Adrenal Disorders in Childhood & Adolescence

1. Adrenal Disorders in
Childhood & Adolescence
A N Gorsuch MA DM FRCP
Consultant Endocrinologist
KSS Deanery PLEAT Day, Conquest Hospital
8 July 2011

2. Adrenal Disorders
Scope of this session
Congenital adrenal hyperplasia (CAH)
illustrated by a case followed through 43 years
–
–
–
–
–
steroid biochemistry
pathology
clinical features
investigations
management
Addison’s disease

3. Congenital Adrenal Hyperplasia
A N Gorsuch
August 1999, updated July 2011

4. Case 1 – neonatal period 1968
First (only) child
Parents young, healthy, unrelated, of Welsh descent
Pregnancy uneventful
BW 3.320 kg at 42/40, length 50cm
(library photo)
Ambiguous genitalia
• enlarged clitoris
• partial fusion of labia
Comments, questions, suggestions?
(to be continued)

5. Corticosteroid biosynthesis
• Supply of cholesterol
• Transport to inner mitochondrial membrane
– StAR (steroidogenic acute regulatory) protein
• Hydroxylases
–
–
–
–
Cytochrome P450 family
NADPH-linked
Mitochondrial & microsomal
5 types involved (4 in adrenal cortex)
• Dehydrogenases
– NADP+-linked
– Microsomal

6. Cholesterol
21
18
20
12
17
11
13
16
1
19
10
HO
14
9
2
3
8
7
5
4
15
6
StAR
Steroidogenic acute regulatory protein
mitochondrial uptake

7. Side-chain cleavage
21
Cholesterol
20
11
HO
3
P450scc (CYP11A)
5
4
17
6
- Mitochondria
- ACTH stimulates

8. Side-chain cleavage
21
Pregnenolone
O
20
11
HO
3
5
4
6
17
HO

9. 17-α-hydroxylation
21
Pregnenolone
O
20
11
17
P45017α
HO
3
5
4
6
(17α-hydroxylase, CYP17)
- smooth endoplasmic reticulum

10. 17-α-hydroxylation
17 α-hydroxy-pregnenolone
11
HO
3
5
4
6
21
O
20
17
OH

11. 5
Formation of ∆ , 3-oxo group
17 α-hydroxy-pregnenolone
11
HO
3
21
O
20
17
OH
5
4
6
∆5,3β-hydroxysteroid dehydrogenase
- Smooth endoplasmic reticulum

12. 5
Formation of ∆ , 3-oxo group
17 α-hydroxy-progesterone
11
3
O
5
4
6
21
O
20
17
OH

13. 21-hydroxylation
P45021
17 α-hydroxy-progesterone
11
3
O
5
4
6
21
O
(21-hydroxylase, CYP21)
20
17
OH
-smooth endoplasmic reticulum

14. 21-hydroxylation
OH
21
11-deoxycortisol
O
20
11
3
O
5
4
6
17
OH

15. 11-β-hydroxylation
OH
21
11-deoxycortisol
O
20
11
3
O
5
4
6
P45011β/18 (11β-hydroxylase, CYP11B1)
- mitochondrial membrane
17
OH

16. 11-β-hydroxylation
OH
21
Cortisol
O
20
HO
11
3
O
5
4
6
17
OH

17. Formation of 17-oxo group
17 α-hydroxy-pregnenolone
11
21
O
20
17
OH
P45017α
HO
3
5
4
6
(17α-hydroxylase, CYP17)

18. Formation of 17-oxo group
Dehydroepiandrosterone
DHEA
11
HO
3
5
4
6
O
17

19. Pathways of adrenal
steroidogenesis
Cholesterol
StAR
Cholesterol
(mitochondrial)
+
P-45017α
Pregnenolone
P-45017α
17OHPregnenolone
Dehydroepiandrosterone
17OH-Progesterone
Androstenedione
3βHSD
Progesterone
17βHSD
P-45021
(Testosterone)
11-deoxycorticosterone 11-deoxycortisol
P-450aro
ACTH
_
Corticosterone
P-450aldo
Aldosterone
Mineralocorticoid
5αR
Oestradiol
P-45011
DHT
Cortisol
Glucocorticoid
Androgen

