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Extern Conference 17 th May 2007. History Chief complaint  A 6 week-old girl was referred to our hospital with history of severe vomiting for 3 days.

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Presentation on theme: "Extern Conference 17 th May 2007. History Chief complaint  A 6 week-old girl was referred to our hospital with history of severe vomiting for 3 days."— Presentation transcript:

1 Extern Conference 17 th 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 mmol/l, K mmol/l, Cl - 84 mmol/l, HCO 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 Antepartum  G 2 P 1 A 0  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 (P 50 )  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:  T 37.5° C, pulse 131 bpm regular, BP 99/49 mmHg (P 75 -P 90 ), RR 48 /min  Weight 3,600 g (P 3 -P 10 ), Length 53 cm (P 10 -P 25 ), Head circumference 37 cm (P 50 ) 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 S 1 and S 2, no murmur, capillary refill less than 2 seconds Abdomen:  Soft, not tender, liver and spleen not palpable, no palpable mass

10 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

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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 Ambiguous genitalia Gonad palpable Gonad not palpable* Male pseudohermaphroditism True hermaphroditism Female pseudohermaphroditism

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

15 Differential diagnosis 1.Congenital adrenal hyperplasia (CAH) 2.Maternal androgen excess 3.Aromatase deficiency 4.Androgenic target hypersensitivity 5.Multiple congenital malformations 6.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 The adrenal gland Adrenal cortex  Zona glomerulosa (15%) aldosterone  Zona fasciculata (75%) cortisol  Zona reticularis (10%) androgen Adrenal medulla Renin angiotensin aldosterone system and K+ 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

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 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

26 Diagnosis of CAH

27 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 in the non-palpable gonad cases 4.DNA Analysis Pre-pubertal uterus with bilateral ovaries and no visualization of the testes 46, XX 61 ng/dl (normal 7-59 ng/dl)* 20 ng/dl (normal < 10 ng/dl)* Result pending

28 Treatment of adrenal crisis Glucocorticoids replacement  Hydrocortisone 100 mg/m 2 /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/m 2 /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: NaHCO 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/m 2 /day 1 ) 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 Date 25/4/5026/4/5029/4/503/5/504/5/506/5/508/5/5011/5/5014/5/50 BW (g) 3,6003,6403,6804,0004,1504,3004,4704,6204,750 Na /K (mmol/l) Cl /HCO 3- (mmol/l) 135/ /15 134/ /19 133/5.7 96/18 135/ /21 137/ /21 138/ /18 139/ /23 138/ /13 135/ /22 BUN/Cr (mg/dl) 6/0.3 Treatment Cortef (mg/m 2 /d) Florinef (g/d) Na + replacement (g/d) EKG normal TFT normal Urine Na /K (mmol/l) Cl (mmol/l) 33/ Clinical irritable & poor feeding URI afebrile active D/C Plan: wean Cortef ® to 30 mg/m 2 /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

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

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

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

37 Thank you for your attention


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