Dr. Sandip Gupta
PGT, PEDIATRICS
B.S.M.C.H.
Definition
 When the external genitalia do not appear completely male or

completely female .
 Incidence:1in 2000 live b...
When to suspect
 Micropenis: Stretched penile










length<2.5cm in a term newborn
Asymmetry of labioscrotal f...
Disorder of Sexual Differentiation(DSD)
 Also known as disorder of sexual development (Nelson) is

defined as a congenita...
Types
46,XX virilized female

46,XY undervirilized male

 Congenital adrenal hyperplasia  Defects in testicular differen...
Incidence
 The exact data on the incidence and prevalence of

conditions causing ambiguous genitalia are limited.
 Conge...
Incidence-India
Etiology and clinical profile of ambiguous genitalia studied (n=109)
1) Genetic females with virilisation ...
Embryology
 Sexual differentiation-3 stages
1. Determination of chromosomal sex (at conception)
2. Gonadal differentiatio...
 Gonad develops from
 Somatic cells (arise from mesonrphric cells and coelomic
epithelium)- sertoli cells/granulosa cell...
Embryology
 Testicular development is guided by TDF which is encoded

by the SRY gene on the short arm of the Y chromosom...
Embryology
Wolffian duct develops into the following:
 Epididymis
 Vas deferens
 Ejaculatory duct and seminal vesicles
Embryology
 In the absence of the Y chromosome , gonads differentiate

into ovaries at around 11-13 weeks gestation.
 Ab...
Embryology
 Undifferentiated external genitalia includes the following:
 Urogenital tubercle
 Urogenital swelling

 Ur...
Embryology
 In males DHT leads to development of these three structures

into :
 Glans penis
 Scrotum
 Penile shaft
 ...
Embryology
 True hermaphroditism have both testicular and ovarian tissue

in the gonads.
 In patients with pure gonadal ...
History
 Maternal drug ingestion esp. in 1st trimester







(androgen, antiandrogen, progestins, antiseizure medica...
External genitalia Examination
 Streched penis length,
 width of corpora,
 presence of chordee,
 position of the ureth...
External genitalia Examination
 Gonadal size ,position & descent should be noted a gonad

below inguinal ligament is usus...
Investigations
 Serum electrolytes
 Blood sugar
 Hormonal study
 Karyotyping
 Ultrasonography
 Genitogaphy,

 Sinog...
DIAGNOSTIC ALGORITHM
Algorithm for evaluation of 46,XX DSD
Ambiguous genitalia
46 XX Karyotype

Uterus present
17 Hydroxy progesterone
Normal
O...
Algorithm for evaluation of 46,XY DSD
Ambiguous genitalia
Karyotype 46 XY
USGlvis
Pelvis
No uterus

Uterus present

hCG st...
Ultrasonography
 Identify müllerian structures- uterus, ovaries, fallopian tubes

and upper half of vagina
 Allows visua...
Genitography
 Helps to determine ductal anatomy.
 In a neonate with ambiguous genitalia, a catheter can be

inserted int...
Genetic Evaluation
 KARYOTYPE

 FISH
 Presence of SRY
 X and Y probes for gonadal biopsies
 Specialized molecular gen...
Endocrinal Evaluation
Hypothalamic/pituitary/gonadal Axis:
• Gonadotropins: LH, FSH
• Gonadal response: Testosterone, DHT...
hCG stimulation test
 Evaluation of gonadal axis in children
 Dynamic & reliable test for leydig cell evaluation in boys...
Interpretation
 2 to 20 times rise in testosterone

1)adequate rise indicates presence of functioning testes
2)if rise is...
GnRH stimulation test
 Assess the pituitary function and degree of pubertal maturation

in DSD
 Evaluation of B/L crypto...
Interpretation
 In normal cases FSH&LH values rise at 30 min and later

decline at 60 min
 Initially there is predominan...
MANAGEMENT
DSD Team Participants
 Pediatrician
 Medical Geneticist
 Pediatric Urologist
 Pediatric Endocrinologist

