MBBS lecture topic

1. DISORDERS OF SEX DEVELOPMENT
(DSD)
(Ambiguous genitalia)
P.N 1

2. DEFINITION OF DSD
(DSDs) are defined as conditions involving the following elements:
1. Ambiguous genitalia (e.g., 46,XX virilizing congenital adrenal
hyperplasia; clitoromegaly; micropenis)
2. Congenital disjunction of internal and external sex anatomy
(e.g., Complete Androgen Insensitivity Syndrome; 5-alpha
reductase deficiency)
3. Incomplete development of sex anatomy (e.g., vaginal
agenesis; gonadal agenesis)
4. Sex chromosome anomalies (e.g., Turner Syndrome;
Klinefelter Syndrome; sex chromosome mosaicism)
5. Disorders of gonadal development (e.g., ovotestes)
P.N 2

3. 1. DSD conditions usually present with:
1. Atypical genitalia in the newborn period
or
2. Delayed puberty in an adolescent.
2. DSDs include anomalies of
1. The sex chromosomes,
2. The gonads,
3. The reproductive ducts (internal genitalia)
4. The external genitalia.
P.N 3

4. CLASSIFICATION OF DSD
BY THE CHICAGO CONSENSUS IN 2005.
There are three broad groups:
1. Sex chromosome DSD,
2. 46, XX DSD, (formerly known as female
pseudohermaphroditism) and
3. 46, XY DSD (formerly known as male
pseudohermaphroditism)
P.N 4

5. 46,XX DSD
(formerly known as female pseudohermaphroditism)
1. Androgen Exposure
1. Fetal/Fetoplacental Source
1. 21-Hydroxylase (P450c21 or CYP21) deficiency
2. 11β-Hydroxylase (P450c11 or CYP11B1) deficiency
3. 3β-Hydroxysteroid dehydrogenase II (3β-HSD II)
deficiency
4. Cytochrome P450 oxidoreductase (POR)
5. Aromatase (P450arom or CYP19) deficiency
6. Glucocorticoid receptor gene mutation
2. Maternal Source
1. Virilizing ovarian tumor
2. Virilizing adrenal tumor
3. Androgenic drugs (contd)
P.N 5

6. 2. Disorder of Ovarian Development
1. XX gonadal dysgenesis
2. Testicular DSD (SRY+, SOX9 duplication)
3. Undetermined Origin: Associated with genitourinary
and gastrointestinal tract defects
P.N 6

7. 46,XY DSD
(formerly known as male pseudohermaphroditism)
1. Defects in Testicular Development
2. Deficiency of Testicular Hormones
3. Defect in Androgen action
(contd)
P.N 7

8. Defects in Testicular Development
1. Denys-Drash syndrome (mutation in WT1 gene)
2. WAGR syndrome (Wilms tumor, aniridia, genitourinary
malformation, retardation)
3. Deletion of 11p13
4. Campomelic syndrome (autosomal gene at 17q24.3-q25.1) and
SOX9 mutation
5. XY pure gonadal dysgenesis (Swyer syndrome)
6. Mutation in SRY gene
7. XY gonadal agenesis
8. Unknown cause
P.N 8

9. Deficiency of Testicular Hormones
1. Leydig cell aplasia
2. Mutation in LH receptor
3. Lipoid adrenal hyperplasia (P450scc or CYP11A1)
deficiency; mutation in StAR (steroidogenic acute
regulatory protein)
4. 3β-HSD II deficiency
5. 17-Hydroxylase/17,20-lyase (P450c17 or CYP17)
deficiency
6. Persistent müllerian duct syndrome:
1. Antimüllerian hormone gene mutations
2. Receptor defects for antimüllerian hormone
P.N 9

10. Defect in Androgen action
1. Dihydrotestosterone deficiency because of 5α-
reductase II mutations or AKR1C2/AKR1C4 mutations
2. Androgen receptor defects:
a. Complete androgen insensitivity syndrome
b. Partial androgen insensitivity syndrome (Reifenstein
and other syndromes)
3. Smith-Lemli-Opitz syndrome (defect in conversion of 7-
dehydrocholesterol to cholesterol, DHCR7)
P.N 10

11. Sex Chromosome DSD
1. 45,X (Turner syndrome and variants)
2. 47,XXY (Klinefelter syndrome and variants)
3. 45,X/46,XY (mixed gonadal dysgenesis, sometimes a
cause of ovotesticular DSD)
4. 46,XX/46,XY (chimeric, sometimes a cause of
ovotesticular DSD)
P.N 11

