18. Disorders of sexual development

Question 1

What are DSDs?

Answer 1

Disorders of sexual development

Congenital condition where development of chromosomal, gonadal or anatomical sex is atypical

Question 2

What are the 3 sub-types of DSDs and how are they defined?

Answer 2

Defined by karyotype

1. Sex chromosome DSD (KS, TS)
2. 46,XY DSD
3. 46,XX DSD

Question 3

What is the cause of the majority of cases of 46,XX males?

Answer 3

80-90% have de novo unbalanced X-Y translocation

Portion of Y includes SRY, distal part of X

Question 4

What is the phenotype of 46,XX males?

Answer 4

Hypogonadism, gynaecomastia, ambiguous genitalia, infertility

Question 5

What is the case of the minority of 46,XX males?

Answer 5

Do not have SRY

Inappropriate activation of downstream pathway (SOX9, RSPO1, WNT4 mutation)

Question 6

What are the 3 main causes of 46,XY phenotypic females?

Answer 6

1. Swyer syndrome (SRY mutation)
2. Androgen insensitivity syndrome (AR gene)
3. Disorders of androgen synthesis

Question 7

What is the clinical phenotype of Swyer syndrome?

Answer 7

Pure/complete gonadal dysgenesis, streak gonads, female external genitalia, high risk of gonadoblastoma

Question 8

What causes Swyer syndrome?

Answer 8

SRY mutation

Question 9

How are AISs characterised clinically?

Answer 9

Individuals with 46,XY karyotype:

1. Feminisation of external genitalia at birth
2. Abnormal secondary sexual development in puberty
3. Infertility

Question 10

What are the 3 sub-types of androgen insensitivity syndrome?

Answer 10

1. CAIS - typical female external genitalia
2. PAIS - predominantly female, predominantly male, or ambiguous external genitalia
3. MAIS - typical male external genitalia

Question 11

What causes androgen insensitivity syndrome?

Answer 11

Androgen receptor function

AR gene

XLR

Question 12

What causes defects in androgen biosynthesis

Answer 12

Rare enzyme defects at various points along the production pathway of testosterone from cholesterol

Question 13

What is the role of androgens?

Answer 13

Includes testosterone

Responsible for masculinisation of male genitalia in developing fetus & development of secondary male sexual characteristics at puberty

Question 14

What is the most common cause of CAH?

Answer 14

21-hydroxylase deficiency

CYP21A2 - AR

95% of CAH

Question 15

How is CAH characterised metabolically?

Answer 15

Impaired synthesis of cortisol from cholesterol by the adrenal cortex

21-OHD CAH = excessive adrenal androgen biosynthesis

Question 16

What are the clinical sub-types of 21-OHD CAH?

Answer 16

Continuum:

1. Salt wasting - sodium balance affected - leads to vomiting, dehydration, poor feeding, poor weight gain, fatality + prenatal virilisation
2. Simple virilising - prenatal virilisation only
3. Non-classical - adolescent onset of virilisation only

Question 17

How are at risk CAH pregnancies treated and why?

Answer 17

Mother and child after birth treated with dexamethasone (corticosteroid)

Prevents virilisation

Question 18

How is 46,XX gonadal dysgenesis characterised?

Answer 18

Female phenotype but fail to proceed through puberty

Hypergonadotropic hypogonadism

Streak gonads

Infertility

Question 19

What causes 46,XX gonadal dysgenesis?

Answer 19

FSHR (AR)

BMP15 (XL) - exclusively affects females who inherited mutation from unaffected father

Question 20

What is the cause of the majority of mutations in 21-OHD CAH?

Answer 20

SNVs due to gene conversion with unprocessed pseudogene, CYP21A1P and dels/dups due to unequal crossing over