 Gynecologis...
General guidelines for gender
assignment
 Try to match the baby’s sex assignment to the chromosomal

and gonadal sex if p...
Treatment
Treatment options include :
 Reconstructive surgery
 Hormone therapy
Reconstructive surgery
 Goals
Cosmetic
 to make a boy’s or a girl’s genitalia look natural
 restoring sexual function
...
Reconstructive surgery
 For girls : sexual function of organs is often not compromised

despite any ambiguous appearance....
Reconstructive surgery
 For boys : surgery is complicated but often successful. It

includes :
 Lengthening of the incom...
Hormone therapy
 Depending on severity of condition, hormone therapy alone

may be enough to correct the initial hormonal...
Prediction of fertility
 Ovaries are generally functional but testicular tissue is

generally dysgenetic
 XX patients wi...
 Pts with gonadal dysgenesis, partial AIS, 17-OHD are infertile

either because testis are abnormal or there is no uterus...
Hormone Biosynthesis Pathway
Congenital Adrenal Hyperplasia
 Incidence – 1 in 12000
 Most common cause of ambiguous genitalia in female newborn


Au...
CAH due to 21-OH deficiency
Classic salt wasting

Classic simple
virilizing

Males

Females

Males

Females

Age at dx

Bi...
Management
 Medical –

Stablisation of general condition
Correction of electrolyte abnormalities
After stabilisation – re...
Management
 Surgical –

Females with severe virilisation – early recession of clitoris
followed by vaginoplasty
Mild viri...
Antenatal management (CAH)
5 alpha reductase deficiency
 Autosomal recessive
 Male have small phalus or ambiguous genitalia with with

perineoscrot...
Treatment
 Medical management –

Males – testosterone enanthenate 25 mg i.m. monthly X 3mths
may increase penile length
F...
Surgical treatment
 Females

Feminizing genitoplasty - gonadectomy, restructuring of the
labioscrotal folds into labia, a...
Androgen insensitivity syndrome(AIS)
 Also known as Androgen receptor defects
 M/c form of male DSD
 Frequency 1/20,000...
Clinical presentation
 Extreme failure of virilization
 Genetic male invariably reared as female since birth
 Testes ma...
Investigation
 Serum Gonadotropins

LH & FSH leading to testosterone &estrogen
 hCG stimulation test (Twofold or greater...
Treatment
 Remove inguinal hernias
 Gonadectomy before or immediately after completion of

puberty (increased risk of go...
Ambiguousgenitalia best
Ambiguousgenitalia best
Ambiguousgenitalia best
Ambiguousgenitalia best
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Ambiguousgenitalia best

