This document provides an overview of approach to a child with ambiguous genitalia. It defines ambiguous genitalia and discusses incidence. It outlines signs that should prompt suspicion of a disorder of sex development. It then describes normal external genitalia in male and female children. Key terminology related to sex and gender is defined. The document discusses normal sexual development and etiologies of disorders of sex development including 46,XX DSD, 46,XY DSD, ovotesticular DSD, and sex chromosome DSD. Approaches to evaluation and specific conditions are summarized.
Call Girls Service Jaipur {9521753030} ❤️VVIP RIDDHI Call Girl in Jaipur Raja...
Approach to dsd siddarth mahajan
1. Approach to a Child with
Ambiguous Genitalia
Student Name – Siddharth Mahajan
Guide - Dr. Nilofer Mujawar
2. Ambiguous Genitalia
• Definition: Any case in which the external
genitalia do not appear either completely
male or completely female.
• Incidence:
– Full range of Disorders of Sex Development(DSD) –
1:1500 births
– With significant genital ambiguity – 1:5000 births
3. When to suspect???
• A penis and bilaterally non-palpable testes.
• Unilateral cryptorchidism with hypospadias.
• Peno-scrotal or perineo-scrotal hypospadias, with
or without micro-phallus, even if the testes are
descended.
• Apparently female appearance with enlarged
clitoris or inguinal hernia.
• Overtly abnormal genital development such as
cloacal exstrophy.
• Asymmetry of labioscrotal folds, with or without
cryptorchidism.
• Discordance of external genitalia with prenatal
karyotype.
4. Normal External Genitalia in a MALE Child
• Stretched Penile length
> 2.5 cm
• External urethral opening
at the tip of the penis
• Scrotum is relatively larger
& having darker skin
• Both testes in scrotum
5. Normal External Genitalia in a FEMALE Child
• Labia minora & clitoris
are completely covered
by Labia majora.
• Skin of the labia majora
is darker.
• Mucuoid, non-purulent
discharge may be
observed from vagina.
• Occasionally mild
withdrawal bleeding from
vagina due to maternal
hormones
6. Terminologies:
1. Genetic / Chromosomal sex
2. Gonadal sex
3. Phenotypic / Anatomic sex
4. Gender identity
5. Gender role
6. Sexual orientation
7. 1) Genetic sex
• Determined by chromosomal complement of
the zygote.
• Presence or absence of specific genes
necessary for normal sexual development.
• In male SOX9 , SF1 ,WT1
• In Female WNT4, DAX1
8. 2) Gonadal sex
• Undifferentiated gonads develop in the bilateral
genital ridges around 6 weeks of gestation and begins
to differentiate by 7 weeks.
• SRY (Sex determining Region on Y chromosome) which
encode the primary testis determining factor on the
short arm of Y chomosome causes undifferentiated
gonads to develop into testis.
• In absence of SRY & Testis determining factor - normal
female pathway continue- which is by default.
10. 4) Gender Identity
• Person’s self identification as male or female
• One’s internal sense of gender
11. 5) Gender Role
• Expression of characteristics that are sexually
dimorphic within a general population
(clothing/ toys preferences, physical
aggression, grooming behavior, etc.)
• One’s gender related behavior and interests in
society.
12. 6) Sexual orientation
• Choice of sexual partner and erotic interest (
heterosexual, homosexual, bisexual )
13. Normal Sexual Development
2 phases -
1. “Sex Determination” – the development of
the undifferentiated gonad into testis or
ovary.
2. “Sexual Differentiation” – the phenotypic sex
develops through the action of gonadal and
other hormones.
14. Important enzymes and hormones:
• hCG - LH Testosterone (in testes)
• 5α-reductase - Testosterone
Dyhydrotestosterone
• Aromatase - testosterone estrogen
22. Any variation or interruption in this
normal process of sexual development,
may affect development of
Gonads, Internal Duct system &/or External
Genitalia.
23. Disorder of sexual development (DSD)
• Disorder of sexual development (DSD)
condition in which development of
Chromosomal ,
Gonadal or Anatomical sex is atypical.
24. Red flags for possible DSD in apparent
male or female infants!!!
