Reference : CME's on DSD, Ambiguous genitalia and Gender identity disoreder.

1. Presented by : Dr.Umbreen Minhas
Plastic surgery , Holy Family Hospital.

3. Sexual differentiation-3 stages
 Determination of chromosomal sex (at conception)
 Gonadal differentiation (at 6-7 wks of gestation)
 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)

4.  Gonads develop 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

5.  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 MIF (causes regression of the mullerian ducts) and Leydig cells which
produce testosterone (promotes maturation of spermatogonia and regulatesmale
phenotype).

6.  Wolffian duct develops into the following:
 Epididymis
 Vas deferens
 Ejaculatory duct and seminal vesicles

7.  In the absence of the Y chromosome , gonads differentiate into ovaries at around
11-13 weeks gestation.
 Absence of MIF leads to persistence of mullerian structures which develop into:
 Fallopian tubes
 Uterus
 Cervix
 Vagina

8. Differentiation of Internal Genitalia(wolffian and
mullerian duct)
and urogenital sinus in Male and Female

9. Male (requires DHT):
 labioscrotal fold = scrotum
 urethral fold / groove = urethra & penile shaft
 genital tubercle = glans penis
Female (requires nil):
 labioscrotal fold = labia majora
 urethral fold = labia minora
 genital tubercle = glans clitoris

13.  When the external genitalia do not have the typical
anatomic appearance of normal male or female genitalia.
 Most cases present in newborn period.
 Incidence is 1:2000 live births
 Caused by various DSD’s.

14.  Social and medical emergency
It can cause emotional and psychosocial stress to parents and family
75% have salt wasting fatal nephropathies (If unrecognized can cause
circulatory collapse and cardiac failure CAH )

16.  Micropenis: Stretched penile length<2.5cm in a term newborn
 Asymmetry of labioscrotal folds
 B/L cryptorchidism
 U/L cryptorchidism with hypospadias

17.  B/L testes with perineoscrotal or penoscrotal hypospadias
 Female external genitalia with clitoromegaly >1cm or inguinal hernia
 Overtly abnormal genitals like cloacal exstrophy

19.  Also known as disorder of sexual determination
 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
 Syndromes associated with ambiguous genitalia

20. Congenital adrenal hyperplasia
 21-hydroxylase deficiency,
 11-hydroxylase deficiency
 3 beta hydroxysteroid dehydrogenase deficiency

21. . A 46,XX female infant with severe virilization caused
by salt wasting congenital adrenal hyperplasia because
of 21-hydroxylase deficiency. Figure shows significant
clitoromegaly, fusion of the labioscrotal folds with
hyperpigmentation, no palpable gonads, single urethral
meatus

22. Aromatase deficiency(fetal and maternal)
 patients are unable to convert androgen precursors to estrogen. Aromatase
deficiency in the placenta leads to virilization of both the mother and the fetus
Virilizing maternal conditions
 CAH
 Adrenal/ovarian tumors
 Drugs-progestin,androgen

23.  Gonads are palpable
-Androgen receptor disorder
including complete or partial androgen insensitivity
The phenotype of patients with androgen insensitivity depends on the
degree of tissue responsiveness to androgen activity.

24.  Patients with complete androgen insensitivity have female external genitalia with
a blind vaginal pouch. These individuals typically present in adolescence with
primary amenorrhea, though in some instances they are identified earlier because
of inguinal or labial swellings containing testes
 Patients with partial androgen insensitivity can present with a wide range of
phenotypes, from ambiguous genitalia to phenotypic males who present with
infertility in adulthood.

25.  II-Inadequate testosterone production / defects in biosynthesis
 Leydig cell aplasia /hypoplasia
 Inadequate testosterone metabolism due to 5 a-reductase deficiency
 Drugs:
 Cyproterone acetate block androgen receptors
 Finasteride Inhibit 5α-reductase

27.  Ovotesticular DSD (true hermaphrodites )
 Mixed gondal dysgenesis (46X, 46XY)
 Complete gonadal dysgenesis (46,XY)

28.  Very rare
 90% present with ambiguous genitalia
 2/3 raised as M
 Chromosomal pattern 46,XX 75%
 mosaic (XX/XY) > 46,XY
TRUE HERMAPHRODITISM/OVOTESTICULAR DSD

29.  Has both ovarian & testicular tissue
 Lateral testis on one side & ovary on the other
 Unilaterl ovotestis on one side & normal gonads on the other
 Bilateral 2 ovotestis

30. Infant with penile hypospadias, chordee, and
bilaterally undescended testes who was found to have true
hermaphroditism

31. MIXED GONDAL DYSGENESIS (46X, 46XY)
 2n d most common cause of ambiguous genitalia in the newborn
 45,XO/46,XY M phenotype/ deficient virilization
 Testis on one side & streak gonads on the other
 Testis is dysgenetic/non sperm producing
 Unilat. unicornuate uterus on the streak gonad side
 Varying degrees of inadequate musculinization

32.  46XY
 Bilateral dysgenetic testes
 Uterus is present
 Inadequate virilization & cryptorchidism
 Wide range of phenotypes
 Sex of rearing F

33. Syndromes with ambigous genitalia
 Turner syndrome (45,x)
 Klinefelter syndrome (47,XXY)
 Camptomelic dysplasia
 Denys-Drash syndrome
 Frasier syndrome
 WAGR syndrome
 Robinow syndrome

35.  Evaluating a newborn with ambiguous genitalia can be challenging and requires prompt
investigation to determine the underlying cause.
 A multidisciplinary team approach.
 Parents should always be included in discussions about evaluation and management, and
they should be key stakeholders in the sex-assignment decision.

