Disorders of sexual differentiation

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Chapter 14 Disorders of sexual differentiation

Yasmin Jayasinghe

Definition. Disorders of sexual differentiation (DSD) occur where the development of chromosomal, gonadal or anatomic sex are atypical. The terms ‘intersex’ or ‘hermaphrodite’ are no longer accepted. The term now encompasses all atypical development (e.g. müllerian) agenesis.

Incidence. Incidence is 1 in 5000 live births; therefore, it is rare. However, the situation requires rapid and sensitive assessment, knowledge of which is important.

Normal sexual differentiation

Undifferentiated gonads begin to develop during the fifth week after conception. During the sixth week, migration of primordial germ cells into the gonad is completed. So far, around 20 genes have been found to be involved in testicular and ovarian determination.

Male phenotypic development

Presence of the sex-determining region on the Y chromosome (SRY gene) causes differentiation of the gonad into a testis. (Several other genes are also involved in testicular development, mutations of which will result in 46XY sex reversal or ambiguous genitalia—for example, SRY, SOX9 and Wilms’ tumour 1 (WT1).) Testis produces fetal testosterone and antimüllerian hormone (AMH), which act in exocrine fashion causing ipsilateral regression of müllerian ducts and development of wolffian structures. 5-alpha-reductase converts testosterone to dihydrotestosterone in order to virilise the cloaca.

Female phenotypic development

Two X chromosomes are required for normal ovarian development. The absence of SRY and the presence of DAX1 gene on the X chromosome inhibits testicular development. AMH is absent and müllerian development occurs.

Abnormal sexual development

• Sex chromosome abnormalities can interfere with gonadal differentiation (e.g. mutations in WT1 SRY, SOX 9, DAX 1).
• Lack of testosterone is due to failure of testicular differentiation or biosynthetic (Leydig cell) defects.
• Reduction or absence of 5-alpha-reductase causes impaired cloacal response to testosterone, but there is normal response by the wolffian structures.
• An androgen receptor defect (androgen insensitivity) causes lack of cloacal response to androgens, regression of müllerian structures due to AMH, and no development of male internal genitalia (vas deferens, seminal vesicles, epididymis).
• Deficiencies in AMH (produced by Sertoli cells) cause growth of müllerian structures.
• A 46XX male occurs when the SRY gene is present on the X chromosome due to atypical crossover during meiosis.

Classification of DSD

Classification is according to chromosomes, gonadal histology and phenotype.

Sex chromosome DSD

• 45XO Turner’s syndrome
• 47XXY Klinefelter’s syndrome

Undervirilisation of 46XY individuals

• faults of androgen production (3–beta–hydroxysteroid dehydrogenase deficiency (3ßHSD II), 17-beta-hydroxysteroid dehydrogenase deficiency (17ßHSD III))
• end-organ receptor defect (androgen insensitivity syndrome (AIS))
• defects in testosterone metabolism (5-alpha-reductase deficiency)
• XY gonadal dysgenesis, SOX9 or WT1 mutations
• drugs: spironolactone

Virilisation of 46XX individuals

• congenital adrenal hyperplasia (CAH)
• exposure in utero to androgen-producing tumour (fetal or maternal)
• maternal drugs: danazol, methyltestosterone, androgenic progesterone

Ovotesticular DSD

• Gonads are ovotestis.
• Diagnosis is by gonadal biopsy.
• Commonest chromosomes are 46XX; also associated with 46XX/XY, 45XO/46XY and 46XY.

Unclassified anatomical abnormalities

• Mayer-Rokitansky-Küster-Hauser syndrome (müllerian agenesis)
• cloacal exstrophy

Presentations of DSD

• ambiguous genitalia
• apparent female genitalia: clitoromegaly, posterior labial fusion, inguinal/labial mass
• apparent male genitalia: non-palpable testes, micropenis, hypospadius
• genital karyotype discordance
• delayed puberty, primary amenorrhoea
• inguinal hernia in female
• virilisation
• pelvic tumour

Newborn investigation of ambiguous genitalia

Key points

• There needs to be an immediate referral to experts in a collaborative multidisciplinary DSD team.
• Postpone gender assignment in infants born with ambiguous genitalia prior to expert consultation. An answer is usually available within 2–3 days. Refer to the child as ‘the baby’ until then. The first interactions families have with healthcare providers are remembered, and have long-lasting consequences.
• Gender identity, gender role and sexual orientation are distinct entities. It is hoped that assigned gender in childhood will be congruent with gender identity; however, gender dissatisfaction may manifest later in life. Gender dissatisfaction is not predictable by karyotype, androgen exposure, degree of genital virilisation or assigned sex.
• Ongoing psychological support, family-centred care and education, and full disclosure to the family and young patient that evolves over a developmental time line, are standards of care.