• Apparent “Male Infant”
– Bilateral undescended testes
– Bifid scrotum
– Hypospadias with one other abnormal finding
(undescended testis/micropenis)
• Apparent “Female Infant”
– Clitoromegaly
– Single genitourinary opening
– Inguinal hernia
25. ETIOLOGIC CLASSIFICAION OF DISORDERS OF
SEX DEVEOPMENT
1) 46XX DSD
2) 46XY DSD
3) OVOTESTICULAR DSD
4) SEX CHROMOSOME DSD
31. 46, XY DSD
(Incomplete Masculinization of the Genetic Male)
Disorder External genitalia Gonads Karyotype
3) Disorders of testosterone metabolism
5 α-reducatase deficiency Ambiguous Testes 46,XY
4) End organ resistance to testosterone
Complete androgen insensitivity
syndrome
Female Testes 46,XY
Partial androgen insensitivity
syndrome
Ambiguous Testes 46,XY
5) Vanishing testes syndrome Variable Absent
gonads
46,XY
6) Lack of anti-mullerian hormone or
AMH receptor
Male Testes,
uterus,
fallopian
tubes
46,XY
32. Disorders of Gonadal Differentiation
Disorder External genitalia Gonads Karyotype
Ovo-testicular DSD Ambiguous Ovarian
and
testicular
tissue
46,XX;
46,XY;
46,XX/
46,XY
Mixed gonadal dysgenesis Variable Streak
gonad and
dysgenetic
testis
45,X/
46,XY;
46,XYp-
46,XY complete gonadal dysgenesis Female or
ambiguous
Dysgenetic
testes or
streak
gonads
46, XY
46,XX testicular DSD Male or
ambiguous
Testes 46,XX
33. Approach to DSD
DSD with no palpable gonads
Uterus present Uterus absent
Elevated
17 OHP
Normal 17 OHP
XX
CAH
XX X, X/XY, XY XX/ XY
Maternal
androgen,
ovotesticula
r DSD
Gonadal
dysgenesis
Ovotestic
ular DSD
46,XY DSD with intra
abdominal gonad or
vanishing testes
syndrome
34. Approach cont..
DSD with at least one palpable gonad
Uterus present
Karyotype
XY or
X/XY
XX or XX/XY
or rarely XY
Further testing: baseline LH, FSH,
Testosterone hCG stimulation
test, gonadal biopsies
Uterus absent
Karyotype XY
Baseline LH, FSH, T,
hCG stimulation test
Low T
response
High T,
low DHT
High T and
DHT, poor
response to
T injections
T biosynthetic
defect, gonadal
dysgenesis
5α-reductase
deficiency
Androgen
insensitivity
syndrome
Gonadal
dysgenesis
Ovotesticular
DSD
38. 1- 46,XX DSD (female pseudohermaphrodite)
Gonads not palpable
Exposure to excessive androgens in utero
• Congenital adrenal hyperplasia (CAH)
– The most common cause of ambiguous genitalia
60-70%
– Results from enzymatic defect in the conversion of
cholesterol to cortisol ↑↑ ACTH ↑↑ adrenal
androgens & steroid precursors.
A-21- hydroxylase deficiency 95% ↑17-OH P
B-11 β-hydroxylase deficiency ↑11-deoxycortisol
+ ↑ BP
C-3β-hydroxysteroid dehydrogenase def.
↑pregnelonone
39. CAH
A-21- hydroxylase deficiency 95%
• ↑17-OH P
• Autosomal recessive.
• ↑↑adrenal androgens musculinization of F
genitalia/Mullerian structures unaffected.
• Clitoral hypertrophy, labial fusion with
hyperpigmentation, displacement of urethra,
single perineal orifice (urogenital sinus)
• Wolffian derivatives absent.
• Androgen effect on the brain “Tom boy”
behaviour
• Puberty is delayed, menses is irregular & fertility
is reduced in the salt wasting form & Pt not
compliant with Rx.
40. External genitalia of a patient with congenital
adrenal hyperplasia secondary to 21-hydroxylase deficiency,
showing labioscrotal fusion and clitoromegaly
41. A-21- hydroxylase deficiency
1. Classical form 1: 10-15000
– Cortisol & aldosterone deficiency
– Salt wasting & virilisation of varying degrees
2-Simple virilising form
– Aldosterone production is reduced but not to the
point of salt wasting
3-Non-classic form 1:500
– No ambiguous genitalia
– Late onset premature pubarche & advansed bone
age
menstrual disturbance & hirsutism in
adult F
42. CAH
B- 11 β-hydroxylase deficiency
• Autosomal recessive
• Musculinization of F genitalia
• cortisol, ↑↑ adrenal androgens
• ↑↑11-deoxycortisol & 11-deoxycorticosterone ↑↑ BP, K
C- 3β-hydroxysteroid dehydrogenase def.
