Sex Determination

Question 1

How is gender primarily determined?

Answer 1

Gender is determined primarily by the sex chromosomes. The presence of the testis determining factor (SRY gene) on the short arm of the Y chromosome results in the development of a male phenotype. The presence of two X chromosome (and no Y chromosome) is necessary for normal female development.

Question 2

Where is the SRY region located?

Answer 2

The presence of the testis determining factor (SRY gene) is located on the short arm of the Y chromosome.

Question 3

At what point can the embryo be morphologically determined as male or female?

Answer 3

From fertilisation until 5-7 weeks of embryonic development gender cannot be determined morphologically. At this stage the embryo is described as bipotent or sexually ‘indifferent’. Until 7 weeks the gonadal ridges could develop into either testes or ovaries. From 7 weeks onwards gender development contines as defined by the sex chromosome complement.

Question 4

At what stage of embryo development is the embryo described as bipotent or sexually ‘indifferent’?

Answer 4

From fertilisation until 5-7 weeks of embryonic development gender cannot be determined morphologically. At this stage the embryo is described as bipotent or sexually ‘indifferent’.

Question 5

From what point do the sex chromosomes begin to influence embryo development?

Answer 5

Until 7 weeks the gonadal ridges could develop into either testes or ovaries. From 7 weeks onwards gender development contines as defined by the sex chromosome complement.

Question 6

Describe male sexual development after 7 weeks.

Answer 6

From 7 weeks in the male the SRY gene activates a cascade of other genes. Some of these genes are on the autosomes and some are on the Y chromosome and they are all involved in male sexual development. As a result testis development is initiated. Once developed the testes release testosterone and the result is normal male sexual develpment.

Question 7

Describe female sexual development after 7 weeks.

Answer 7

In females it was long thought that sexual development was simply the default position in the absence of the SRY gene. However, it is now recognised that the presence of 2 X chromosomes is required for normal female development.

Question 8

List 6 chromosomal locations (and the genes present at these locations) that can result in abnormal sexual development when disrupted.

Answer 8

WT1: 11p13
SF1: 9q33
LHX9: 1q31-32
SOX9: 17q24-25
DAX1: Xp21
SRY: Yp

Question 9

Summarise what is required for normal sexual development to take place.

Answer 9

1) . The presence of a normal sex chromosome compliment
2) . The correct function of the many genes within the sex determination cascade
3) . The correct response of hormone receptors

Question 10

What is sex reversal in males?

Answer 10

A male phenotype with a female karyotype.

Question 11

What is usually the cause of sex reversal in males?

Answer 11

80% of cases of sex reversal in males have a small segment of Y chromosome material - including SRY - in place of the distal part of one X chromosome.

XX males are invariably infertile.

20% of sex reversed males have no SRY and have partial male or ambiguous sexual development.

Question 12

Are sex reversed males fertile?

Answer 12

XX males are invariably infertile.

Question 13

What is usually the cause of sex reversal in females?

Answer 13

XY females usually carry a copy of the SRY gene on the Yp.

In Sweyer syndrome there is a genetic mutation either in the SRY gene or within another gene in the male sex determination cascade.

Other patients have androgen insensitivity syndromes and they have normal SRY function but have a failure of response of an androgen receptor.

Question 14

What is Sweyer syndrome?

Answer 14

In Sweyer syndrome there is a genetic mutation either in the SRY gene or within another gene in the male sex determination cascade. Sweyer syndrome is one cause of sex reversal in females (XY females).

Sweyer syndrome is also known as pure gonadal dysgenesis. Patients with Sweyer syndrome have ‘streak’ gonads. Externally they have a female appearance but ther is failure of pubertal development and they are infertile. They have a high risk (about 30%) of developing gonadoblastoma (a pre-cancerous change). The removal of gonads in the first decade of life is recommended to remove gonadoblastoma risk).

Question 15

What are the 2 most common causes of sex reversal in females? (XY females)

Answer 15

1) . Sweyer syndrome

2) . Androgen insensitivity syndrome

Question 16

List the symptoms of Sweyer syndrome.

Answer 16

Sweyer syndrome is also known as pure gonadal dysgenesis.

• ‘Streak’ gonads.
• Externally they have a female appearance
• Failure of pubertal development
• Infertile
• They have a high risk (about 30%) of developing gonadoblastoma (a pre-cancerous change). The removal of gonads in the first decade of life is recommended to remove gonadoblastoma risk).

Question 17

What are the symptoms of complete androgen insensitivity?

Answer 17

Complete androgen insensitivity is also known as Testicular Feminisation. It is a disorder of androgen receptor function.

