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 revealedNa+ 122 mmol/l, K mmol/l,Cl mmol/l, HCO3- 15 mmol/lblood 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 AntepartumG2P1A0No maternal drug or hormonal usageNo complication of pregnancyIntrapartumCesarean section due to previous cesarean sectionTerm AGA infant, birth weight 3,200 g (P50)Apgar score 10, 10 at 1, 5 minuteAmbiguous genitalia
6 History Family history : The second child of family Her sister is healthy.No consanguinityNo history of ambiguous genitalia, precoccious puberty or neonatal death in her familyDrug History:No history of drug or food allergy
7 HistoryNutrition: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 /minWeight 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 dehydrationSkin:Mild hyperpigmentation at nipple and genitalia
9 Physical examination Head, eye, ear, nose and throat: AF 2 x 2 cm. PF fingertip, no dysmorphic featuresRespiratory system:Normal breath sound, no adventitious soundCardiovascular system:Normal S1 and S2, no murmur, capillary refill less than 2 secondsAbdomen:Soft, not tender, liver and spleen not palpable, no palpable mass
10 Physical examination Extremities: Nervous system: Genitalia: No deformityNervous system:Grossly intactGenitalia:Phallus: length 3.3 cm, width 1.2 cmFused labioscrotal fold with few rugae and hyperpigmentation, no palpable gonadSingle urethral opening at perineoscrotal region
12 Problem list: 2 month-old girl with Ambiguous genitalia without palpable gonadSevere vomiting and lethargy for 3 daysFailure to thriveDehydrationMild hyperpigmentation at nipples and genitaliaHyponatremia, hyperkalemia and wide anion gap metabolic acidosisMineralocorticoid deficiency
13 Approach to ambiguous genitalia Gonad palpableGonad not palpable*Male pseudohermaphroditismTrue hermaphroditismFemale pseudohermaphroditism
14 Female pseudohermaphroditism DefinitionThe situation where chromosomal and gonadal gender are female but the external genitalia resembling male.Androgen excess is the key
16 Congenital Adrenal Hyperplasia The most common cause of ambiguity in the newbornAutosomal recessive pattern of inheritance (Mutation in chromosome 6p21.3)An enzymatic defect in adrenal steroid biosynthesis90% of CAH caused by 21-Hydroxylase deficiencyA type of primary adrenal insufficiency
17 Renin angiotensin aldosterone system and K+ The adrenal glandRenin angiotensin aldosterone system and K+Adrenal cortexZona glomerulosa (15%) aldosteroneZona fasciculata (75%) cortisolZona reticularis (10%) androgenAdrenal medullaCRH and ACTHCRH and ACTHCRH and ACTH
19 Congenital adrenal hyperplasia It was classified into 3 formsSalt wasting 21-hydroxylase deficiency (classic form) about 2/3 of all patientsVirilizing 21-hydroxylase deficiencyNon-classic 21-hydroxylase deficiency
20 Salt wasting 21-hydroxylase deficiency Glucocorticoids and mineralocorticoids deficiencySalt wasting crisis since infancy (7-14 days old)Failure to thrive, vomiting, hypotensionCortisol deficiency stimulate the production of ACTH which cause hyperpigmentationAndrogen excessFemale infant: Ambiguous genitalia since birth, which range from fused labioscrotal folds to perineal hypospadiaMale infant: Normal genitalia, usually presented with signs and symptoms of adrenal insufficiency
21 Salt wasting 21-hydroxylase deficiency Mineralocorticoid deficiencySalt cravingMalaiseWeight lossHypotension or shockHyponatremiaHyperkalemiaMetabolic acidosis Plasma renin activityCorticosteroid deficiencyHypoglycemiaHyponatremiaHypotension or shockMalaisePoor appetiteWeight lossNausea, vomitingAbdominal pain
22 Salt wasting 21-hydroxylase deficiency Severe clitoral hypertrophy from masculinization of the external genitalia of a 46,XX patient caused by CAH22
23 Virilizing 21-hydroxylase deficiency Glucocorticoids deficiency but not for mineralocorticoidsNo salt wasting crisisAndrogen excessFemalePseudohermaphroditismMalePrecocious puberty
