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

Newborn investigation of ambiguous genitalia

Key points

• There needs to be an immediate referral to experts in a collaborative multidisciplinary DSD team.

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