Investigations

• monitor weight and fluid balance, and check electrolytes and plasma 17-rennin activity (PRA)
• hydroxyprogesterone, testosterone, gonadotrophins, AMH
• karyotype with SRY detection
• abdominopelvic and renal ultrasound
• urogenital sinogram to evaluate urethra and vagina

Gender assignment

Influencing factors include diagnosis, genital appearance, therapeutic options, fertility potential, cultural practices and pressures, and parental views.

Turner’s syndrome (TS)

Incidence. Incidence is 1 in 2000 to 1 in 5000 live born.

Clinical presentation

• 45XO or mosaicism 45,X/46,XX or 45,X/46,XY
• clinically short stature and pubertal failure along with other stigmata
• diagnosis: clinical, karyotype (note that follicle-stimulating hormone (FSH) levels may be markedly elevated up to 2 years of age, then nadir to near normal levels at age 4–10 years before rising again)
• spontaneous puberty with menses may occur in 9% of XO (and up to 30%–50% of mosaics)
• 2% may conceive spontaneously; pregnancy may be achieved through oocyte donation, but there is a high risk of pregnancy complications: 30% miscarriage; 7% stillbirth; 34% of live births will have a malformation (e.g. Down syndrome, TS)
• aortic dissection with maternal mortality of 2%
• medical complications must be monitored: osteoporosis, hypertension, diabetes, obesity, thyroid disorders, Crohn’s disease, sensorineural hearing loss, cardiovascular anomaly including aortic root dilatation and risk of dissection

Management

• gonadectomy if Y component (present in 6% on karyotype) to avoid malignancy
• growth hormone
• optimal to start oestrogen therapy at bone age of 12 years in those on growth hormone, and 11 if not (although coordination with paediatric endocrinologist is advised); start with very low doses, and aim to complete feminisation over 2–3 years (may add progesterone when withdrawal bleeding occurs)

Congenital adrenal hyperplasia (CAH)

Incidence. Incidence is 1 in 14,500.

Clinical presentation

Clinical presentation varies, although it is often diagnosed after birth, and includes:

• ambiguous genitalia
• salt-losing crisis
• hypertension
• virilisation and amenorrhoea in late-onset CAH
• >90% identify as females

Pathophysiology

• autosomal recessive disorder
• enzymatic defect in the synthesis of cortisol with loss of adrenal–pituitary feedback control
• result: an increase in adrenocorticotropic hormone (ACTH), adrenal hyperplasia, increase adrenal androgen production

21-hydroxylase deficiency

• accounts for ≥95% of cases of CAH
• due to mutations in CYP21 gene
• classic CAH (both alleles affected) presents in newborn period with ambiguous genitalia and three-quarters are salt losing
• diagnosis: based on raised 17-hydroxyprogesterone, +/– decreased Na, increased K, decreased aldosterone, increased PRA
• treatment: corticosteroids and, if salt-losing, fluorohydrocortisone
• monitor with 17-hydroxyprogesterone and PRA
• increase glucocorticoids during stress, illness, surgery
• surgery: 6 weeks to 6 months: clitoroplasty, labioplasty, vaginoplasty
• in pregnancy, administration of maternal dexamethasone, starting in the first trimester; may prevent virilisation in up to one-third of female babies

• degree of suppression of the fetal pituitary–adrenal axis can be gauged by maternal oestriol and 17-hydroxyprogesterone levels
• prenatal testing for mutations in CYP21 is available

11-beta-hydroxylase deficiency

• due to mutations in CYP11B1
• 11-deoxycortisol and 11-deoxycorticosterone levels high, resulting in salt-retention
• presentation: with ambiguous genitalia, cryptorchidism, hypertension and hypernatraemia

3-beta-hydroxysteroid dehydrogenase

• mutations in HSD3B2 gene
• very rare, severe adrenal insufficiency, may be salt-losers, mild virilisation of female or undervirilisation of male (testosterone deficiency)

20,22-desmolase deficiency

• addisonian crisis

Androgen insensitivity syndrome (AIS)

Incidence. Incidence is 1 in 20,000 to 1 in 64,000 XY births.