12. Ovotesticular DSD
(the simultaneous presence in the same individual of
both, histologically proven, testis and ovary.)
1. XX
2. XY
3. XX/XY chimeras
P.N 12

13. EVALUATION
(AMBIGUOUS GENITALIA)
1. Definition. Ambiguous genitalia are present when the
sex of an infant is not readily apparent after
examination of the external genitalia.
2. Incidence.
1. Congenital adrenal hyperplasia is the most
common cause 1 in 14,000 to 1 in 28,000,
followed by
2. androgen insensitivity and
3. mixed gonadal dysgenesis.
4. Hypospadias (1 in 300 births, but only a minority
of these patients has DSD)
P.N 13

14. Embryology
1. The early fetu (XX or XY), is bipotential and can undergo either
male or female differentiation.
2. The innate tendency of the embryo is to differentiate along
female lines
3. If the Y chromosome (having SRY gene) is present, the gonads
differentiate as testes.
4. The testes then produce testosterone, which is converted to
dihydrotestosterone (DHT) in the target organ cells by 5α-
reductase.
5. DHT induces male differentiation of the external genitalia. The
testes descend behind the peritoneum and normally reach the
scrotum by the eighth or ninth month.
P.N 14

15. 6. In the female fetus, where the Y chromosome/SRY
gene is absent, the gonads form ovaries (even in 45,X
Turner syndrome, histologically normal ovaries are
present at birth).
7. As ovaries do not produce testosterone, female
differentiation proceeds.
8. Two X chromosomes are needed for further
differentiation of ovaries.
9. If part or all of the second X chromosome is missing,
ovarian development fails, resulting in atrophic,
whitish, streaky gonads by 1–2 years of age.
P.N 15

16. 10. Normal male.
1. At ~9 weeks postconceptional age, in the presence DHT,
masculinization begins with lengthening of the anogenital
distance.
2. The urogenital and labioscrotal folds fuse in the midline,
leading to the formation of the scrotum and the penis.
11. Normal female.
1. In the female fetus, the anogenital distance does not
increase.
2. The urogenital and labioscrotal folds do not fuse and instead
differentiate into the labia majora and minora.
3. The urogenital sinus divides into the urethra and the vagina.
P.N 16

17. Pathophysiology
1. Virilization of female infants (female pseudo
hermaphroditism):
a. Many belong to this group. They have a 46,XX
karyotype, are SRY negative, and have exclusively
ovarian tissue.
b. The most common cause of excess fetal androgens is
congenital adrenal hyperplasia (CAH)
c. Most common cause of CAH is is 21-hydroxylase
deficiency
P.N 17

18. 2. Inadequate virilization of male infants (male pseudohermaphroditism).
a. These patients have a 46,XY karyotype and exclusively testicular
tissue.
b. Inadequate androgen production
1 3β-HSD II deficiency
2 17-Hydroxylase/17,20-lyase (P450c17 or CYP17)
deficiency
3 Deficiency of Müllerian-inhibiting substance
c. Testicular unresponsiveness to human chorionic gonadotropin
(hCG) and luteinizing hormone (LH)
d. Anorchia (absent testes caused by loss of vascular supply to the
testis during fetal life).
e. Incomplete end-organ response to androgen.
f. Decreased end-organ response to androgen
g. 5α-Reductase deficiency
P.N 18

19. 3. Disorders of gonadal differentiation:
1. True hermaphroditism. The presence of both a testis and
an ovary (or ovotestes) in the same individual: 46,XX or
mosaics of 46,XX/45,X/46,XY/multiple X/multiple Y
2. Gonadal dysgenesis: pure and mixed
3. Chromosome abnormalities, syndromes, and associations:
trisomies 13 and 18, triploidy
4. Single-gene disorders and syndromes: Smith-Lemli-Opitz
syndrome, Rieger syndrome, CHARGE syndrome
5. Camptomelic dysplasia
6. VATER/VACTERL association
P.N 19

20. Clinical presentation
1. History.
a. Family history of early neonatal deaths (a death in early
infancy accompanied by vomiting and dehydration may be
secondary to CAH),
b. Consanguinity of the parents (increased risk for autosomal
recessive disorders), and female relatives with amenorrhea
and infertility (male pseudohermaphroditism or
chromosomal anomalies)
c. Ingestion or topical use of drugs during pregnancy
(particularly androgens or progestational agents).
P.N 20

21. Physical examination
1. General examination.
a. Dysmorphic features (syndromes and chromosomal
abnormalities),
b. Hypertension or hypotension, areolar hyperpigmentation,
and signs of dehydration (as signs of CAH).
2. Gonads:
a. The number, size, and symmetry of gonads should be
evaluated.
b. Palpable gonads below the inguinal canal are usually
testes.
c. Ovaries are not found in scrotal folds or in the inguinal
region. However, the testes may be intra-abdominal.
P.N 21