• V rare
• Autosomal recessive
• ↑↑pregnelonone
• cortisol, aldosterone & androgens
• Salt wasting
• Undervirilised M almost complete feminization
• Partial def mildly virilized F
43. 1-46XX, F Pseudohermaphrodites
• II-Virilizing maternal ovarian/adrenal tumors
Ovarian tumors luteoma of pregnancy,
arrhenoblastoma, hilar cell tumor, masculinizing stromal
cell tumor & krukenberg tumor, lipoid cell tumor
Rare Adrenal tumors- adrenocortical carcinoma,
adenoma.
• III-Ingestion of androgens
V. rare
progestogens eg.19-nortestosterone, danazol, T,
norethinodrone
• IV-Placental aromatase deficiency
defective conversion of androgens (T& ASD) to
estrogens(mutation of CYP19 aromatase gene).
44. 2. 46,XY DSD (Male Pseudohermaphrodite)
Gonads are palpable
I-Androgen receptor disorder with normal
testosterone level/Partial androgen insensitivity
80%
(Complete androgen insensitivity “testicular
feminization” unambiguous genitalia, F
phenotype)
• A wide spectrum of phenotypes
F with clitoromegaly---M hypospadias or
micropenis.
• ↑↑ LH, T & estrogens
• No correlation between the concentration of
androgen receptors & the degree of virilization
45. 2-46,XY DSD (Male Pseudohermaphrodite)
II-Inadequate testosterone production / defects in
biosynthesis
1- 17 β-hydroxysteroid dehydrogenase def.
(testicular enzyme)
• Rare autosomal recessive
• F phenotype/ absent mullerian structures
• Partial form ambiguous genitalia
• Testis in inguinal canal or labia
• Well differentiated wolffian duct structures
• Virilization at puberty with ↑↑ ASD , Normal T
47. II-Inadequate testosterone biosynthesis
Adrenal enzymes (V rare) CAH
2- 3 β-hydroxysteroid dehydrogenase def.
• Salt wasting
• F phenotype (complete form)/ambiguous
genitalia (partial form)
3- 17 α-hydroxylase def./ associate with 17-20-
lyase def
• Variable phenotype
• Severe form DX at puberty with water
retention, ↑↑ BP & hyperkalemia.
4- Congenital Lipoid adrenal hyperplasia
• Rare, caused by StAR enzyme deficiency.
• Defect in the synthesis of 3 types of steroids
• Severe salt wasting
• F phenotype
• Blind vagina without uterus
48. 2-46,XY DSD (Male Pseudohermaphrodite)
III- 5 α-reductase def.
• Wide range of phenotypes
• All have differentiated wolffian ducts
• Virilization at puberty & male identity
• ↑↑ T : DHT ratio / N or ↑ M T level
• Most are raised as females
IV-Leydig cell hypoplasia
• Impaired T production
• Phenotype is usually F/ absent mullerian structures
V- Drugs
• Cyproterone acetate block androgen receptors
• Finasteride Inhibit 5α-reductase
49. External genitalia of patient with 5α-reductase
deficiency; clitoromegaly with marked labioscrotal fusion
and small vaginal introitus
50. 3-True hermaphroditism/ Ovotesticular DSD
• Very rare
• 90% present with ambiguous genitalia
• 2/3 raised as M
• All have urogenital sinus & most cases have uterus
• Chromosomal pattern 46,XX 75%
mosaic (XX/XY) > 46,XY
• Has both ovarian & testicular tissue
1-Lateral testis on one side & ovary on the other
2-Unilaterl ovotestis on one side & normal gonads
on the other
3-Bilateral 2 ovotestis
51. Infant with penile hypospadias, chordee, and
bilaterally undescended testes who was found to have true
hermaphroditism
52. 4-Partial/Mixed gonadal dysgenesis
• 2nd 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
46XY
– Bilateral dysgenetic testes
– Uterus is present
– Inadequate virilization & cryptorchidism
– Wide range of phenotypes
– Sex of rearing F
53. 5-Defects of testis maintenance /Bilateral vanishing
testis
• XY
• Absent or rudimentary testis
• A spectrum of phenotypes
• Sex of rearing M with T replacement (most of the
time)
6-Abnormal karyotype
• Triploidy 69XXY ambiguous genitalia 50%
Lethal
• 47XXY & 47XYY may present with ambiguous g.
