ndividuals with 46, XX testicular disorder of sex development (46, XX testicular DSD), which is sometimes still referred to as 46, XX male syndrome, have a female karyotype, male external genitalia, two testicles, azoospermia and absence of Mullerian structures. The majority demonstrate the presence of SRY (sex-determining region of Y) within their genome, most commonly on one of the X chromosomes.
SRY: sex-determining region on the Y chromosome; AIS: androgen insensitivity syndrome; MIS: Müllerian inhibiting substance; T: testosterone; DHT: dihydrotestosterone; LH: luteinizing hormone; p450scc: P450 side chain cleavage. * If SRY is negative in an infant with a 46XY karyotype, this indicates SRY deletion or mutation.
Disorder of sexual development revised
Disorders Of Sexual
Sex and Gender
• genetic sex - chromosomes
• anatomical sex - internal and
• sexual identity - one’s identity as
male or female
• social meaning attached to being
male or female
• gender identity - sense of being
male or female
• gender role - expectations about
how a male or female should
• sex: possessing both male and
female reproductive organs
• gender: possessing both male and
a congenital discrepancy between external
genitalia, gonadal and chromosomal sex .
Studies conducted in Western countries,
with low rates of consanguinity, show that
truly ambiguous genitalia have an
estimated incidence of 1:5,000 births.
•The incidence of ambiguous genitalia
in Saudi Arabia has been estimated at
1:2,500 live births; whilst in Egypt, it
has been estimated at 1:3,000 live
Normal Prenatal Development:
Internal & External Genitalia
• Sexual differentiation:
Gonadal development Starts at 8 weeks
The sex-determining region on the Y
chromosome (SRY )dictates testicular
development and testicular hormones
promote male development
A. Female infants Virilization:
They have a 46,XX karyotype, are SRY-negative,
and have exclusively ovarian tissue.
B. Inadequate virilization of male infants:
This problem is caused by inadequate
androgen production or incomplete end-
organ response to androgen.
C. Disorders of gonadal differentiation
True hermaphroditism. The presence of both a
testis and an ovary (or ovotestes) in the same
D. Chromosome abnormalities, syndromes, and
associations. Gonadal dysgenesisis
ambiguous genitalia have been reported
occasionally in trisomies 13 and 18 and triploidy.
The initial evaluation of the infant with ambiguous
genitalia should include :
• physical examination
• evaluation of the sex chromosomes
• assessment of internal anatomy by ultrasound
• Measurment of adrenal and gonadal steroid
Prenatal exposure to androgens (eg,
progesterones, danazol) or endocrine
disrupters ( phenytoin, aminoglutethimide).
Maternal virilization in pregnancy (placental
aromatase deficiency, luteoma).
• Family history of:
females who are childless or have amenorrhea
female relatives with amenorrhea and infertility
unexplained infant deaths (congenital adrenal
• History of consanguinity (or homogeneous
population) (recessive disorders, eg, CAH
or disorders of androgen biosynthesis).
The physical examination should include:
• General examination: should address the
presence of any of the following:
• features (syndromes and chromosomal
abnormalities), hypertension or
• hyperpigmentation, and signs of
2. Genitalia: careful inspection and
palpation of the genitalia
the number of urogenital openings
• Measures of the phallus/clitoris and
• Bilaterally nonpalpable testes:
• ( This patient with bilateral cryptorchidism had a 46,XX
(stretched penile length less than 2.5 cm
in a full-term infant); microphallus
without associated hypospadias is not
"ambiguous," but may be a marker of
The mean full-term length is 3.5 cm with
the 2-standard deviation range, from 2.8
to 4.2 cm.
• (clitoral width >6 mm or clitoral length >9 mm) (in a 46,XX
infant with 21-hydroxylase deficiency)
• Discordant genitalia and sex
• (This patient with male phenotypic appearance had a 46,XX
karyotype and sex reversal)
1-Ultrasonography of the abdomen and pelvis:
• 2. Contrast studies to outline the internal anatomy
• vesiculocystoureterography, and intravenous urography) may
be indicated before reconstructive
2-Retrograde urethrogram may be necessary, although most
surgeons find direct visualization by cystoscopy/vaginoscopy to
be the single best method of assessing the urethral and vaginal
3-In some complicated cases (particularly those infants with
elements of male and female gonads/internal reproductive
structures), laparoscopic visualization with gonadal biopsy, may
be required to completely inventory the reproductive structures
HOW TO APPROTCH:
• The results of the karyotype permit classification of the infant
into one of three diagnostic categories that guide further
evaluation, as suggested by a consensus conference :
• XX DSD
• XY DSD
• Mixed sex chromosome DSD
• Abnormal karyotype. Mixed gonadal dysgenesis with a
dysplastic gonad is the great risk for
• infants with abnormal karyotype and ambiguous genitalia.
Hormone studies are unlikely to be
• revealing in this circumstance. DNA analysis may allow
detection of SRY gene material in 46,XX phenotypic males
• and be useful in determining whether Y material is present in
a 45,X individual, placing the patient at
• risk for gonadoblastoma.
Medical therapy for disorders of sex development (DSDs)
depends on the underlying cause and is indicated for the
conditions associated with ambiguous genitalia, including
congenital adrenal hyperplasia (CAH).
1-Supplemental hormone therapy in cases of compromised
gonadal function .
2-Hormonal induction of puberty should attempt to replicate
normal pubertal maturation to induce secondary sexual
characteristics, a pubertal growth spurt, and optimal bone
The controversy primarily revolves around issues of gender
Gender assignment by the physician and family may not
correlate with gender preference by the patient in adulthood.
Remember that the most important sex organ is the brain,
which may undergo hormonal imprinting in utero.
The testes in patients with complete androgen insensitivity
syndrome and those with partial androgen insensitivity
syndrome and raised female should be removed to prevent
Preserve Fertility. In addition to addressing surgery to alter
anatomical differences, it is important to consider maintaining
potential for future fertility for those who are candidates.
Today, technological advances allow for fertility enhanced
through in vitro fertilization (IVF) and intracytoplasmic sperm
• Advantages of Performing Early Cosmetic Genital Surgery
• it may be reasonable to advocate early surgery, between the
ages of 6 and 18 months.
normalization" of the child's atypical genitalia minimizes family
distress and mitigates stigmatization and gender-identity
confusion. Second, literature supports better surgical outcomes
when surgery is performed early (including gonadectomy).
• Advantages of Delaying Early Cosmetic Genital Surgery
• True" Sex Assignment and Gender Identity. Gender identity is
far from straightforward. It is a complex biological and
psychological process with prenatal and postnatal influences.
After gender is determined, parents are often led to believe
the true sex of their child has been identified. Parents find
comfort in knowing the "truth" (true identity) regarding their
infant's "maleness" or "femaleness" has been confirmed.
provided by mental health staff with expertise in DSD should
facilitate team decisions about gender assignment/
reassignment, timing of surgery, and sex hormone
• The following consultations may be obtained:
• Geneticist/genetic counselor