Clinical: Paediatric Clinical Session

Question 1

Ann-Marie is a 7 years old girl who has Tanner Stage 2 breast development that has been present for 2.5 years (minimal breast development, without further development, no pernicious puberty).

Discuss the possible physiological mechanisms that have led to these changes.

Answer 1

Note that patient has not developed into puberty, i.e. her breast development has r_emained at Tanner stage 2._ This excludes precocious puberty as puberty by definition is a progression of stages.

Most likely is a very low excess in oestrogen with possible transient increase causing breast development and then no further release/exposure.

This is benign premature thelache (appearance of breast development). Possible causes include:

• Factitious exposure to estrogen (mum’s cream/pills?)
• Obesity (fat contains aromatase (AàE2), increased E2 (if no exogenous A, then not much convert to E2))
• Ovarian cyst (happen cyclically, increased oestrogen, but regress periodically (1 month))
• Environmental factors (exogenous source) (most common), e.g. oestrogen pill (contraceptive), plastic (oestrogen effect), soy milk, home remedies (laced with drugs), inhaled steroids

Question 2

Describe estrogen feedback

Answer 2

Estrogen feedback can be classical- acts back on pituitary and hypothalamus to reduce signalling but this change in response is slow as protein synthesis is required (changing receptor expression ect)

And this is different to the non classical pathway, estrogen in this way binds GnRH cells and the response is rapid, in this pathway the t_ranscription factor CREB i_s significant and it’s likely its fast effects d_ownregulate LH_ involving ion channel modulation.

So we have different pathways responding to estrogen! One quick and one slower I think is the key

Question 3

A phenotypic female child is born with a slightly prominent clitoris and some labial fusion. Karyotype is 46 XY (genetically male). An USS of her pelvis shows an absent uterus and gonads are not seen. Further examination reveals bilateral pea sized firm mobile masses (testis, gonads) in both inguinal regions.

1) If a uterus was absent, outline the possible conditions this child could have.

Answer 3

This child is phenotypical female, genotypical male.

Because testes are present in inguinal region, this implies functional SRY gene.

Because there is an a_bsent uterus_, this further supports functional SRY gene (causes development of sertoli cells secreting AMH to lead to mullarian duct regression).

This case appears to be an undervirilised male, which may result from testosterone deficiency or testosterone insensitivity (resistance), so testis does not descend fully. This is lack of external genital development (leydig cells problem). Potential causes include:

• LH receptor mutation in leydig cells à decreased androgen production à female phenotype
• Androgen receptor defect (androgen resistance) (most common)
• Biosynthetic mutation in testosterone à more androgen intermediate, less testosterone à some virilisation
• 5 alpha reductase deficiency/mutations (rare) à decreased DHT

Do a blood test for level of free testosterone compared to DHT, which compares difference between androgen biosynthesis and androgen resistance problem.

Question 4

A phenotypic female child is born with a slightly prominent clitoris and some labial fusion. Karyotype is 46 XY (genetically male). An USS of her pelvis shows an absent uterus and gonads are not seen. Further examination reveals bilateral pea sized firm mobile masses (testis, gonads) in both inguinal regions.

2) If a uterus was present, how does this change the possible causes?

Answer 4

If there was a uterus present, this would suggest sertoli cells problems (sertoli cells deficiency, AMH deficiency, AMH receptor mutation). Potential causes include:

• Frasier syndrome (no/deficient Sertoli cells)
• SRY or SOX9 gene mutation?
• 46XXY? (streak gonad (gonad dysgenesis, less germ cells) so no AMH production)