• Mosaic 46XX/46XY, 46XX/47XXY variable genitalia
54. Dysmorphic syndromes Associated with
Ambiguous Genitalia
1) Prader Willi Syndrome -46XY -
Cryptorchidism
- Small penis
- Obesity
- Mental Retardation
1) Seckel’s Bird- Headed Dwarfism - 46XY
- Cryptorchidism
- IUGR
- Microcephaly with severe Mental Retardation
1) Opitz Syndrome of Hypospadias and Telecanthus - 46 XY
- Hypospadias
55. Dysmorphic syndromes..
4) Aarskog Syndrome - 46XY
- Scrotal overiding of base of penis
- Pectus Excavatum
- Ocular hypertelorism
5) Camptomelic Dwarfism - 46 XY
- Micrognathia - Cleft
palate - Multiple osseous
defect
6) Cornelia de Lange Syndrome
- Cryptorchidism
- Hypoplasia of penis
56. QUES…
CASE- 1
• A full term normal delivered baby presented with mild respiratory
distress, reticular pattern &prolonged CRT with sign of shock
• LAB reports-
– CBC-WNL
– CRP-negative
– S. Na- 128 meq/dl
– S. K- 5.4 meq/dl
– RFT- blood urea-64mg/dl
– S. Creat- 1.1
– ABG shows- met. Acidosis
– pH-7.14
58. • DIAGNOSIS= 46XX FEMALE DSD WITH 21
HYDROXYLASE DEFICIENCY
• Baby was resuscitated with fluids ; Started
upon initially with injectable hydrocort; Then
on oral hydrocort & fludrocort…
59. QUES…
CASE- 2
• A 22 day old baby was brought by mother for routine checkup
as she found unusual genitals. no other complaints bilaterally
the folds had palpable round body.
• Lab test- S. Na- 138; S. K – 4.4
61. • DIAGNOSIS= Complete androgen insensitivity
• Also called testicular feminisation (female
phenotype)
62. Relevant History in a child with
Ambiguous Genitalia
• Most cases either isolated occurrences or inherited as
AR or X linked trait.
• Family history of unexplained neonatal deaths (CAH).
• Family history of hypospadias, cryptoorchidism,
amenorrhea.
• History of infertility in close relatives.
• Maternal drug exposure during pregnancy -
androgens, progestin, phenytoin.
• Placental insufficiency ( HCG initiates synthesis of
testosterone in fetal testes).
64. • Anogenital ratio-
• Distance between the anus and the posterior
forchette divided by the distance between
anus and the base of the clitoris.
• Ratio > 0.5 cm is indicative of 1 st trimester
androgen exposure
• Posterior fusion of the labioscrotal folds
increse anogenital ratio.
65. Clinical Examination in Ambiguous
Genitalia
4. Female component:
- labia majora / minora
- Urethral opening
- vaginal opening
- Identify clitoris : measure(N < 1cm)
- S/o virilization/ masculinization
- Posterior labial fusion
- Palpate inguinal region and labia majora for
gonads
- Per rectal examination – uterus
66. Clinical Examination in Ambiguous
Genitalia
5. Relevant general and systemic examination
- height
- weight
- dysmorphic features
- f/o Turner syndrome
- breasts
67. DIAGNOSTIC TESTS
1) Karyotyping: results available in 72 hours by FISH
(fluoroscent in situ hybridisation) technique
Buccal smear highly unreliable for karyotype but
applicable for FISH
2) Serum 17- Hydroxyprogesterone level - increased
in 21 hydroxylase deficiency
- normal level 100-200 ng/ dl
68. DIAGNOSTIC TESTS
3) ACTH Stimulation test:
- Done to confirm diagnosis of CAH in case 17
hydroxyprogesterone level is boderline or non diagnostic
range
- 35 mcg/kg (max 0.25 mg) synthetic ACTH I.V
- collect venous sample and assess 17 hydroxyprogesterone
level
-Will be increased 4-5 times over baseline in CAH
45-60 min
69. DIAGNOSTIC TESTS
4) HCG Stimulation test
1000 U/m2 hCG IM OD X 3 days
24 hours after last test
Measure serum testosterone and DHT levels
Testosterone <100 ng /dl
- Deficiency of various
enzyme of steroid
biosynthesis
- Leydig cell hypoplasia
70. DIAGNOSTIC TESTS
5) Testosterone Trial test: Leydig cell hypoplasia
25-50 mg testosterone IM every monthly for 3months X 3 doses
Increase in phallic length atleast 1.5 cm ( 0.5 cm/mon)
positive response
6) Baseline levels of –
• Pregnenolone
• Progesterone
• 17 Hydroxypregnenolone
• 17 Hydroxyprogesterone
• Dehydroepiandrosterone ( DHEA)
• Androstenedione
• Testosterone
• Dihydrotestosterone (DHT)
• Cortisone
71. DIAGNOSTIC TESTS
7) Gonadal Biopsy
Done > 18 months of age and > 9 kg weight
Diagnosis of : a) Ovotesticular DSD
b) Gonadal dysgenesis with Y chromosomes
c) Dysgenetic testis
d) XX male
e) Leydig cell hypoplasia
f) Persistent mullerian duct syndrome
8) Genital skin biopsy and study of cultured fibroblast
- Androgen receptor resistance
- 5 alpha reductase levels
72. DIAGNOSTIC TESTS
9) USG/ MRI
- MRI is found to be marginally more sensitive than
USG, for evaluation of gonads.