  1. 1. Dr. Sandip Gupta PGT, PEDIATRICS B.S.M.C.H.
  2. 2. Definition  When the external genitalia do not appear completely male or completely female .  Incidence:1in 2000 live births  Most cases present in newborn period  Social and medical emergency
  3. 3. When to suspect  Micropenis: Stretched penile        length<2.5cm in a term newborn Asymmetry of labioscrotal folds A penis with B/L nonpalpable testis U/L cryptorchidism with hypospadias Perineoscrotal or penoscrotal hypospadias with or without microphallus even if testes are descended. Apparently female external genitalia with clitoromegaly or inguinal hernia Overtly abnormal genitals like cloacal exstrophy Discordance of external genitalia with prenatal karyotype.
  4. 4. Disorder of Sexual Differentiation(DSD)  Also known as disorder of sexual development (Nelson) is defined as a congenital condition in which development of chromosomal,gonadal & anatomical sex is different.  Preferred over older terminology such as ambiguous genitalia, pseudohermaphroditism and intersex  Atypical development of genetic, gonadal and phenotypic sex  Includes disorders grouped under 4 major headings  46,XX virilized female  46,XY undervirilized male  Gonadal differentiation and chromosomal disorders
  5. 5. Types 46,XX virilized female 46,XY undervirilized male  Congenital adrenal hyperplasia  Defects in testicular differentiation  21-hydroxylase deficiency,  Defects in testicular biosynthesis  11-hydroxylase deficiency  Defects in androgen action  3 beta hydroxysteroid dehydrogenase deficiency  Aromatase deficiency(fetal and maternal)  Glucocorticoid receptor gene mutation  Virilizing maternal conditions  CAH  Adrenal/ovarian tumors  Drugs-progestin,androgen Ovotesticular DSD  XX  XY  XX/XY chimera Sex chromosome DSD  45X(turner syndrome)  47XXY(klinefelter syndrome)  45,X/46,XY(mixed gonadal dysgenesis)  46,XX/46XY
  6. 6. Incidence  The exact data on the incidence and prevalence of conditions causing ambiguous genitalia are limited.  Congenital adrenal hyperplasia accounts for most of the cases  Incidence of CAH 1 in 15000, AIS 1 in 20,000 (Avery’s disease of newborn 9th ed)
  7. 7. Incidence-India Etiology and 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.
  8. 8. Embryology  Sexual differentiation-3 stages 1. Determination of chromosomal sex (at conception) 2. Gonadal differentiation (at 6-7 wks of gestation) 3. Phenotypic sex determination (at 8-12 wks of gestation)  Stage 1 depends upon sex chromosome complement of fertilizing sperm  Stage 2 depends upon SRY gene of Y chromosome  Stage 3 depends upon testosterone and Mullerian Inhibiting Factor (MIF)
  9. 9.  Gonad develops from  Somatic cells (arise from mesonrphric cells and coelomic epithelium)- sertoli cells/granulosa cells  Germ cells (arise from yolk sac and migrate to genital ridge)Leydig cell/theca cell
  10. 10. Embryology  Testicular development is guided by TDF which is encoded by the SRY gene on the short arm of the Y chromosome.  Under the influence of the TDF ,germ cells in the genital ridge differentiate into Sertoli cells which secrete MIS (causes regression of the mullerian ducts) and Leydig cells which produce testosterone (promotes maturation of spermatogonia and regulates male phenotype).
  11. 11. Embryology Wolffian duct develops into the following:  Epididymis  Vas deferens  Ejaculatory duct and seminal vesicles
  12. 12. Embryology  In the absence of the Y chromosome , gonads differentiate into ovaries at around 11-13 weeks gestation.  Absence of MIS leads to persistence of mullerian structures which develop into:  Fallopian tubes  Uterus  Cervix  Vagina
  13. 13. Embryology  Undifferentiated external genitalia includes the following:  Urogenital tubercle  Urogenital swelling  Urogenital folds
  14. 14. Embryology  In males DHT leads to development of these three structures into :  Glans penis  Scrotum  Penile shaft  In absence of DHT, these structures develop into  Clitoris  Labia majora  Labia minora
  15. 15. Embryology  True hermaphroditism have both testicular and ovarian tissue in the gonads.  In patients with pure gonadal dysgenesis,both gonads are streak gonads.  Patients with mixed gonadal dysgenesis have a testis on one side and a streak gonad on the other
  16. 16. History  Maternal drug ingestion esp. in 1st trimester     (androgen, antiandrogen, progestins, antiseizure medication.) H/O virilization in mother may suggest androgen producing tumour (adrenal or ovarian,) placental aromatase deficiency,CAH. Past h/o early death of infants may suggest a previously missed androgenital deficiency Family h/o affected sibling or family member (CAH, hypospadias, infertility, delayed puberty , cryptorchidism, consanguinity) Neonatal death.
  17. 17. External genitalia Examination  Streched penis length,  width of corpora,  presence of chordee,  position of the urethral meatus,  presence of vaginal opening  pigmentation &symmetry of scrotum &labioscrotal fold  Anogenital ratio>0.5 is an indicator of 1st trimester androgen exposure. CAH with ambiguous genitalia
