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Ambiguous Genitalia

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Ambiguous Genitalia Ambiguous Genitalia Individuals who have a genital appearance that does not permit gender declaration are said to have ambiguous genitalia (AG). This includes infants with bilateral cryptorchidism, perineal hypospadias with bifid scrotum, clitoromegaly, posterior labial fusion, phenotypic female appearance with palpable gonad (with or without inguinal hernia), and infants with discordant genitalia and sex chromosomes. This is a neonatal emergency. The commonest cause of AG is congenital adrenal hyperplasia (CAH) Two major concerns are:- • Underlying medical issues - dehydration, salt loss (adrenal crisis) - urinary tract infection - bowel obstruction • Decision on sex of rearing or psychosocial issues - avoid wrong sex assignment - prevent gender confusion EVALUATION Ideally, baby/child with parents should be brought to a competent team of experienced paediatric endocrinologist, surgeon, psychiatrist and geneticist. 1. HISTORY - exclude CAH in all neonates • Parental consanguinity. • Obstetric: previous abortions, stillbirths, neonatal deaths. • Pregnancy: drugs taken, exogenous androgens, endocrine disturbances. • Family History: Unexplained neonatal deaths in siblings and close relatives o Infertility, genital anomalies in the family o Abnormal pubertal development o Infertile aunts • Symptoms of salt wasting in the first few days to weeks of life. • Increasing pigmentation • Progressive virilisation 2. PHYSICAL EXAMINATION • Dysmorphism (Turner phenotype, congenital abnormalities) • Cloacal anomaly • Signs of systemic illness • Hyperpigmentation • BP • Appearance of external genitalia o size of phallus, erectile tissue o position of urethral opening (degree of virilisation) o labial fusion / appearance of scrotum o presence / absence of palpable gonads o presence / absence of cervix (per rectal examination) o position & patency of anus • Psychosocial behaviour (older children) Algorithms Approach to Ambiguous Genitalia Ambiguous Genitalia Karyotype Palpable Gonads Absent Present CAH Screen Positive Negative Endocrine profile, Ultrasound scan Ultrasound Scan Genitogram Genitogram Gonadal inspection and biopsy 3. INVESTIGATION • Chromosome karyotype • Ultrasound for uterus, vagina & urinary system • Genitogram • Exclude salt losing CAH o Serial BUSE in neonatal period o Urine Na, K at the time of presentation o Serum 17-hydroxyprogesterone (taken after the first day of life) o Cortisol, testosterone, renin o 24 - hour urine for pregnanetriol • Testosterone, LH, FSH • LHRH stimulation test (stimulated LH, FSH at 0’, 30’, 60’) • hCG stimulation (testosterone, DHT at Day 1 & 4) • Androgen receptor study (may not be available) • DNA analysis for SRY gene (sex-determining region on the Y chromosome) Trial of testosterone enanthate 25 mg IM monthly 3x doses This is done to demonstrate adequate growth of the phallus and is essential before a final decision is made to raise an ambiguous child as a male. 4. Differential Diagnosis Uterus present Uterus absent 46 XX, Virilising CAH 46 XY, Androgen insensitivity syndrome 46 XX, Foetal exposure to excessive androgen 46 XY, 5-alpha reductase deficiency 46 XY, 45XO/46XY 46 XY, Defect in testosterone synthesis Gonadal dysgenesis True hermaphroditism Differential Diagnosis Hyperpigmentation + - - - Palpable gonad(s) - + + + Uterus present + + - - Dysmorphism - +/- - - Systemic illness + - - - Diagnosis 21-hydroxylase Gonadal Partial AIS Testosterone deficiency dysgenesis biosynthesis True defect hermaphroditism Karyotype 46 XX XO/XY 46 XY 46 XY 46 XY 46 XX 5. Management Goals • Preserve fertility • Ensure normal sexual function • Phenotype and psychosocial outcome concordant with the assigned sex General considerations • Admit to hospital. Salt losing CAH which is life threatening must be excluded. • Urgent diagnosis • Do not delay decision on sex assignment • Do not register the child until final decision is reached • Protect privacy of parents and child pending diagnosis • Counseling of parents that intersex condition is biologically explainable. • Encourage bonding Gender Assignment : Gender assignment and sex of rearing should be based upon the most probable adult gender identity and potential for adult function. Factors to be considered in this decision include :- • Diagnosis • Fertility potential • Adequacy of the external genitalia for normal sexual function. A minimum phallic length of 2 cm when considering male sex of rearing. • Endocrine function of gonads. Capacity to respond to exogenous androgen. • Parents’ socio-cultural background, expectations and acceptance • Psychosocial development in older children. Decision about sex of rearing should only be made by an informed family after careful evaluation, documentation, and consultation. Gender Reinforcement • Appropriate name • Upbringing, dressing • Treatment and control of underlying disease e.g. CAH • Surgical correction of the external genitalia as soon as possible • Assigned female - 46,XX, 46,XY, Gonadal dysgenesis, True hermaphroditism - Remove all testicular tissue - Vaginoplasty after puberty • Assigned male - 46XY - Orchidopexy - Remove all Mullerian structures - Surgical repair of ‘hypospadias’ - KIV gonadectomy if dysgenetic Notes : 1. In complete testicular feminisation, bringing up the child as a male is strictly contraindicated as the phallic size will not increase in size even with high dose of androgens. 