- For internal genital structures, both modalities
were found to be equally sensitive and specific
with no false positive results.
- USG still remains the modality of choice for
screening patients with DSD
- MRI is helpful in cases with equivocal USG
findings.
.
73. • 10) Genetic testing:
– Particularly in CAH and complete androgen
insensitivity.
– Techniques like whole genome and exome
sequencing
– helpful in reaching a diagnosis for in infants with
46XY DSD, because a definitive diagnosis is
currently not found in many.
74. TREATMENT :
• Requires a team of doctors involving
a number of specialities –
• Pediatrician,
• pediatric endocrinology,
• urology,
• plastic surgery,
• medical genetics and
• psychology
76. RECONSTRUCTIVE SURGERY :
• Goal is cosmetic, to make a boy’s or a girl’s
genitalia
look natural and also in hopes of restoring sexual
function
• May need repeat surgeries later in life
• Certain types of surgery are most successful
when
carried out soon after birth, while others may be
delayed till further child developement
77. • FOR BOYS : surgery is complicated but often
successful. It includes :
– Lengthening of the incomplete penis
– an 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
78. • 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
79. ESTROGEN REPLACEMENT THERAPY
For induction of puberty ( 10-12yrs):
Conjugated estrogen ( Premarin) 0.3 mg every other day for 6-12 mon.
Increase to 0.3 mg/day for another 6-12 mon. Increase to 0.625
mg/day ( days 1-26 of each mon).
(or)
Ethinyl estradiol 50 ng/day. Increase by 50-100 ng/ kg/ day q6-12 mon
to a dose of 20-30 ug/ day)
(or)
Transdermal estrogen patches 0.025 mg/day twice weekly and
increased every 6-12 mon ( 0.0375 mg/day, 0.05 mg/day)
(and)
Cyclic estrogen and progesterone therapy if uterus is present.
Medroxyprogesterone acetate (Provera) 5-10 mg/day ( days 15-26)
80. TESTOSTERONE REPLACEMENT
THERAPY
For induction of puberty (12-14 yr):
50 mg IM testosterone enanthate or cypionate
monthly starting at 12-13 years of age
Gradually increase by 25-50 mg/ 6-12 mons to a
dose of 200mg q 2-3 week
82. PSYCHOSOCIAL SUPPORT TO PARENTS
• Show the baby to the parents
• Counsel both parents together
• Do not commit- unless sure
What to tell the parents?
• The baby is healthy but the external genitalia is incompletely developed &
tests are necessary to determine the sex
• There are other babies with similar condition
• A No. of treatable conditions can result in atypical genetalia
• Reassurance that a good outcome can be anticipated
• How long the process of investigation will take ? Around 3-4 Wk
• Give them appt times & names of the people who will see them
• To talk about their fears of future sexual identity & sexual orientation of
their child preferably with psychologist or social worker
• Support when it comes to facing their friend & relatives
83. TAKE HOME MESSAGE
• DSD is a medical emergency and social
emergency
• Rule out CAH in a child who is not growing
well and presents with adrenal crisis
• Multidisciplinary approach
• Phenotypic sex- guides investigations
• Do not commit sex/gender of rearing unless
sure
84. References
• Nelson Textbook of Paediatrics
• Paediatric Endocrine Disorders – Meena Desai
• Wherrett DK. Approach to the infant with a
suspected disorder of sex development.
Pediatric Clinics of North America. 2015 Aug
31;62(4):983-99
• Manual of Neonatal Care (7th edition) – John P.
Cloherty
• PG textbook of Paediatrics – Piyush Gupta
TT test neg – AIS subsequent trial with high dose 50-100 mg monthly 3-4 mons. Positive = partial AIS, neg- complete AIS
Girls start with low dose estg therapy to initiate breast budding with advancing bone age. Cyclic progesterone is added to decrease the r/o dysplasia. Est maintain feminization and protect against osteoporosis.