1. Extern Conference
17th May 2007

2. History Chief complaint
A 6 week-old girl was referred to our hospital with history of severe vomiting for 3 days

3. 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 mmol/l,
Cl mmol/l, HCO3- 15 mmol/l
blood sugar was 126 mg/dl.

4. 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.

5. History Birth history G2P1A0 No maternal drug or hormonal usage
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

6. 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

7. History
Nutrition:
Breastmilk and formula every 2 hours

8. Physical examination Vital signs: General appearance: Skin:
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

9. 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

10. Physical examination Extremities: Nervous system: Genitalia:
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

12. 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

13. Approach to ambiguous genitalia
Gonad palpable
Gonad not palpable*
Male pseudohermaphroditism
True hermaphroditism
Female pseudohermaphroditism

14. Female pseudohermaphroditism
Definition
The situation where chromosomal and gonadal gender are female but the external genitalia resembling male.
Androgen excess is the key

15. Differential diagnosis
Congenital adrenal hyperplasia (CAH)
Maternal androgen excess
Aromatase deficiency
Androgenic target hypersensitivity
Multiple congenital malformations
Unknown etiology

16. 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

17. Renin angiotensin aldosterone system and K+
The adrenal gland
Renin angiotensin aldosterone system and K+
Adrenal cortex
Zona glomerulosa (15%) aldosterone
Zona fasciculata (75%) cortisol
Zona reticularis (10%) androgen
Adrenal medulla
CRH and ACTH
CRH and ACTH
CRH and ACTH

18. Steroid biosynthesis

19. 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

20. 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

21. 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

22. Salt wasting 21-hydroxylase deficiency
Severe clitoral hypertrophy from masculinization of the external genitalia of a 46,XX patient caused by CAH 22

23. Virilizing 21-hydroxylase deficiency
Glucocorticoids deficiency but not for mineralocorticoids
No salt wasting crisis
Androgen excess
Female
Pseudohermaphroditism
Male
Precocious puberty

24. 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

25. Diagnosis of CAH 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
Imaging study
Pelvic ultrasonography for gonads and female internal sex organs
Chromosomal study
To confirm gender
DNA Analysis

26. Diagnosis of CAH

27. Diagnosis of CAH Hormonal study Imaging study Chromosomal study
Result pending
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
Imaging study
Pelvic ultrasonography for gonads and female internal sex organs
Chromosomal study
To confirm gender in the non-palpable gonad cases
DNA Analysis
61 ng/dl (normal 7-59 ng/dl)*
20 ng/dl (normal < 10 ng/dl)*
Pre-pubertal uterus with bilateral ovaries and no visualization of the testes
46, XX
Result pending

28. Treatment of adrenal crisis
Glucocorticoids replacement
Hydrocortisone 100 mg/m2/day
Fluid replacement
NSS cc/kg in minutes, then
5%D/NSS to 5%D/N/2 20 cc/kg
Hypoglycemia
2-3 cc/kg of 25% dextrose iv bolus
Hydrocortisone 309 mg/m2/day
5% D/N/5 (MT+7% def)

29. 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 cc/kg iv in 10 minutes

30. 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®) ( 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:

31. 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

32. irritable & poor feeding
Date
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
BW (g)
3,600
3,640
3,680
4,000
4,150
4,300
4,470
4,620
4,750
Na /K (mmol/l)
Cl /HCO3- (mmol/l)
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
BUN/Cr (mg/dl)
6/0.3
Treatment
Cortef (mg/m2/d)
Florinef (g/d)
Na+ replacement (g/d)
100
0.1 1 72 2 55
0.2
0.15 43 30 48
1.5
EKG
normal
TFT
Urine Na /K (mmol/l)
Cl (mmol/l)
33/1.9 25
Clinical
irritable & poor feeding
URI afebrile active
D/C
This slide shows clinical coarse of the patient when she was admitted in Siriraj hospital. During weaning off hydrocortisone from stress dose to maintenance dose, her clinical, body weight, blood pressure and serum electrolytes were monitored regularly. Because the mineralocorticoids effects of hydrocortisone we may have to increase the dosage of fludrocortisone when tapering off hydrocortisone. Such as these days when serum electrolytes showed the picture of mineralocorticoid deficiency, so we adjusted the fludrocortisone dosage and the electrolyte returned to normal. In this day (11/5/50), she had URI symptoms, that was a stress, and loosed her weight for 70 grams in 24 hours, so we increased the hydrocortisone dosage from 30 to 48 mg/sqm/day, maintained this for a week and weaned to 30 mg/sqm/day, which is the maximal dosage that does not effect the growth.
Plan: wean Cortef® to 30 mg/m2/d in three days after discharge

33. 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
The discharge planning was surgical correction of her genitalia and counseling her parents how to adjust the dosage of hydrocortisone, in case of stress, such as infection. They should know when to bring her child back to the hospital. The side effects of medication on the growth and development. And, finally, if there is a plan for the next child, the recurrent risk is ¼ and prenatal diagnosis would be discussed.

34. 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
What the GPs have to know is, when you found the newborn with ambiguous genitalia, never let he or she go back home without follow up. Because newborn with classic CAH, which is the most common cause of female pseudohermaphroditism, begin to show signs and symptoms in the second week of life, so the visits for clinical and serum electrolytes should be scheduled weakly.

35. 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
And if adrenal insufficiency was suspected, don’t forget to take the critical sample before the treatment started. Which are cortisol, glucose, electrolytes and another 5 cc of clotted blood for hormonal study.

36. Special thanks to
ผศ. พญ. จีรันดา สันติประภพ
พญ. กานต์สุดา พิเชษสุดา

37. Thank you for your attention