Clinical presentation

• XY karyotype, mutation in androgen receptor gene

Complete AIS

• phenotypic female, testes may be present in inguinal hernias at birth
• testes function normally, resulting in production of AMH; therefore, absent müllerian structures and blind-ending vagina
• normal androgen production; however, target tissues are unresponsive and male phenotype does not develop
• absent axillary and pubic hair
• female gender identity: manage with gonadectomy, vaginal dilators or vaginoplasty when mature enough; hormone replacement therapy

Partial AIS

• spectrum of ambiguous genitalia, pubic and axillary hair present
• gender identity may be male or female

Müllerian agenesis

• XX karyotype, absent uterus, blind ending vagina, axillary and pubic hair present
• often diagnosed in puberty due to primary amenorrhoea
• rudimentary müllerian structures may cause pelvic pain
• managed with vaginal dilators when ready

Surgery

Role of surgery

• goals: restore anatomy for menstruation, sexual function; promote sexuality and reproductive function; prevent urologic complications
• feminising genitoplasty—may involve:

• clitoroplasty with preservation of neurovascular bundle
• labioplasty
• neovaginal construction or simple Y–V flap vaginoplasty
• gonadectomy in XY containing karyotypes due to risk of dysgerminoma, gonadoblastoma

— high risk of malignancy (15%–50%): intrabdominal dysgenetic gonads, partial AIS with non-scrotal gonads
— low risk 2%–3%: complete AIS, ovotesticular DSD

• may defer removal of gonads until after puberty in complete AIS (peripheral conversion of androgens to oestrogen allows spontaneous induction of puberty); however, risk increases over time

Timing of surgery

• At large Australian multidisciplinary centres of excellence, with defined protocols, most surgery in females born with ambiguous genitalia is performed up to and including 6 months of age, collaboratively between the surgeon and gynaecologist, with excellent long-term outcomes compared to other countries (6% require revision in adolescence, and around 25%–30% may need to use dilators, compared to around 50% revision rates worldwide).
• Parents must be informed that there are those who advocate no sex assignment, allowing the child to choose for themselves when old enough; however, data are limited.
• When diagnosis of vaginal agenesis is made in later childhood or early puberty, vaginoplasty is best deferred, as most women can create a neovagina with the use of dilators alone (80% success rate). If surgery is required, success in the older population depends on successful use of a vaginal mould or dilators postoperatively (inappropriate to perform in young children).

Further reading

Allen L. Disorders of sexual development. Obstetrics and Gynecology Clinics of North America. 2009;36:25-45.

Creighton S.M. Long-term outcome of feminization surgery: the London experience. British Journal of Urology International. 2004;93(Suppl3):S44-S46.

Hughes I.A. Intersex. British Journal of Urology International. 2002;90:769-776.

Karnis M.F., Reindollar R.H. Turner syndrome in adolescence. Obstetrics and Gynecology Clinics of North America. 2003;30:303-320.

Lean W.L., Deshpande A., Hutson J., Grover S.R. Cosmetic and anatomic outcomes after feminizing surgery for ambiguous genitalia. Journal of Pediatric Surgery. 2005;40:1856-1860.

Lee P., Houk C.P., Ahmed F., et al. Consensus statement on management of intersex disorders. Pediatrics. 2006;118:e488-e500.

Migeon C.J., Wisniewski A.B. Human sex differentiation and its abnormalities. Best Practice and Research Clinical Obstetrics and Gynaecology. 2002;17:1-18.

Warne G., Grover S., Hutson A., et al. A long-term outcome study of intersex conditions. Journal of Pediatric Endocrinology and Metabolism. 2005;18:555-567.

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