM 2015, 10(2) 364-389

Confirming the diagnosis of AI

• Site of pathology often evident from clinical presentation

• Serum cortisol during stress • > 500 nmol/l (but may be higher)

• Normal am cortisol 140 – 500nmol/L (afternoon ~ 1/3 am value)

• Short synacthen test • Synacthen dose 250 ug > 2 yr, 125ug <2 yr, 15ug/kg infants

• At 60 minutes peak cortisol > 500 nmol/l ; increment > 280

• Reliable in primary adrenal disease

• Useful in secondary adrenal insufficiency; but note limitations:• Not within 2 weeks of trauma, surgery, change in steroid dose

• Risk of false “normal” results

• If synacthen not possible, morning cortisol + ACTH level

• Renin + aldosterone levels

Laboratory evaluation of adrenal insufficiency

Test Criteria Utility Limitations

Random cortisol

Normal cortisol >600 nmol/l.

Definite AI <35

Acutely ill or hypoglycemic patients.

Useful if high.

Often indeterminate

Morning cortisol

Normal >600 Abnormal<140

Measure of HPA function in stable patients

Often indeterminate, not a good predictor alone

Urinary free cortisol

Not well established

? Normal in 20% with AI

ACTH level Primary AI : ACTH > 100 pg/ml (22 pmol/l)

Localizing. Best test to separate primary from central AI

Not useful as a diagnostic test for AI. Difficult assay.

Acute adrenal crisis

• Fluids - volume resuscitation, glucose

• 0.9% NaCl 20 ml/kg (up to 60ml/kg for shock)

• For hypoglycaemia dextrose 0.5-1.0 g/kg)

• Hydrocortisone bolus 100 mg/m2 BSA

• repeat if poor response, then 100 mg/m 2 QID

• Cardiovascular monitoring and support if needed

• Collect blood for EUC, glucose, ACTH, cortisol,

plasma renin

• Measures to lower K – usually only if very elevated

• Consider and investigate possible aetiology

Long term management

• Hydrocortisone replacement

• 8-12 mg/m2/day in 3-4 doses (start with 8)

• Higher doses for primary vs secondary AI

• Fludrocortisone 0.1 to 0.2 mg daily (start with 0.1)

• Sodium supplements for neonates & infants < 12 mths

• Education of parents, carers, school

• Written instructions for stress cover

• Review instructions at least annually

• Teach family to use IM hydrocortisone

• Medical alert precautions (bracelet, card)

• On call endocrine team contact details

• Screen for other autoimmune diseases periodically

Monitoring replacement

• Monitoring replacement

• Clinical judgement• Symptoms (wellness / energy), height, weight, BP, pigmentation

• CAH• 17OHP, androstenedione, testosterone, PRA, (electrolytes)

• Addison’s disease • PRA, ACTH, (electrolytes)

• Secondary adrenal insufficiency • clinical

• cortisol levels not usually helpful, 24 hour profiles in some cases

Treatment principles for CAH

1. Physiological steroid replacement

2. Suppression of excess ACTH

• To prevent pigmentation

3. Suppression of excess androgens

• To avoid virilisation in females

• To avoid precocious puberty males & females

4. Achieve normal growth

5. Avoid obesity

6. Fertility

7. Psychological well being

Initial treatment

• Hydrocortisone• Starting dose 20 mg/m²/day in 3 divided doses

• Can use higher doses in infancy, but reduce asap

• Do not use suspension

• Fludrocortisone

• 0.15-0.2 mg/day

• Neonates are relatively insensitive to

mineralocorticoids and need larger doses

• + Salt supplementation 3-4 mmol/kg/day

• 1 mmol/kg.day

Long term treatment

• Hydrocortisone 10-15 mg/m²/day

• Over treatment• Growth delay

• Cushingoid features

• PCOS

• Under treatment• Hyperandrogenism

• Advanced bone age

• Precocious puberty

• Short adult height (early epiphyseal closure) − Note pubertal growth is diminished

• Fludrocortisone 0.05-0.2 mg/day

Additional considerations

• Stress dosing for febrile illness (>38.5 C),

gastroenteritis with dehydration, surgery with

general anaesthesia, major trauma

• Not for mental and emotional stress, minor illness or

before physical exercise

• Medical alert precautions

• Monitoring:

• Consistently timed hormone measurement – avoid

complete suppression of androgen levels

• Clinical: height, weight, and physical examination

• Annual bone age after age 2 years

Summary and key points

• Wide spectrum of adrenal disease in

childhood – understanding adrenal gland

development and physiology is essential to

aid diagnosis and management

• Tailor therapy to aetiology and age

• Careful clinical & assay monitoring to avoid

consequences of over or under-treatment

• Education of patients and carers is critical,

with regular review of stress management