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Ambiguous Genitalia
- 1. Speaker: Abhinav Agarwal ClinicalCase Presentation (NICU)
- 2. Presenting features: EarlyPreterm (33 wk) weighing 1900g Appropriate for gestational age Born to G2P1L1 mother by emergency LSCS for meconium stained amniotic fluid Vigorous at birth Did not receive delivery room resuscitation Admitted for NNH at 96 hr without any incompatibility No H/O any antenatal drug intake except iron and folate On further interrogation - elder sibling, 1.5-year old, also have ambiguous genitalia
- 3. Examination at birth Stable vitals Genital examination: Underdeveloped scrotum Median raphe + Bilateral gonads not palpable Penile length = 4 mm Hypospadias + No hyperpigmentation Rest systemic examination normal
- 4. Plan In viewof above observations - Virilized female Congenital adrenal hyperplasia Rule out virilizing maternal conditions Undermasculanised male Androgen insensitivity 5 alpha reductase deficiency Testosterone biosynthesis defects
- 5. Investigations: Date 1/2/16 4/2/167/2/16 Day of life 3 h 64 h Day 6 Dextrose 65 82 88 17- OHP 9.53 (normal) Serum cortisol 14.4 (normal) Karyotyping Awaited Hb 14.9 TC 23,900 DC N75 L16 E5 Platelet 3.63 lac Urea 57 Creatinine 0.7 Sodium 136 Potassium 4.5 USG abdomen Bilateral testis + in superficial inguinal ring, no mullerian structures present, ? adrenals appear bulky.
- 6. Elder siblingIndex case
- 7. Approach to babywith ambiguous genitalia When to suspect – Micropenis: Stretched penile length <2.5cm in a term newborn Asymmetry of labioscrotal folds B/L cryptorchidism U/L cryptorchidism with hypospadias B/L testes with perineoscrotal or penoscrotal hypospadias Female external genitalia with clitoromegaly (> 1 cm) or inguinal hernia Overtly abnormal genitals like cloacal exstrophy
- 8. History 1) Family history-CAH, hypospadias, cryptorchidism, infertility, pubertal delay, consanguinity 2) Neonatal death- male sibling from vomiting or dehydration (CAH) 3) Maternal drug exposure- androgens, antiandrogens (finasteride, spironolactone), estrogens, progestins, phenytoin 4) Maternal virilization during pregnancy- virilizing adrenal or ovarian tumor, placental aromatase
- 9. Examination 1) External genitalia- •Stretched penile length <2.5 cm in term infant - microphallus clitoris >1cm length, >0.6 cm diameter - clitoromegaly • Presence of chordee • position of urethral meatus • presence of vaginal opening • pigmentation and symmetry of scrotum or labioscrotal folds • Anogenital ratio- distance between anus and posterior
- 10. 2). Gonadal size,position and descent- should be carefully noted • palpable gonad below inguinal ligament usually a testis • an ovotestis or uterus may present as inguinal hernia 3). Associated anomalies- other dysmorphic features suggesting Denys-Drash syndrome, WAGR syndrome etc.
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- 13. Investigations Serum electrolytes Blood sugar Hormonal study (17-OHP and testosterone – 1st line) after 72 hrs of life Karyotyping- using FISH for SRY region Ultrasonography- • to see mullerian structure • to visualize testis and its position • to visualize adrenal glands (CAH) • to see associated malformations in kidneys, ureter, bladder Genitogram MRI- when USG is indeterminate Exploratory laparotomy/ Laparoscopy
- 14. Endocrinal Evaluation Hypothalamic/pituitary/gonadal Axis: •Gonadotropins: LH, FSH • Gonadal response: Testosterone, DHT, estrogen Adrenal function: • Electrolytes, 17-OH-P • DHEAS • Cortisol Response to challenges: • GnRH stimulation • HCG stimulation
- 15. Discussion: Disorders ofsex development (DSD)/ Intersex - congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical Old terminology- New terminology (4 types) - 46, XX DSD - psuedohermaphroditism - 46, XY DSD - true hermaphroditism - Sex chromosome DSD -Syndromes with ambiguous genitalia
- 16. Types of DSD 1).46,XX virilized female Congenital adrenal hyperplasia 21-hydroxylase deficiency, 11-hydroxylase deficiency 3 beta hydroxysteroid dehydrogenase deficiency Aromatase deficiency(fetal and maternal) Virilizing maternal conditions CAH Adrenal/ovarian tumors Drugs-progestin, androgen 2). 46,XY undervirilized male Disorders of testis development- -LH receptor mutation -Vanishing testis (gestational loss of testis) Defects in androgen synthesis - 17β HSD defect - 3β HSD defect - 17,20 lyase defect Defects in testosterone metabolism - 5 α reductase type 2 deficiency End organ resistance- - Androgen insensitivity syndrome (AIS) -Partial -Complete
- 17. 3). Gonadal differentiationand chromosomal disorders Ovotesticular DSD (true hermaphroditism) Mixed gonadal dysgenesis (45X, 46XY) Complete gonadal dysgenesis (46,XY) 46,XX testicular DSD 4). Syndromes with ambiguous genitalia Campomelic dysplasia Denys-Drash syndrome Frasier syndrome WAGR syndrome Robinow syndrome