36.  Family history
Ambiguous genitalia, infertility or unexpected changes at puberty may suggest a
genetically transmitted trait
 -CAH ---autosomal recessive--occur in siblings
 -Partial androgen insensitivity---X-linked
 -XY gonadal dysgenesis ---sporadic

37. Consanguinity ↑↑the risk of autosomal recessive disorders
A Hx of neonatal death may suggest a missed diagnosis of CAH

38.  Pregnancy history
 Maternal Hx of virillization
 -Placental aromatase def. allows fetal adrenal androgens to virilize both mother &
fetus
 -Maternal poorly controlled CAH
 -Androgen secreting tumors
 Medications
 -Progestins
 -Androgens
 -Antiandrogens
 Phenytoin

39.  > Adolescent Pt
 When ambiguity first noted?
 Any pubertal signs?
 Onset of menarche ?

40. Abnormal facial appearance or other dysmorphic features suggesting a multiple
malformation syndrome
Evidence of salt wasting
Skin tugor
poor tone
Dehydration :
low BP, vomiting, poor feeding
Hyper pigmentation of the skin due ↑↑ ACTH

41. Abdominal masses
In adolescent evidence of hirsutism/ virilization

42.  Note the size and degree of
differentiation of the phallus, since
variations may represent ,
 clitoromegaly
 Note the position of the urethral meatus
- hypospadiasis

43.  Labioscrotal folds may be separated or
folds may be fused at the midline, giving
an appearance of a scrotum
 Labioscrotal folds with increased
pigmentation suggest the possibility of
increased corticotropin levels as part of
adrenogenital syndrome

46.  AMH level is a reliable marker of the presence and function of testicular tissue
and can be helpful in evaluating undervirilized XY individuals. AMH levels will be
low in cases of
 vanishing testes, XY gonadal dysgenesis, or persistent müllerian duct syndrome.
AMH levels can be elevated in cases of androgen insensitivity and
hypogonadotropic hypogonadism

47.  Evaluation of gonadal axis in children
 Dynamic & reliable test for leydig cell evaluation in boys
 Assess testosterone secretion by testis
 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

48.  High ratio of testosterone : DHT ------- of 5a-reductase deficiency.
 Inadeqaute response to HCG stimulation(↑↑ 17-OHP, DHEA, ASD)-------
Gonadal dysgenesis , inborn error of Testosterone biosynthesis ,
LH receptor defect.
High testosterone levels in an undervirilized 46,XY patient should raise suspicion
for androgen insensitivity

49.  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.

50. 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

53.  Pediatrician
 Medical Geneticist
 Pediatric Urologist
 Pediatric Endocrinologist
 Gynecologist
 Pediatric Psychologist
 Cytogeneticist
 Social Worker

54.  General guidelines
 The choice must be the result of full discussion between parents & medical team.
 The decision is guided by
 Anatomical condition & functional abilities of the genitalia
 Fertility potential (presence of F internal genital organs)
 The etiology of the genital malformation
 The family’scultural & religious background
 Girls with CAH are fertile & must always be assigned a female sex.

55.  In cases which can not be fertile, gender assignment will depend on:
 The appearance of the external genitalia
 The potential for unambiguous appearance
 The potential for normal sexual functioning
 True hermaphroditism F since ovarian function may be preserved & may be
fertile

56.  Great care should be taken in declaring a male sex considering:
 Potential for reconstructive surgery
 Probability for pubertal virilization
 Response of the external genitalia to exogenous & endog. T
 Pt with small phallus & poor response to androgens may be reared as F

57.  Treatment options include :
 Reconstructive surgery
 Hormone therapy

58.  KEY POINTS :
 Male
 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

59.  For girls :
 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

60.  1-Genital surgery for Female
 Timing of surgery …..controversial
 hree components of a feminizing genitoplasty
 Clitoroplasty 3-6M of age for F with CAH
 Vaginoplasty delayed until the individual is ready to start sexual life
 2-Genital surgery for M
 More difficult & involves several steps

61.  The treatment strategy is similar for all patients assigned to the male gender.
 Most of these patients have a small penis with a penoscrotal, scrotal, or perineal
hypospadias; a severe ventral curvature; and a partial or complete prepenile
scrotum
 Preoperative treatment with testosterone is helpful in those cases with a small penis
 Our preferred approach now is to perform a one-stage hypospadias repair in patients
with an adequate urethral plate, using the extended applications of the tubularized
incised plate urethroplasty described by Snodgrass
 The scrotoplasty should be delayed until after the hypospadias repair is completed
(six months or more )

