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17th May 2007
History
 Chief complaint
 A 6 week-old girl was referred to our hospital
with history of severe vomiting for 3 days
History
 History of present illness
 3 days before admission, she had severe
vomiting and lethargy without fever, diarrhea
or dysuria. She was admitted to a local
hospital. Her investigation:
serum electrolyte study revealed
Na+ 122 mmol/l, K+
7.1 mmol/l,
Cl- 84 mmol/l, HCO3- 15 mmol/l
blood sugar was 126 mg/dl.
History
 History of present illness
 24 hours after admission, she developed
generalized tonic clonic seizure, and cyanosis
but she had no bladder or bowel incontinence
during convulsion.
 She received initial treatment and was
referred to Siriraj hospital.
History
 Birth history
Antepartum
 G2P1A0
 No maternal drug or hormonal usage
 No complication of pregnancy
Intrapartum
 Cesarean section due to previous cesarean section
 Term AGA infant, birth weight 3,200 g (P50)
 Apgar score 10, 10 at 1, 5 minute
 Ambiguous genitalia
History
 Family history :
 The second child of family
 Her sister is healthy.
 No consanguinity
 No history of ambiguous genitalia, precoccious
puberty or neonatal death in her family
 Drug History:
 No history of drug or food allergy
History
 Nutrition:
 Breastmilk and formula every 2 hours
Physical examination
 Vital signs:
 T 37.5° C, pulse 131 bpm regular, BP 99/49 mmHg
(P75-P90), RR 48 /min
 Weight 3,600 g (P3-P10), Length 53 cm (P10-P25),
Head circumference 37 cm (P50)
 General appearance:
 Lethargy, not pale, no jaundice, no sign of
dehydration
 Skin:
 Mild hyperpigmentation at nipple and genitalia
Physical examination
 Head, eye, ear, nose and throat:
 AF 2 x 2 cm. PF fingertip, no dysmorphic features
 Respiratory system:
 Normal breath sound, no adventitious sound
 Cardiovascular system:
 Normal S1 and S2, no murmur, capillary refill less
than 2 seconds
 Abdomen:
 Soft, not tender, liver and spleen not palpable, no
palpable mass
Physical examination
 Extremities:
 No deformity
 Nervous system:
 Grossly intact
 Genitalia:
 Phallus: length 3.3 cm, width 1.2 cm
 Fused labioscrotal fold with few rugae and
hyperpigmentation, no palpable gonad
 Single urethral opening at perineoscrotal region
Problem list: 2 month-old girl with
 Ambiguous genitalia without palpable gonad





Severe vomiting and lethargy for 3 days
Failure to thrive
Dehydration
Mild hyperpigmentation at nipples and genitalia
Hyponatremia, hyperkalemia and wide anion gap
metabolic acidosis
 Mineralocorticoid deficiency
Approach to ambiguous genitalia
Ambiguous genitalia
Gonad palpable
Male
pseudohermaphroditism
Gonad not palpable*
True hermaphroditism
Female
pseudohermaphroditism
Female pseudohermaphroditism
 Definition
 The situation where chromosomal and gonadal
gender are female but the external genitalia
resembling male.
 Androgen excess is the key
Differential diagnosis
1.
2.
3.
4.
5.
6.
Congenital adrenal hyperplasia (CAH)
Maternal androgen excess
Aromatase deficiency
Androgenic target hypersensitivity
Multiple congenital malformations
Unknown etiology
Congenital Adrenal Hyperplasia
 The most common cause of ambiguity in the newborn
 Autosomal recessive pattern of inheritance (Mutation
in chromosome 6p21.3)
 An enzymatic defect in adrenal steroid biosynthesis
 90% of CAH caused by 21-Hydroxylase deficiency
 A type of primary adrenal insufficiency
The adrenal gland
Renin angiotensin aldosterone system
and K+
 Adrenal cortex
CRH and ACTH
 Zona glomerulosa (15%) aldosterone
 Zona fasciculata (75%) cortisol
CRH and
 Zona reticularis (10%) androgen
ACTH
 Adrenal medulla
CRH and
ACTH
Steroid biosynthesis
Congenital adrenal hyperplasia
 It was classified into 3 forms
 Salt wasting 21-hydroxylase deficiency (classic
form) about 2/3 of all patients
 Virilizing 21-hydroxylase deficiency
 Non-classic 21-hydroxylase deficiency
Salt wasting 21-hydroxylase deficiency
 Glucocorticoids and mineralocorticoids deficiency
 Salt wasting crisis since infancy (7-14 days old)
 Failure to thrive, vomiting, hypotension
 Cortisol deficiency stimulate the production of ACTH
which cause hyperpigmentation
 Androgen excess
 Female infant: Ambiguous genitalia since birth, which
range from fused labioscrotal folds to perineal hypospadia
 Male infant: Normal genitalia, usually presented with
signs and symptoms of adrenal insufficiency
Salt wasting 21-hydroxylase deficiency
 Mineralocorticoid
deficiency
 Salt craving
 Malaise
 Weight loss





Hypotension or shock
Hyponatremia
Hyperkalemia
Metabolic acidosis
 Plasma renin activity
 Corticosteroid
deficiency
 Hypoglycemia
 Hyponatremia