20. 21-hydroxylase deficiency
one of the commonest known autosomal recessive disorders
Cholesterol
StAR
Cholesterol
(mitochondrial)
+
P-45017α
Pregnenolone
P-45017α
17OHPregnenolone
Dehydroepiandrosterone
17OH-Progesterone
Androstenedione
3βHSD
Progesterone
17βHSD
P-45021
(Testosterone)
11-deoxycorticosterone 11-deoxycortisol
P-450aro
ACTH
_
Corticosterone
P-450aldo
Aldosterone
Mineralocorticoid
5αR
Oestradiol
P-45011
DHT
Cortisol
Glucocorticoid
Androgen

21. Classical 21-hydroxylase deficiency
Pathophysiology
Cholesterol
(mitochondrial)
++
Pregnenolone
17OHPregnenolone
Dehydroepiandrosterone
Progesterone
17OH-Progesterone
Androstenedione
P-45021
11-deoxycorticosterone 11-deoxycortisol
(Testosterone)
Oestradiol
ACTH
DHT
_
Aldosterone
Mineralocorticoid
Cortisol
Glucocorticoid
Androgen

22. Classical 21-hydroxylase deficiency
Anatomy
Cerebriform hyperplasia in an 18-day-old infant with
salt-wasting congenital adrenogenital syndrome

23. Classical CAH 21-hydroxylase deficiency
Incidence & effects
Incidence ~ 1 in 14 000 live births
higher in some populations
• Ashkenazy Jewish
• ‘Celtic’
75%: salt-wasting adrenocortical insuff at ~7-10 days
Other effects
Female
– ambiguous external genitalia
– internal (müllerian) organs usually normal
– hirsutism, delayed menarche, subfertility, polycystic ovaries
Male
– genitalia usually normal
– precocious ‘pubarche’ (adrenarche)
– testicular adrenal rests, usually benign

24. Ambiguous genitalia:
diagnosis – 1
Examination
– identify urethral meatus
– gonads
Blood biochemistry (NOT in first 24h; special reference ranges in prematurity)
– U&E
– at least, random 17-hydroxyprogesterone (17-OHP) . Result >100 nmol/l
diagnostic. False –ve possible if mother on glucocorticoid treatment.
– ideally, also cortisol, 11-deoxycortisol, 17-OH-pregnenolone,
androstenedione, maybe deoxycorticosterone & dehydroepiandrosterone
– borderline results: repeat pre- and 1-hr-post synacthen 250mcg
– (plasma renin activity / aldosterone not helpful – overlap with normal)
Rapid karyotype
Genotyping identifies ~95% of mutations
USS pelvis
Urinary steroid profile important in past, still useful in some cases

25. Ambiguous genitalia:
diagnosis – 2
Gonads
palbable?
Uterus
on USS?
N
Y
Uterus
on USS?
N
XY male
pseudohermaphrodite
17-OHP
high?
Y
N
N
Karyotype
Y
XX
X/XY
X/XXY
Mixed
gonadal
dysgenesis
Y
XX Female
CAH
XY
XX/XY
True
hermaphrodite
Female
pseudohermaphrodite
Assign the baby’s sex only when diagnostic information is available
(multidisciplinary team, with parents)
White PC. Congenital Adrenal Hyperplasias. Best Prac Res Clin Endocrinol Metab 2001; 15(1): 17-41

26. Neonatal diagnosis of CAH
Ambiguous genitalia – see previous slides
Adrenal crisis (mainly in male babies at 7-10 days)
– biochemistry / genotyping as above
Neonatal screening – ‘Guthrie’ cards for 17-OHP
Not currently offered in UK
under review – report expected March 20121
Standard in USA since 2008, also in NZ etc
+ve in ~0.5% of all tests, specificity only 2%
– normal result after mult antenatal glucocorticoid Rx: repeat after 2 wks
– borderline result: repeat, or genetic testing
– high result: U&E and 17-OHP etc on fresh blood
1 http://www.screening.nhs.uk/policydb.php?policy_id=65 accessed 4/7/11