24 Nonclassic 21-hydroxylase deficiency Mild degree of hyperandrogenismFemalePCOD, acne, hirsutism, infertility, irregular menstruationMalePrecocious puberty, advanced bone age, accerelated growth during childhood
25 Diagnosis of CAH Hormonal study 17-hydroxyprogesterone level is diagnosticProgesterone levelTestosterone levelCortisol level (take critical sample before treatment)250 mcg ACTH stimulation test in borderline caseImaging studyPelvic ultrasonography for gonads and female internal sex organsChromosomal studyTo confirm genderDNA Analysis
27 Diagnosis of CAH Hormonal study Imaging study Chromosomal study Result pendingHormonal study17-hydroxyprogesterone level is diagnosticProgesterone levelTestosterone levelCortisol level (take critical sample before treatment)250 mcg ACTH stimulation test in borderline caseImaging studyPelvic ultrasonography for gonads and female internal sex organsChromosomal studyTo confirm gender in the non-palpable gonad casesDNA Analysis61 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 testes46, XXResult pending
28 Treatment of adrenal crisis Glucocorticoids replacementHydrocortisone 100 mg/m2/dayFluid replacementNSS cc/kg in minutes, then5%D/NSS to 5%D/N/2 20 cc/kgHypoglycemia2-3 cc/kg of 25% dextrose iv bolusHydrocortisone 309 mg/m2/day5% D/N/5 (MT+7% def)
29 Treatment of adrenal crisis HyponatremiaDeficit therapy: ΔNa x 0.6 x BWReplacement half of the deficit in 8-12 hoursMT: 2-3 mEq/kg/dayHyperkalemiaEKG monitoringif K+ > 6 mmol/l: kayexalate po. or by enemaif K+ > 7 mmol/l: NaHCO3 1-2 mmol/kg ivif EKG abnormality: 10% Calcium gluconate cc/kg iv in 10 minutes
30 Maintenance treatment in CAH Glucocorticoids replacementTo suppress adrenal androgenHydrocortisone (Cortef®) (12-18 mg/m2/day1)Mineralocorticoids replacementTo return normal electrolytes and plasma renin activityFludrocortisone (Florinef®) ( mg/day)NaCl supplement in infant1-3 g/day added to formula or foodsBeware of hypertension1 Merke D P, Bornstein S R. Lancet 2005; 365:
31 Maintenance treatment in CAH Stress dosingIncrease hydrocortisone dosage to 3-5 folds of normal daily dosageSame fludrocortisone dosageUndesired effect of treatmentExcessive cortisol replacement in infancy cause short stature in adulthoodMeasure weight, length, adrenal steroid level, plasma renin activity and serum electrolytes
32 irritable & poor feeding Date25/4/5026/4/5029/4/503/5/504/5/506/5/508/5/5011/5/5014/5/50BW (g)3,6003,6403,6804,0004,1504,3004,4704,6204,750Na /K (mmol/l)Cl /HCO3- (mmol/l)135/4.2100/15134/4.2101/19133/5.796/18135/6.2100/21137/4.2101/21138/5.0105/18139/4.7103/23138/5.9105/13135/4.5101/22BUN/Cr (mg/dl)6/0.3TreatmentCortef (mg/m2/d)Florinef (g/d)Na+ replacement (g/d)1000.11722550.20.154330481.5EKGnormalTFTUrine Na /K (mmol/l)Cl (mmol/l)33/1.925Clinicalirritable & poor feedingURI afebrile activeD/CThis 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 parentsMedical dosage adjustment in case of stressSigns and symptoms of adrenal crisisSigns and symptoms of cortisol excessPuberty, growth and developmentRecurrent risk and prenatal diagnosis for the next pregnancyThe 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 messageNewborn with ambiguous genitalia should not go home without follow upCAH is the most common cause of female pseudohermaphroditismClinical presentationPoor feeding, poor weight gainInactive, lethargy, vomitingSalt losing begins in the second week of lifeFollow up clinical and serum electrolytes weeklyWhat 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 importantTake the critical sample before start treatmentSerum cortisol, glucose, electrolytesAnd clotted blood 5 ml centrifuge then store serum at 4˚C for hormonal studyAnd 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 toผศ. พญ. จีรันดา สันติประภพพญ. กานต์สุดา พิเชษสุดา