Hypotension or shock
Malaise
Poor appetite
Weight loss
Nausea, vomiting
Abdominal pain
Salt wasting 21-hydroxylase deficiency
Severe clitoral
hypertrophy from
masculinization of the
external genitalia of a
46,XX patient caused
by CAH
Virilizing 21-hydroxylase deficiency
 Glucocorticoids deficiency but not for
mineralocorticoids
 No salt wasting crisis
 Androgen excess
 Female
 Pseudohermaphroditism
 Male
 Precocious puberty
Nonclassic 21-hydroxylase deficiency
 Mild degree of hyperandrogenism
 Female
 PCOD, acne, hirsutism, infertility, irregular
menstruation
 Male
 Precocious puberty, advanced bone age,
accerelated growth during childhood
Diagnosis of CAH
1. Hormonal study
 17-hydroxyprogesterone level is diagnostic
 Progesterone level
 Testosterone level
 Cortisol level (take critical sample before treatment)
 250 mcg ACTH stimulation test in borderline case
2. Imaging study
 Pelvic ultrasonography for gonads and female
internal sex organs
3. Chromosomal study
 To confirm gender
4. DNA Analysis
Diagnosis of CAH
Diagnosis of CAH
Result pending
1. Hormonal study





17-hydroxyprogesterone level is diagnostic
61 ng/dl (normal 7-59 ng/dl)*
Progesterone level
Testosterone level
20 ng/dl (normal < 10 ng/dl)*
Cortisol level (take critical sample before treatment)
250 mcg ACTH stimulation test in borderline case
2. Imaging study
Pre-pubertal uterus with bilateral ovaries and no
visualization of the testes
 Pelvic ultrasonography for gonads and female internal sex
organs
3. Chromosomal study
46, XX
 To confirm gender in the non-palpable gonad cases
4. DNA Analysis
Result pending
Treatment of adrenal crisis
 Glucocorticoids replacement
 Hydrocortisone 100 mg/m2/day
 Fluid replacement
 NSS 10-20 cc/kg in 30-60
Hydrocortisone
309 mg/m2/day
5% D/N/5 (MT+7%
minutes, then
def)
 5%D/NSS to 5%D/N/2 20 cc/kg
 Hypoglycemia
 2-3 cc/kg of 25% dextrose iv bolus
Treatment of adrenal crisis
 Hyponatremia
 Deficit therapy: ΔNa x 0.6 x BW
 Replacement half of the deficit in 8-12 hours
 MT: 2-3 mEq/kg/day
 Hyperkalemia
 EKG monitoring
 if K+ > 6 mmol/l: kayexalate po. or by enema
 if K+ > 7 mmol/l: NaHCO3 1-2 mmol/kg iv
 if EKG abnormality: 10% Calcium gluconate
0.5-1 cc/kg iv in 10 minutes
Maintenance treatment in CAH
 Glucocorticoids replacement
 To suppress adrenal androgen
 Hydrocortisone (Cortef®) (12-18 mg/m2/day1)
 Mineralocorticoids replacement
 To return normal electrolytes and plasma renin activity
 Fludrocortisone (Florinef®) (0.05-0.3 mg/day)
 NaCl supplement in infant
 1-3 g/day added to formula or foods
 Beware of hypertension
1
Merke D P, Bornstein S R. Lancet 2005; 365: 2125-36
Maintenance treatment in CAH
 Stress dosing
 Increase hydrocortisone dosage to 3-5 folds of
normal daily dosage
 Same fludrocortisone dosage
 Undesired effect of treatment
 Excessive cortisol replacement in infancy
cause short stature in adulthood
 Measure weight, length, adrenal steroid level,
plasma renin activity and serum electrolytes
Date
BW (g)
Na /K (mmol/l)
Cl /HCO3- (mmol/l)
BUN/Cr (mg/dl)
25/4/50
26/4/50
29/4/50
3/5/50
4/5/50
6/5/50
8/5/50
11/5/50
14/5/50
3,600
3,640
3,680
4,000
4,150
4,300
4,470
4,620
4,750
135/4.2
100/15
134/4.2
101/19
133/5.7
96/18
135/6.2
100/21
137/4.2
101/21
138/5.0
105/18
139/4.7
103/23
138/5.9
105/13
135/4.5
101/22
72
0.1
1
72
0.1
55
0.2
55
0.15
43
0.15
30
0.15
2
2
2
2
2
48
0.15
1.5
48
0.15
1.5
URI
afebrile
active
D/C
6/0.3
Treatment
 Cortef (mg/m2/d)
 Florinef (g/d)
 Na+ replacement (g/d)
100
0.1
1
EKG
normal
TFT
normal
Urine Na /K (mmol/l)
Cl (mmol/l)
Clinical
33/1.9
25
irritable
& poor
feeding
Plan: wean Cortef® to 30 mg/m2/d in three days after discharge
Discharge planning
 Consult urologist for surgical correction
 Counseling the parents
 Medical dosage adjustment in case of stress
 Signs and symptoms of adrenal crisis
 Signs and symptoms of cortisol excess
 Puberty, growth and development
 Recurrent risk and prenatal diagnosis for the
next pregnancy
Take home message
Newborn with ambiguous genitalia should
not go home without follow up
 CAH is the most common cause of female
pseudohermaphroditism
 Clinical presentation
 Poor feeding, poor weight gain
 Inactive, lethargy, vomiting
 Salt losing begins in the second week of life
 Follow up clinical and serum electrolytes
weekly
Take home message
In case of suspected adrenal insufficiency
 Early diagnosis and treatment is the most
important
 Take the critical sample before start treatment
 Serum cortisol, glucose, electrolytes
 And clotted blood 5 ml centrifuge then store serum
at 4˚C for hormonal study
Special thanks to
 ผศ. พญ. จีรันดา สันติประภพ
 พญ. กานต์สุดา พิเชษสุ ดา
Thank you for your attention