27. Management of CAH
Glucocorticoid replacement / androgen suppression
–
–
–
–
–
children: hydrocortisone 10-20mg/m2 per day, divided doses
adults: usually dexametasone
larger dose at bed-time to suppress ACTH
beware over-replacement
monitor
17-α-progesterone and androstenedione (?testosterone, cortisol, ACTH etc)
growth, bone age, BP, U&E, skin; osteoporosis scans in adults
Correction of salt-wasting
– 9-a-fludrocortisone 100-400mcg/day (long-acting)
– plus sodium chloride supplements until able to select saltier foods
– monitor BP, U&E, oedema (?renin)
Corrective surgery to genitalia
Genetic counselling & psychological support

28. Case 1 – neonatal period 1968
(continued)
Initial (?timing) urinary steroid profile ‘normal’
Aged 9 days: vomiting, hypotensive, Na+↓, K+↑
Repeat steroid profile
abnormal: CAH (21-hydroxylase deficiency)
IV resuscitation
Rx glucocorticoid and mineralocorticoid

29. Case 1: Infancy
Steroid replacement
–
–
–
–
various regimens tried
poor growth, hypertensive
crises when tried without mineralocorticoid
finally settled on
hydrocortisone 5mg tds
fludrocortisone 50mcg bd
Corrective surgery aged 2yr 9 mth
– partial clitoridectomy (preserving glans) & vaginoplasty
library photos © Endopics

30. Case 1: Childhood to mid-teens
•
•
•
•
•
•
•
on hydrocortisone 10/5/10 mg + fludro 100/50 mcg
satisfactory growth up 10th centile from age 9
menarche at 13
ht 1.545m wt 52.0kg BMI 21.8 at age 15
lively, ‘a tomboy’
gynae review: ‘tidying up’ suggested when fully mature
moved to Hastings from Surrey 1983

31. Case 1: Aged 20
• androgens not fully suppressed
even on hydrocortisone totalling 40mg/day
• transferred to dexametasone 500mcg bd
androgens then well controlled
• fludrocortisone 200 mcg daily
• gynae opinion
– menstruating normally so internal organs functioning
– full examination not possible
– consider EUA & laparoscopy in due course

32. Case 1: Aged 21 (1989)
•
•
•
•
17-hydroxyprogesterone & androstenedione normal
BP 130/90, K+ 3.9, dermal atrophy, weight up
dexametasone 500mcg reduced from bd to od
fludrocortisone reduced from 200 to 150mcg daily
– BP then 110/70, andro & 17-OHP well controlled, weight down
• thinking of getting married at some time in the future
– considering OCP & referral back to gynaecologist
– soon afterwards …

33. Case 1: Pregnancy
Aged 21 – 1st pregnancy 1989-90
– tired: dexametasone* increased to 250/500mcg
then developed purple striae so reduced to 250mcg bd
–
–
–
–
Na+ <140: fludrocortisone increased to 100mcg x12 /wk div
androgens remained well suppressed
ELCS at 39/40, glucocorticoid cover
baby normal & well
pre-discharge 17-OHP sample lost; 10-day 17-OHP normal.
Age 26: 2nd pregnancy 1994-5
– similar, but dexametasone* 250/500mcg needed to control
androgens, ?leading to excess weight-gain
– baby normal
– reduced weight subsequently on Dex 250mcg on
* hydrocortisone or prednisolone now recommended in pregnancy

34. CAH and Pregnancy
• Pregnancy in a woman with CAH
1999: the placenta blocks androgens, prednisolone &
hydrocortisone, but passes dexametasone
– reassure that CAH unlikely to affect baby
unless parents related or Ashkenazy Jews etc
– preferably use hydrocortisone tds or prednisolone
– continue fludrocortisone
– monitor as in non-pregnant state; doses may need adjusting
• Prenatal diagnosis & treatment where fetus at risk
– amniocyte/chorionic villus genetic analysis
– amniotic fluid 17-OHP has been used
– dexamethasone to mother (crosses placenta)

35. Case 1: Current status
Age 42 (2010)
–
–
–
–
–
–
Well
on dexametasone 250mcg on
fludrocortisone recently increased to 200mcg as renin up
17OHP, Andro, DHEA, ACTH, Testo, renin all normal
clinic BP up, awaiting monitoring
Mirena coil.