2. In complete testicular feminisation the testis is not removed till after puberty . By doing so, the normal stimulus of pituitary gonadotrophins results in some gonadal function. A desired side effect, probably from oestrogen (a metabolite of testosterone) being breast development. (A less satisfactory breast development is achieved with oestrogen therapy following prepubertal oestrogen). Because of a risk of malignancy, the cryptorchid testis should be removed after puberty. Vaginoplasty may be needed (after puberty). 3. Bilateral inguinal hernia is rare in girls (femoral hernia is the rule). Always suspect the presence of gonads. References : Evaluation of the infant with ambiguous genitalia. Christopher P Houk, Lynne L Levitsky. 2004 Uptodate online 12.1 (www.uptodate.com) Management of the infant with ambiguous genitalia. Christopher P Houk, Lynne L Levitsky. 2004 Uptodate online 12.1 (www.uptodate.com) CONGENITAL ADRENAL HYPERPLASIA (CAH) A. Presentation Management of CAH 1. Neonatal period 1. Correction of salt deficit • Ambiguous genitalia 2. Correction of cortisol deficiency. • Salt loss (75%) 3. Designation of correct sexual • F/H of previous unexplained identity neonatal death 2. Hyperpigmentation (90%) in both sexes 3. Boy with precocious puberty but small testis (volume <4 ml) 4. Virilisation of a girl 5. Hypertension B. Management of salt losing crisis 1. Shock • Normal saline (0.9%) bolus or 5% dextrose in NS : 10 - 20 ml/kg • Correct hypoglycemia : 2 - 4 mg/kg of 10% glucose • Correct hyperkalaemia with administration of glucose and insulin if necessary. • Rehydrate using 1/2 NS 5% dextrose • Monitor hydration status, BP, HR, glucose NB : Hypotonic saline or 5% dextrose should not be used because it can worsen hyponatraemia. 2. Steroid replacement • Hydrocortisone 4 - 6 mg/kg/dose 6 hourly Later when patient is in no stress, change to oral hydrocortisone at 15 - 20 mg/m 2/day. • Fludrocortisone 100 - 150 mcg daily when tolerating orally. Titrate dose till plasma electrolytes return to normal. 3. Supplemental oral salt 1 - 2 g daily Tail off IV hydrocortisone & IV fluids Monitor symptoms, weight gain, BUSE. C. Long Term Management of CAH The various therapeutic rules outlined for simple virilizing form during medical and surgical stress apply to the salt-losing form as well. • Tablet hydrocortisone 10 - 20 mg/m 2/day, divided into 2 - 3 daily doses using the least effective dose to normalize 17-OHP serum level. Duration of treatment : life long. • Fludrocortisone 100 – 200 mcg daily. Duration of treatment : life long. The dose of fludrocortisone may decrease due to salt intake in the normal diet. • Salt 1-2 g daily, about 8 mEq/kg/day for the first 2 years of life. The dose maybe decreased after early infancy. Salt tablet can often be discontinued as older children’s taste for salty food increases. • Treatment during stress as in fever, vomiting, diarrhoea and surgery (Refer to section E) • Medic alert : is life-saving in an emergency situation. • Surgical correction of the external genitalia before second year of life. • Vaginoplasty after puberty. D. Long Term Monitoring of CAH • Height, weight, BP - 3 monthly • Aim for normal height velocity • Bone age yearly if necessary • Investigations - Plasma 17-OHP - Plasma renin activity. If it is not available, do serum Na and K - Testosterone or androstenedione • Ensure normal growth, pubertal development & psychosocial development concordant with the sex of rearing • Signs of over-treatment : ↓↓↓ height velocity, hypertension, delayed bone age • Signs of under-treatment : ↑↑↑ height velocity, advanced bone age • Psychological & emotional support E. Treatment of CAH During Stress Patients on prolonged glucocorticoid therapy have an unresponsive hypothalamic-pituitary- adrenal axis and therefore unable to respond to stress with an increased cortisol secretion. For this reason additional glucocorticoid must be provided. Stress is often aggravated because patients are unable to retain oral therapy during acute illness. 1. Infection Minor infection : Any increase in medication may not be required e.g. in URTI. Moderate stress : It is necessary to double
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