22. Gonads contd.
d. Phallus length: Measured from the pubic ramus to the tip of the
glands, a stretched penile length in a full-term infant should be
≥2.0 cm.
e. Urethral meatus: Look for hypospadias (usually accompanied by
chordee).
f. Labioscrotal folds:
1. Range from unfused labia majora, variable degrees of
posterior fusion, and bifid scrotum to fully fused, normal-
appearing scrotum.
2. The presence of a vaginal opening or urogenital sinus should
be determined.
3. A rectal examination, to determine presence of a uterus,
may be considered. P.N 22

23. Laboratory studies
1. Initial evaluation. chromosome analysis; Fluorescent in situ
hybridization techniques
2. Detection of SRY gene material in 46,XX phenotypic males and in
a 45,X
3. Buccal smears are unreliable and therefore obsolete
4. 17-hydroxyprogesterone (17-OHP), testosterone,
dihydrotestosterone levels
5. Sodium, and potassium levels
6. Androstenedione levels are measured to diagnose 17-ketosteroid
reductase deficiency.
7. LH and follicle-stimulating hormone (FSH). A diagnosis of
gonadotropin deficiency is suspected if these values are low.
P.N 23

24. 7. hCG stimulation test.
a. hCG is administered to stimulate gonadal steroid
production when testosterone values are low (as in
gonadotropin deficiency or a defect in testosterone
synthesis).
b. A rise in the testosterone level confirms the presence of
Leydig cells and, by implication, testicular tissue.
c. In patients with 5α-reductase deficiency, the basal T-to-
DHT ratio may be normal but elevated after hCG
stimulation.
8. Assessment of pituitary function: thyroid function tests, growth
hormone levels, ACTH stimulation test, and imaging studies of
the pituitary gland
P.N 24

25. Radiographic studies
1. Ultrasonography to evaluate:
1. adrenal hyperplasia
2. uterus
3. presence and localization of gonads
• Contrast studies to outline the internal anatomy (sinography,
urethrography, vesicocystoureterography, and intravenous
urography) may be indicated in complex cases and before
reconstructive surgery.
• Magnetic resonance imaging (MRI): sensitivity may only be
marginally improved over ultrasound.
P.N 25

26. MANAGEMENT
GENERAL
1. multidisciplinary team
2. protect the privacy of child and parents
3. treatment of psychosocial aspects
4. gender should be assigned and a team of specialists
5. Circumcision should be delayed in any infant with a
DSD
P.N 26

27. Medical management in the neonatal period
and early infancy
1. Congenital adrenal hyperplasia.
a. Glucocorticoid therapy:
i. Hydrocortisone 10 to 20 mg/m2/d as3 divided doses
ii. Adjustments for growth and during periods of stress
iii. Alternatively, IM cortisone acetate in children <6 months
as oral hydrocortisone may be absorbed erratically in
these infants.
b. Mineralocorticoid therapy.
i. Fludrocortisone acetate 0.05–0.1 mg daily orally
ii. Dose does not change with increase of body size or during
stress.
iii. Some endocrinologists also recommend sodium
supplementation (1–5 mEq/kg/d).
P.N 27

28. 2. Incompletely virilized genetic male:
b. Treatment with depo-testosterone might be
considered by the team of specialists depending on
the results of the diagnostic evaluation.
3. For patients with DSD who have Y-chromosome
material and intraabdominal gonads, gonadectomy is
generally recommended because of the risk of gonadal
tumors, many of which are malignant.
P.N 28

29. surgical treatment
1. In the past it was thought that surgical treatment of ambiguous
genitalia to create a female appearance, particularly when a
vagina is present, was more successful than construction of male
genitalia.
2. controversy exists regarding the timing of the performance of
invasive and definitive procedures, such as surgery.
3. an expert multidisciplinary team should consider deferring
elective surgical repairs and gonadectomies until the child can
participate in the informed consent for the procedure
P.N 29

30. Prognosis, gender assignment, long-term care.
1. It is now believed that prenatal and early exposure of the brain
to androgens, if present, influences gender-specific behavioral
patterns and sexual identity in addition to the external
appearance of the genitalia or their future function
2. Children with gender dysphoria, homosexuality and bisexuality
are the most frequent diagnoses.
3. The pediatrician, pediatric endocrinologist, and psychologist,
along with the appropriate additional specialists, should provide
ongoing compassionate, supportive care to the patient and the
patient’s family throughout childhood, adolescence, and
adulthood
P.N 30