- 18. Algorithm for evaluationof 46,XX DSD Uterus present 17 Hydroxy progesterone Increased Normal Normal Ovotestis on USG Biopsy: Ovarian folicles & testicular tubules Ovotesticular DSD (true hermaphroditism) CAH Maternal virilization/ Exogenous androgen exposure Maternal virilizing disorders: Medications: Progestins Tumors (adrenal/ovarian) Luteomas of pregnancy Aromatase deficiency MotherBaby Uterus absent 46 XX Testicular DSD
- 19. Algorithm for evaluationof 46,XY DSD Karyotype 46 XY No uterus USG pelvis Uterus present hCG stimulation test Gonadal biopsy: •Persistent mullerian duct syndrome T & DHT: AIS (Ar mutation analysis)/ Idiopathic Normal T & DHT : 5 alpha reductase deficiency T and DHT: LH/FSH : gonadal dysgenesis, leydig cell hypoplasia Precursor steroids : T-biosynthesis defect
- 20. hCG stimulation test Evaluation of gonadal axis in children Assess testosterone secretion by testes 500 IU of hCG given i/m daily for 3 days or 5000U/m2 single dose Serum testosterone, DHT, DHEA, androstenedione, LH & FSH are measured at baseline and then 24 hr after last dose or after 72 hr if single dose was given Collection of 24 hr urine before & after three doses of hCG to detect precursors to detect testosterone biosynthesis defect
- 21. Interpretation 2 to20 times rise in testosterone i.e rise > 0.8 ng/ml or absolute levels > 0.9 ng/ml 1)adequate rise indicates presence of functioning testes 2)if rise is blunted –enzymatic defect in testosterone synthesis, gestational loss of testicular tissue (vanishing testis syndrome), LH receptor mutation 3) ↑ T:DHT ratio(>20:1)- 5 alpha reductase deficiency 4) T: A ratio (<0.8:1) – 17β- HSD deficiency 5) Raised LH,FSH denotes anorchia or primary gonadal failure 6) Increased precursor steroid denotes biosynthesis
- 22. Evaluation of ElderSibling Date Age Features 21/5/14 Birth Ambiguous Genitalia + 24/7/14 2 month Bifid scrotum, hypospadias, Small penis, Anus +, LH = 0.91 (0.02-0.3) FSH = 15.24 (0.16 – 4.1) DHEA = 119.3 (31.6 - 214) 28/7/14 2 month USG: Small soft elongatd homogenous structure with no specific morphology in bilateral inguinal region (? Small undescended testis) Right- 11 x 4.5 mm Left- 10 x 4.9 mm Cortisol = 1.2 mcg/dl (5 – 48) Testosterone = 0.03 ng/dl (75 - 400) 19/8/14 2.5 month 5 alpha reductase = 2.5 ng/dl (prepubertal <3 ng/dl) 25/8/14 3 month hCG stimulation test = poor response (testosterone=16.31 ng/dl) MRI abdomen: bilateral undesended testis in inguinal area + 2/9/14 3.5 month Karyotype = XY 21/5/15 12 month MCU = male type urethra with Normal MCU study 8/2/16 19 month LH = 1.19 mIU/ml (0.02-0.3) Testosterone = <10 ng/dl (75 - 400) hCG stimulation test = poor response
- 23. Final Diagnosis Disordersof testis development- -LH receptor mutation Defects in androgen synthesis - 17β HSD defect - 3β HSD defect - 17,20 lyase defect Gonadal dysgenesis
- 24. Management: General guidelines: Tryto match the baby’s sex assignment to the chromosomal and gonadal sex if possible Try to anticipate pubertal development Consider future function when planning surgeries Try to preserve fertility Respect the opinions of well-informed parents Treatment options include : Reconstructive surgery Hormone therapy
- 25. Incidence in India: Etiologyand clinical profile of ambiguous genitalia studied (n=109) 1) Genetic females with virilisation or FPH –27.5 %(n=30) Congenital adrenal hyperplasia (CAH) was the underlying cause in all cases of FPH Salt wasting form - 23/30 Simple virilising form – 7/30 2) Genetic males undervirilised or MPH –52.3 %(n=57) Androgen insensitivity syndrome - 28% (16/57) 5- alpha reductase deficiency - 23%(13/57) . 3) Disorder of gonadal differentiation- 10.1%(n=11) Gonadal dysgenesis – 9/11 True hermaphrodite – 2/11 4) Syndromic form of ambiguous genitalia- 1.8% (n=2) (Rajesh R. Joshi, Sudha Rao, Meena Desai. Etiology and clinical profile of ambiguous genitalia-an overview of 10 years experience. Indian Pediatrics, 2006;43:974-979.)
- 26. Prognosis in subsequent pregnancies: 46,XX DSD CAH – 25% 46, XY DSD – Complete Gonadal Dysgenesis - Low Androgen Insensitivity Syndrome – Low Hormone Biosynthetic Pathway – 25% Sex chromosome DSD - low Syndromes with ambiguous genitalia – according to syndrome (David Amor. Genetic Counselling. In: Disorders of Sex Development: An Integrated Approach to Management. Eds. John M. Hutson, Garry L. Warne, Sonia R. Grover. Springer, Berlin, Germany, 2012: pp 202-213)
- 27. Sarah Gronert (born6 July 1986) is a retired German tennis player. She won a total of ten titles on the ITF circuit in her career and her best world ranking of 164 came on 14 May 2012 Not end of life:
- 28. Tony Briffa Has Partial Androgen Insensitivity Syndrome. Independent councillor, mayor and deputy mayor in the City of Hobsons Bay, Victoria. Briffa is considered the world's first openly intersex mayor and public office-bearer Tony Briffa was raised as a girl, and lived as a woman until he was 30. Briffa is one of the first people to be public about a