  18. 18. External genitalia Examination  Gonadal size ,position & descent should be noted a gonad below inguinal ligament is ususally a testis.  Abnormal genital development with cliteromegaly or apparently well formed penis with an empty scrotum should raise concern of virilised female with CAH.  Bimanual rectal exam may reveal mullerian strucures cervix or uterus in midline.  Associated anomalies should be noted. (WAGR, SMITH-LEMLI-OPITZ, ROBINOW,GOLDENHAR SYNDROME) Ambiguous genitalia in CAH
  19. 19. Investigations  Serum electrolytes  Blood sugar  Hormonal study  Karyotyping  Ultrasonography  Genitogaphy,  Sinogram  CT  MRI  Exploratory laprotomy/ Laproscopy
  20. 20. DIAGNOSTIC ALGORITHM
  21. 21. Algorithm for evaluation of 46,XX DSD Ambiguous genitalia 46 XX Karyotype Uterus present 17 Hydroxy progesterone Normal Ovotestis on USG Biopsy: Ovarian folicles & testicular tubules Hermaphroditism (Bisexual gonads) Increased CAH Normal Matrnal virilization/ Exogenous androgen exposure Maternal virilizing disorders: Medications: Progestins Tumors (adrenal/ovarian) Luteomas of pregnancy Aromatase deficiency
  22. 22. Algorithm for evaluation of 46,XY DSD Ambiguous genitalia Karyotype 46 XY USGlvis Pelvis No uterus Uterus present hCG stimulation test N/ T & DHT: AIS(Ar mutation analysis)/ Idiopathic Normal T & DHT : 5 alpha reductase deficiency Gonadal biopsy: •True hermaphordite •Persistent mullerian duct syndrome T and DHT: LH/FSH :partial gonadal dysgenesis, leydig cell hypoplasia Precursor steroids : T-biosynthesis defect
  23. 23. Ultrasonography  Identify müllerian structures- uterus, ovaries, fallopian tubes and upper half of vagina  Allows visualization of a neonate's adrenal glands - enlarged in infants with congenital adrenal hyperplasia (CAH) - have a cribriform appearance.  Normal ultrasonographic findings of the adrenal glands do not exclude a diagnosis of CAH.
  24. 24. Genitography  Helps to determine ductal anatomy.  In a neonate with ambiguous genitalia, a catheter can be inserted into the urethra - Contrast is injected to outline the internal ductal anatomy.  Findings - normal urethral anatomy, a müllerian remnant in a male, a common urogenital sinus, or normal female internal genitalia  CT and MRI - may help identify internal anatomy  Endoscopic examination of genitourinary tract .
  25. 25. Genetic Evaluation  KARYOTYPE  FISH  Presence of SRY  X and Y probes for gonadal biopsies  Specialized molecular genetic tests  Mutation analysis of 21-hydroxylase gene  Androgen receptor sequencing  Y chromosome microdeletions
  26. 26. 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
  27. 27. hCG stimulation test  Evaluation of gonadal axis in children  Dynamic & reliable test for leydig cell evaluation in boys  Assess testosterone secretion by testes  500 IU of hCG given i/m daily for 3 days  Serum testosterone, DHT, DHEA, androsteedione, LH & FSH are measured at baseline and then 24 hr after 3rd day  Collection of 24 hr urine before & after three doses of hCG used in analysis of steroid profile to detect testosterone biosynthesis defect
  28. 28. Interpretation  2 to 20 times rise in testosterone 1)adequate rise indicates presence of functioning testes 2)if rise is blunted –enzymatic defect in testosterone synthesis, gestational loss of testicular tissue, LH receptor mutation 3) ↑ T:DHT ratio(>20:1)- 5 alpha reductase def  Raised LH,FSH denotes anorchia or primary gonadal failure  Increased precursor steroid denotes biosynthesis defect
  29. 29. GnRH stimulation test  Assess the pituitary function and degree of pubertal maturation in DSD  Evaluation of B/L cryptorchidism (along with hCG stimulation test) Method: Serum LH, FSH, estradiol, testosterone and SHBG collected, followed by 2.5mcgm/kg GnRH iv is given, then above samples collected at 30 and 60 min.
  30. 30. Interpretation  In normal cases FSH&LH values rise at 30 min and later decline at 60 min  Initially there is predominant FSH response with progressive increase in LH response with pubertal maturation  In primary gonadal failure the basal gonadotropins are elevated with exaggerated response to GnRH
  31. 31. MANAGEMENT
  32. 32. DSD Team Participants  Pediatrician  Medical Geneticist  Pediatric Urologist  Pediatric Endocrinologist  Gynecologist  Pediatric Psychologist  Cytogeneticist  Social Worker
  33. 33. General guidelines for gender assignment  Try to 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
  34. 34. Treatment Treatment options include :  Reconstructive surgery  Hormone therapy
  35. 35. Reconstructive surgery  Goals Cosmetic  to make a boy’s or a girl’s genitalia look natural  restoring sexual function  May need repeated surgeries later in life
  36. 36. Reconstructive surgery  For girls : sexual function of organs is often not compromised despite any ambiguous appearance.  Depending on severity options are :  Uncovering vagina hidden under skin  Removing excess masculine tissue around the clitoris(clitoral reduction) – done once hormone replacement therapy has begun  Testis should be removed soon after birth if female sex of rearing is decided