• Patients with complete androgen insensitivity have female external genitalia but internally they have a short or absent vagina
• At puberty there is normal development of breasts and other female characteistics
• The have primary amenorrhea (absent periods)
• Infertility
• Have intra-abdominal testes
• Low (2-5%) risk of gonadoblastoma

Question 18

Describe androgen resistance syndromes.

Answer 18

• Very rare enzyme defects such as 5alpha-reductase or 17alpha-hydroxylase deficiency are associated with sex reversal with a male karyotype.
• These individuals have a 46,XY karyotype.
• They have bilateral testes and normal secretion of testosterone but externally they have female genitalia.
• At puberty there is virilisation of external genetalia (development of a male pattern).
• Male breast development.
• Reduced spermatogenesis.

Question 19

Describe congenital adrenal hyperplasia (CAH).

Answer 19

Congenital adrenal hyperplasias are enzyme deficiencies affecting steroidogenesis.

Classic CAH such as 21-hydroxylase deficiency affects the carriers in two different ways. If it occurs in a female fetus then the fetus wil be virilised and there will be masculinisation of external genitalia. Where there is an XY karyotype there will be normal male genitalia.

For both XY and XX individuals with CAH it is important to treat the mother with dexamethasone during pregnancy and after birth the child should be treated with hormones.

For both sexes if treatment isn’t carried out then they are ‘salt wasters’ and will often die in the first few weeks of life.

Question 20

How does CAH affect male and female fetuses?

Answer 20

Congenital adrenal hyperplasias are enzyme deficiencies affecting steroidogenesis.

Classic CAH such as 21-hydroxylase deficiency affects the carriers in two different ways. If it occurs in a female fetus then the fetus wil be virilised and there will be masculinisation of external genitalia. Where there is an XY karyotype there will be normal male genitalia.

Question 21

How should CAH be treated?

Answer 21

For both XY and XX individuals with CAH it is important to treat the mother with dexamethasone during pregnancy and after birth the child should be treated with hormones.

Question 22

What usually happens to children affected with CAH if they are not treated?

Answer 22

For both sexes if treatment isn’t carried out then they are ‘salt wasters’ and will often die in the first few weeks of life.

Question 23

What is meant by ‘autosomal sex reversal with a female phenotype’?

Answer 23

This is an XY karyotype with autosomal imbalance in regions carrying other genes in the male determining cascade leading to a female appearance.

e.g. deletions/unbalanced translocations of 9p24, 9q33, 10q26.1 - such individuals will usually have mental retardation and dysmorphism due to an unbalanced karyotype.

Other examples of autosomal sex reversal include abnormalities of 11p13 (WT1 gene). These rearrangements are associated with Wilms tumour, WAGR, Frasier syndrome and Denys-Drash syndrome.

Translocations involving the long arm of chromosome 17 (17q24.3-25.1) may affect the SOX9 gene. This is associated with campomelic dysplasia. Patients with this may have skeletal abnormalities and early death as well as sex reversal.

Question 24

Deletions/translocations in which regions can cause autosomal sex reversal with a female phenotype?

Answer 24

Deletions/unbalanced translocations of:

• 9p24
• 9q33
• 10q26.1
• 11p13 (WT1)
• 17q24.3-25.1 (SOX9)

Question 25

Explain how X chromosome changes can also be associated with sex reversal.

Answer 25

XY females with a duplication within the Xp21 region have a double dosage of DAX1 gene and this disrupts testicular development.

Question 26

What is a true hermaphrodite? What are the features of a true hermaphrodite?

Answer 26

A true hermaphrodite has gonads comprising both ovarian and testicular elements. They have ambiguous external genitalia and most commonly have a 46,XX karyotype with no Y chromosome present. However, occasionally a true hermaphrodite is a chimera (46,XX/46,XY).

Question 27

What is the most common karyotype of a true hermaphrodite?

Answer 27

Most commonly true hermaphrodites have a 46,XX karyotype with no Y chromosome present. However, occasionally a true hermaphrodite is a chimera (46,XX/46,XY).

Question 28

Describe pseudohermaphrodites.

Answer 28

Pseudohermaphrodites have ambiguous genitalia and gonads comprising of either:

• Ovarian elements only = female pseudohermaphrodite
• Testicular elements only = male pseudohermaphrodite

Question 29

What will the gonadal composition of a female pseudohermaphrodite comprise of?

Answer 29

Ovarian elements only = female pseudohermaphrodite

Question 30

What will the gonadal composition of a male pseudohermaphrodite comprise of?

Answer 30

Testicular elements only = male pseudohermaphrodite

Question 31

What processes should be initiated in cases of infants with ambiguous genetalia?

Answer 31

Urgent cytogenetic investigation is indicated in infants with ambiguous genitalia. The karyotypic sex will be one of the factors taken into account when gender assignment is considered. It is important to be aware that infants with ambiguous genitalia and other congenital abnormalities may carry an autosomal imbalance.