62.  3-Gonadectomy to prevent cancer
 What are the facts?
 XY Partial gonadal dysgenesis Gonadolblastoma 55%
 XY complete gonadal dysgenesis Gonadoblastoma 30-66%
 All gonadoblastomas progress to seminoma.?
 Seminoma has a 95% 5-Y survival
 Testicular enzyme defects, 5α-red, partial androgen
 insensitivity Risk of malignancy is negligible before adulthood
 True Hermaphrodite risk is low in XX & higher inXY

63.  Pt raised as F gonadectomy must be performed in childhood
.Gonadectomy is recommended by many physicians followed by HRT

64.  Gonadectomy to remove source of Testosterone :
 in Pt raised as F to prevent progressive virilization especially at puberty
 Laparoscopy
 For evaluation of internal genitalia & gonadal biopsy
 For excision of mullerian structures in pt raised as M or Pt raised as F with non
communicating mullerian structures
 For gonadectomy

65.  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.

66.  Ovaries of true hermaphrodites may also produce adequate levels of estrogen.
 However, the testes of true hermaphrodites and mixed gonadal dysgenesis may
initially show good function that declines during childhood
 Testosterone supplements may be necessary for the establishment of puberty or
in adult life.

68.  Congenital adrenal hyperplasia :
 Most common cause of genital ambiguity in a 46,XX Female.
 Autosomal recessive inheritance
 21-hydroxylase deficiency – in 95% of cases leading to defect in cortisol synthesis
 The block in the production of cortisol leads to shunting of cortisol precursors
toward the androgen pathway, which leads to virilization of the external genitalia

69.  Infants with classic 21-hydroxylase deficiency also have deficient aldosterone
production and can present with a saltwasting crisis (hyponatremia,
hyperkalemia, hypoglycemia,hypovolemia, shock

70.  A 46,XX female infant with
severe virilization caused by salt
wasting congenital adrenal
hyperplasia because of 21-
hydroxylase deficiency. Figure
shows significant clitoromegaly,
fusion of the labioscrotal folds
with hyperpigmentation, no
palpable gonads, single urethral
meatus

71. 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

72.  Surgical –
 Females with severe virilisation – early recession of clitoris followed by
vaginoplasty
 Mild virilisation – medical treatment is adequate

73.  Vaginal agenesis, known as the Mayer-Rokitansky-KusterHauser syndrome
 . In this condition there is absence of the proximal portion of the vagina, resulting
from failure of the sinovaginal bulbs to develop and form the vaginal plate.
 This condition causes the vagina and uterus to be underdeveloped or absent,
although external genitalia are normal.
 Affected women usually do not have menstrual periods due to the absent uterus.
Often, the first noticeable sign of MRKH syndrome is that menstruation does not
begin by age 16 (primary amenorrhea). Women with MRKH syndrome have a
female chromosome pattern (46,XX) and normally functioning ovaries. They also
have normal breast and pubic hair development. Although women with this
condition are usually unable to carry a pregnancy, they may be able to have
children through assisted reproduction

74.  Women with MRKH syndrome have a female chromosome pattern (46,XX) and
normally functioning ovaries.
 They also have normal breast and pubic hair development. Although women with
this condition are usually unable to carry a pregnancy, they may be able to have
children through assisted reproduction
 The diagnosis can be confirmed by pelvic ultrasound and MRI.

75.  Vaginal dilatation is a valid alternative in patients with a vaginal dimple or
introitus.
 A program of daily, graduated dilatations over several months, using Hegar or
similar sounds, can result in a good-sized vagina to allow intercourse. Once a
satisfactory vaginal size is obtained, regular sexual intercourse maintains an
adequate vaginal cavity.
 construction of a skin neovagina and the creation of an intestinal neovagina using
sigmoid, cecum, and small intestine.

81. Young female presented at age of 16 years with absence of mensuration )primary
amenorrhea). She has normal breast and pubic hair development. External genital
examination is normal .No other systemic or musculoskeletal abnormality .
Abdomen and pelvis USG :Vagina and uterus are underdeveloped with normal
overies
Karyotyping :46,XX
condition is classified as MRKH syndrome type 1

82.  Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder that occurs in
females and mainly affects the reproductive system. This condition causes the
vagina and uterus to be underdeveloped or absent, although external genitalia are
normal. Affected women usually do not have menstrual periods due to the absent
uterus. Often, the first noticeable sign of MRKH syndrome is that menstruation
does not begin by age 16 (primary amenorrhea). Women with MRKH syndrome
have a female chromosome pattern (46,XX) and normally functioning ovaries.
They also have normal breast and pubic hair development. Although women with
this condition are usually unable to carry a pregnancy, they may be able to have
children through assisted reproduction

83.  When only reproductive organs are affected, the condition is classified as MRKH
syndrome type 1.
 MRKH syndrome type 2. In this form of the condition, the kidneys may be
abnormally formed or positioned, or one kidney may fail to develop (unilateral
renal agenesis). Affected individuals commonly develop skeletal abnormalities,
particularly of the spinal bones (vertebrae).
 Females with MRKH syndrome type 2 may also have hearing loss or heart
defects.