20.04.18 Disorders of sexual development

Question 1

What are disorders of sexual development

Answer 1

Congenital conditions with atypical development of chromosomal, gonadal or anatomic sex

Question 2

Step 1 in sexual differentiation

Answer 2

Mesonephric mesoderm and coelomic epithelium differentiate into the gonadal ridge by CBX2, SF1, WT1, DMRT1/2.

Question 3

Step 2 in sexual differentitation

Answer 3

• Gonadal differentiation.
• XY embryo: SRY acts as a switch of testicular differentiation. SRY is positively regulated by WT1 and SF1, antagonised by WNT4 and DAX1.
• SRY upregulates SOX9 and other genes involved in testis differentiation

Question 4

Step 3 in sexual differentiation (male)

Answer 4

• Genital differentiation
• Sertoli cells secrete AMH- causing Müllerian duct regression
• Leydig cells respond to human chorionic gonadotropin (hCG) resulting in testosterone production.
• Testosterone binds to androgen receptor in Wolffian ducts and promotes their differentiation into components of male gonaducts.
• Testosterone is transformed to dihydrotestosterone (DHT) by 5alpha-reductase. DHT binds to androgen receptor with a higher affinity than testosterone, driving male differentiation of the urogenital sinus and external genitalia.

Question 5

Step 3 in sexual differentiation (female)

Answer 5

-In the absence of AMH and androgen action, internal and external genitalia develop along the female pathway, independently of the existence of ovaries.

Question 6

Three subgroups of DSD

Answer 6

• Sex chromosome: 45,X = Turner syndrome, 47,XXY= Klinefelter syndrome
• 46,XY DSD= disorders of gonadal (testicular) development, disorders of androgen synthesis/action
• 46,XX DSD= disorders of gonadal (ovarian) development, androgen excess

Question 7

46,XX phenotypic male overview

Answer 7

• Male phenotype, female karyotype.
• Infertile, hypogonadism, gynaecomastia. External genitalia can be normal male or ambiguous.
• In 80-90% of cases they have a small segment of Y chromosome material (including SRY) on the distal part of one X chromosome. Often de novo.

Question 8

46,XY phenotypic female overview

Answer 8

• Female phenotype, male karyotype.

- Mutation in SRY or another gene in male sex determination cascade.

Question 9

46,XY phenotypic female examples

Answer 9

• Swyer syndrome. Gonadal dysgenesis, female external genitalia, failure of pubertal development, infertile. 30% risk of developing gonadoblastoma (removal of gonads is recommended).
• Complete androgen insensitivity (CAI). Disorder of androgen receptor function. Female external genitalia (short/absent vagina), normal development at puberty, infertility. 2-5% risk of gonadoblastoma.
• Androgen resistance/ defects in androgen biosynthesis. e.g. 5α-reductase or 17α-hydroxlyase deficiency. Bilateral testes, normal testosterone secretion, female external genitalia. Virilisation (development of male pattern) of external genitalia at puberty. Male breasts. Reduced spermatogenesis.

Question 10

Congenital adrenal hyperplasia (CAH) overview

Answer 10

• Disorder of androgen synthesis (increased), leading to virilisation of external genitalia in 46,XX fetuses.
• Incidence 1:15,000. 60% of all DSD.
• Autosomal recessive.
• Mutations in CYP21A2 is most common cause of CAH (95% cases).

Question 11

What do androgens do?

Answer 11

• Responsible for the masculinsation of male genitalia in the developing fetus and secondary male sexual characteristics at puberty.
• defects in androgen biosynthesis can lead to varying degrees of under-masculinsation from mild hypospadias to complete female external genitalia.

Question 12

Examples of defects in androgen synthesis

Answer 12

• Defects in testosterone metabolism. e.g. SRD5A2 5 alpha-reductase deficiency. Enzyme is required to convert testosterone to DHT. Leads to incomplete virilisation of the external genitalia.
• Cholesterol synthesis defects. e.g. Smith-Lemli-Opitz syndrome is caused by mutations in DHCR7 gene.
• Defect in testosterone synthesis. e.g. 17 alpha hydroxlyase deficiency (CYP17A1 gene mutations).

Question 13

DSD management

Answer 13

• 1/4500 births have ambiguous genitalia. Although could be higher if internal abnormalities are counted.
• Considered a medical emergency due to the potential association with deficiencies in CAH. Also due to parental anxiety, to correctly assign sex.
• Clinical examination and biochemical endocrinology assessment
• Rapid genetics= QF-PCR/ karyotype.
• Long term= surgical management, hormone replacement therapy, psychosocial care.