  37. 37. Reconstructive surgery  For boys : surgery is complicated but often successful. It includes :  Lengthening of the incomplete penis  Undescended testis that is to be retained is best brought down into the scrotum at the time of initial gonadal biopsy  Correction of chordee and urethroplasty in boys with hypospadias is usually performed between 6 and 18 months of age
  38. 38. Hormone therapy  Depending on severity of condition, hormone therapy alone may be enough to correct the initial hormonal imbalance.  Ability of the gonads to produce appropriate hormones for sex of rearing is a factor in sex assignment.  Advantageous to retain a gonad appropriate to the assigned sex if it is likely to function adequately.
  39. 39. Prediction of fertility  Ovaries are generally functional but testicular tissue is generally dysgenetic  XX patients with CAH have a reasonably high probability of being fertile since they have a uterus and 2 normal ovaries  Women with 46,XX ovotesticular DSD are occasionally fertile
  40. 40.  Pts with gonadal dysgenesis, partial AIS, 17-OHD are infertile either because testis are abnormal or there is no uterus  If child has no chance of fertility and genitalia are sufficiently well developed to function as male, male sex of rearing is advised  Pts with ovotesticular DSD should be raised as female after removing the testicular tissue and leaving the ovary in place
  41. 41. Hormone Biosynthesis Pathway
  42. 42. Congenital Adrenal Hyperplasia  Incidence – 1 in 12000  Most common cause of ambiguous genitalia in female newborn  Autosomal recessive inheritance  No sex prediliction  21-hydroxylase deficiency - common cause of CAH  Young women may present with symptoms of polycystic ovarian syndrome
  43. 43. CAH due to 21-OH deficiency Classic salt wasting Classic simple virilizing Males Females Males Females Age at dx Birth-6mo Birth-1mo 2-4 yr Birth-2yr External genitalia Normal Ambiguous Normal Ambiguous Nonclassic Males Females Child to adult Normal Usually normal; may have clitoromegal y Aldosterone Low Normal Normal Cortisol Low Low Normal 17-OHP Basal>20,000 ng/dL Basal> 10,000 – 20,000 ng/dL ACTH stimulated 1,500 – 10,000 ng/dL % of normal 0 1-2 20-50 21-OH activity Pediatrics Endocrinology, Mechanisms, Manifestations and Management, Ora H. Pescovitz, Erica A. Eugster, 2004 by Lippincott Williams & Wilkins.
  44. 44. Management  Medical – Stablisation of general condition Correction of electrolyte abnormalities After stabilisation – replacement of glucocorticoid and / or mineralocorticoids depending on the general condition  Glucocorticoid replacement :  Hydrocortisone – 10-15mg/m2/d  Prednisolone – 2.5-6mg/m2/d  Mineralocorticoid replacement :  9 fluorohydrocortisone – 0.1-0.2mg/d
  45. 45. Management  Surgical – Females with severe virilisation – early recession of clitoris followed by vaginoplasty Mild virilisation – medical treatment is adequate NEWBORN SCREENING PROGRAMME
  46. 46. Antenatal management (CAH)
  47. 47. 5 alpha reductase deficiency  Autosomal recessive  Male have small phalus or ambiguous genitalia with with perineoscrotal hypospadias,bifid scrotum, inguinal,labio/scrotal testis.  Mullerian structures regress & wolffian duct derivaties present. At puberty they present with primary amenorrhoea and may experience virilization Diagnosis is done by increased testosteron to DHT ratio .
  48. 48. Treatment  Medical management – Males – testosterone enanthenate 25 mg i.m. monthly X 3mths may increase penile length Females - estrogen replacement therapy should be initiated at a bone age of 12 years or once an increase in gonadotropins is observed Dose is tailored to reach adult replacement levels over a 3-4 year range
  49. 49. Surgical treatment  Females Feminizing genitoplasty - gonadectomy, restructuring of the labioscrotal folds into labia, and reduction or recession of the phallus  Males Urethroplasty (Perineoscrotal hypospadias repair is typically a multistage procedure.) Repair of bifid scrotum Chordee repair Orchiopexy
  50. 50. Androgen insensitivity syndrome(AIS)  Also known as Androgen receptor defects  M/c form of male DSD  Frequency 1/20,000 genetic males  X linked recessive disorder  Two types complete AIS Partial AIS(k/a Reifenstein syndrome)
  51. 51. Clinical presentation  Extreme failure of virilization  Genetic male invariably reared as female since birth  Testes may be intra-abdominal/inguinal  AMH causes regression mullerian ducts.  Normal breast (due to peripheral aromatization of testosterone)  Primary amenorrhoea  Absent pubic hair
  52. 52. Investigation  Serum Gonadotropins LH & FSH leading to testosterone &estrogen  hCG stimulation test (Twofold or greater increase in testosterone level in response to HCG suggests normal functioning testicular tissue and helps rule out a defect in testosterone biosynthesis)
  53. 53. Treatment  Remove inguinal hernias  Gonadectomy before or immediately after completion of puberty (increased risk of gonadoblastoma)  Estrogen replacement  Vaginal reconstruction or vaginoplasty may be needed  Supportive counseling for infertility  Genetic counseling for family members

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