36. 21-hydroxylase deficiency:
non-classical
Cholesterol
(mitochondrial)
++
Pregnenolone
17OHPregnenolone
Dehydroepiandrosterone
Progesterone
17OH-Progesterone
Androstenedione
P-45021
11-deoxycorticosterone
(Testosterone)
Oestradiol
ACTH
DHT
_
Aldosterone
Mineralocorticoid
Cortisol
Glucocorticoid
Androgen

37. 21-hydroxylase deficiency:
non-classical
Incidence ~ 1 in 500
– higher in some populations
• Askenazy Jews
• ‘celtic’
Not salt-wasting or glucocorticoid-deficient
Neonatal genitalia normal or mild clitoromegaly
Often presents in adolescent/adult female with hirsutism etc
Precocious virilisation in some males

38. 21-hydroxylase deficiency:
non-classical
•
•
•
•
16-year-old girl
hirsutism
labial thickening
limited breast
development

39. 21-hydroxylase deficiency:
non-classical
• Surgical correction of clitoromegaly in adolescent girl

40. 21-hydroxylase deficiency:
non-classical
• 20-year-old woman
• shaves daily
• mildly cushingoid due
to glucocorticoid overreplacement

41. 11β-hydroxylase deficiency
Cholesterol
(mitochondrial)
++
Pregnenolone
17OHPregnenolone
Dehydroepiandrosterone
Progesterone
17OH-Progesterone
Androstenedione
11-deoxycorticosterone 11-deoxycortisol
ACTH
_
Oestradiol
P45011β
Aldosterone
Mineralocorticoid
(Testosterone)
DHT
Cortisol
Glucocorticoid
Androgen

42. 11β-hydroxylase deficiency
Commonest CAH after 21-hydroxylase deficiency
but still <1 in 100 000 live births
Virilising but not salt-wasting at presentation
Hypertension
May become salt-wasting with glucocorticoid treatment

43. Rare forms of CAH
3β-hydroxysteroid dehydrogenase deficiency
17α-hydroxylase deficiency (hypertensive)
20,22 desmolase deficiency
StAR mutations - ‘lipoid CAH’
Incidence < 1 in 100 000
Genitalia in neonate (no sex hormones)
– in female: female
– in male: ambiguous, or female without uterus etc
Adrenocortical insufficiency
Salt-wasting, except in 17α-hydroxylase deficiency

44. Last slide on CAH
Any questions?
References
• White PC. Congenital Adrenal Hyperplasias. Best Prac Res Clin Endocrinol Metab 2001; 15(1): 17-41
• UpToDate

45. Addison’s disease
Tutorial
June 2000, updated July 2011
A N Gorsuch

46. Addison’s disease
Scope of this session
•
•
•
•
•
•
Definition & History
Pathology
Clinical features
Investigations
Long-term replacement therapy
Management of addisonian crisis

47. Definition & History
Chronic primary adrenocortical insufficiency
Described by Thomas Addison (1795-1860)1
– from Newcastle & Cumberland
– MD (Edin) 1815
– on staff of Guy’s Hospital.
1Addison
T, “On the Constitutional and Local Effects of Disease of the Suprarenal Capsules”, 1855.

48. Epidemiology
Nottingham, 1987-93 1
Prevalence
Incidence
M:F ratio
Age at onset
1Kong
110 10-6
5-6 10-6 y-1
1:3.5
5-79 y; 63% 20-50 y
M-F & Jeffcoate W, Eighty-six cases of Addison’s disease. Clin Endocrinol (1994); 41: 757-761

49. Aetiology
in early 19th century England
Mainly tuberculosis (usually bovine) .
..

50. Aetiology now
Frequency
England 1987-93 1
Organ-specific autoimmunity
93%
Metastatic malignancy
2%
Adrenoleukodystrophy
3%
X-linked recessive, consider in boys under 15
Tuberculosis
1
0%
Kong M-F & Jeffcoate W. Eighty-six cases of Addison's disease.Clin Endocrinol 1994; 41:757-761

