Disorders Of Sexual Development

DR.Asmaa Salah

August 2016

Sex and Gender

•Sex• genetic sex - chromosomes

• anatomical sex - internal and external genitalia

• sexual identity - one’s identity as male or female

•Gender• 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 behave

•Androgyny/hermaphrodism:

• sex: possessing both male and female reproductive organs

• gender: possessing both male and female qualities

Definition:

a congenital discrepancy between external

genitalia, gonadal and chromosomal sex .

Incidence:

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 births.

Normal Prenatal Development:Internal & External Genitalia

• Sexual differentiation:

Gonadal development Starts at 8 weeks gestation

The sex-determining region on the Y chromosome (SRY )dictates testicular development and testicular hormones promote male development

.

Pathophysiology:

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

individual

D. Chromosome abnormalities, syndromes, and associations. Gonadal dysgenesisis

ambiguous genitalia have been reported occasionally in trisomies 13 and 18 and triploidy.

INITIAL EVALUATION

The initial evaluation of the infant with ambiguous genitalia should include :

• History

• physical examination

• evaluation of the sex chromosomes

• assessment of internal anatomy by ultrasound

• Measurment of adrenal and gonadal steroid secretion.

History: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 (androgen insensitivity).

female relatives with amenorrhea and infertility (male pseudohermaphroditism)

unexplained infant deaths (congenital adrenal hyperplasia).

• History of consanguinity (or homogeneous population) (recessive disorders, eg, CAH or disorders of androgen biosynthesis).

Physical examination:

The physical examination should include:

• General examination: should address the presence of any of the following: dysmorphic

• features (syndromes and chromosomal abnormalities), hypertension or hypotension, areolar

• hyperpigmentation, and signs of dehydration .

2. Genitalia: careful inspection and palpation of the genitalia

the number of urogenital openings documented

• Measures of the phallus/clitoris and anogenital ratio

• Bilaterally nonpalpable testes:

• ( This patient with bilateral cryptorchidism had a 46,XX karyotype ).

•Microphallus :

(stretched penile length less than 2.5 cm in a full-term infant); microphalluswithout associated hypospadias is not "ambiguous," but may be a marker of other disorders.

The mean full-term length is 3.5 cm with the 2-standard deviation range, from 2.8 to 4.2 cm.

•Clitoromegaly :• (clitoral width >6 mm or clitoral length >9 mm) (in a 46,XX

infant with 21-hydroxylase deficiency)

•Hypospadias and unilateral nonpalpable gonad ( mixed gonadal dysgensis):

•Discordant genitalia and sex chromosomes:

• (This patient with male phenotypic appearance had a 46,XX karyotype and sex reversal)

Imaging :

1-Ultrasonography of the abdomen and pelvis:

• 2. Contrast studies to outline the internal anatomy (sinography, urethrography,

• vesiculocystoureterography, and intravenous urography) may be indicated before reconstructive

• surgery.

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 anatomy.

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:

• Karyotyping:

• 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.

Mangement:

1- Medication:

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

mineral accumulation

2-Surgery:

The controversy primarily revolves around issues of gender

reassignment.

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

adult malignancy.

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

injection (ICSI).

• 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.

3-Psychosocial management:

provided by mental health staff with expertise in DSD should

facilitate team decisions about gender assignment/ reassignment, timing of surgery, and sex hormone

replacement.

• The following consultations may be obtained:

• Geneticist/genetic counselor

• Endocrinologist

• Surgeon

• Obstetrician/urologist

• Psychologist

Referances:

• UPTODATE

Hum Hered. 2014;77(1-4):108-17. doi: 10.1159/000360763. Epub 2014 Jul 29.

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