51. Polyendocrine AI disease
Primary hypothyroidism
Type 1 diabetes
Graves’
Premature ovarian failure
Hypoparathyroidism
Pernicious anaemia
25%
10%
11%
13% of women
4%
1%
Kong M-F & Jeffcoate W. Eighty-six cases of Addison's disease.Clin Endocrinol 1994; 41:757-761

52. Presentation & clinical features
Usually present: insidious …
–
–
–
–
–
Anorexia, nausea, weight-loss
Fatigue, weakness, lethargy
Postural dizziness & hypotension
Pigmentation
Recurrent hypoglycaemia / falling insulin requirement in DM
May occur
–
–
–
–
–
–
–
–
–
–
Nocturia
Abdominal pain, dyspepsia, back pain
Vitiligo
Supine hypotension
Diarrhoea
Loss of body hair
Erectile failure or amenorrhoea
Mental disturbances
Addisonian crisis: vomiting, dehydration, hypoglycaemia, shock.
Death.

53. Addisonian pigmentation III
Woman aged 40
Weight loss
Dehydrated
Hypotensive

54. Addisonian pigmentation IV
buccal pigmentation

55. Addisonian pigmentation V
gingival pigmentation

56. Addisonian pigmentation VI
extensor creases

57. Addisonian pigmentation VII
recent scar

58. Investigations I
Serum cortisol (09:00)
• Addison’s excluded if >500nmol/l
• adrenocortical insufficiency if <200 at 09:00
• SACTH test needed if 200-500
Short tetracosactrin (Synacthen) test
• high-dose (250mcg);
– normal if baseline >250 and 30-min >600 nmol/l
• low-dose (1 mcg) may be better for CENTRAL
adrenocortical insufficiency of recent onset

59. Investigations II
Biochemistry
•
•
•
•
•
•
•
•
Na+ low or normal, 120-140 mmol/l
K+ high or high-normal, 4.5-8
Glucose may be low
Urea may be raised
Calcium may be raised
Plasma renin activity elevated
Plasma aldosterone low (esp upright)
Hypothyroidism may coexist
Haematology
• Normocytic anaemia usual when hydrated
• Pernicious anaemia may coexist

60. Investigations III
Radiology
• Chest
• Abdomen

61. Long-term replacement therapy - I
Glucocorticoid
•
•
•
•
hydrocortisone (formerly cortisone acetate)
first dose on waking, +1-2 further doses up to 18:00 hr)
maintenance doses e.g. 10/5mg to 15/10/5mg
adjust on clinical grounds; may do cortisol day curves
Mineralocorticoid
• 9a-fludrocortisone 50-300mcg daily
• adjust using BP, U&E, ?PRA (plasma renin activity)
Androgen?
• DHEA may help some otherwise optimally-treated women with
persisting lethargy, low libido or low mood1
• not prescribable, available OTC
• ?try 25-50mg od for 3-6 months, stop if no clear benefit2
1Arlt
et al, NEJM 1999; 341: 1013-1020)
LK. Treatment of adrenal insufficiency in adults. UpToDate. Accessed online 9/6/11
2Nieman

62. Long-term replacement therapy - II
Education
•
•
•
•
Double hydrocortisone during illness, then back to usual
Medic-Alert or similar
Vomiting is dangerous
Vial of hydrocortisone injection & syringe in fridge
Other points
• Depriving of fludrocortisone to treat essential hypertension is
unkind (postural hypotension)
• Beware osteoporosis due to over-replacement
• Consider DEXA scan

63. Management of Addisonian crisis in adult
Blood for cortisol, U&E, Cr, glucose, Ca, FBC
but don’t wait for result
Glucocorticoid parenterally
Known Addisons: Hydrocortisone 100mg IV (or IM) stat, then 100mg 6hrly im or 4-hrly iv
Suspected new case: Dexametasone 4mg IV (or IM) - does not affect
cortisol assay
IVI 0.9% saline, preferably with added glucose;
?1 litre in first 30-60min, total up to 6 litres
CVP line in most cases
May need plasma expander & large amounts glucose
Monitor ECG, TPR, BP, glucose, U&E, Cr
Treat any underlying infection etc.
When stable
Short synacthen test in new case
Change to oral hydrocortisone 20mg tds + (resume) fludrocortisone
Later back to maintenance doses