medical genetics

1.Gemma has just given birth to a boy (Gary), her first child.  The pregnancy was normal and there was an uneventful vaginal delivery.  The next day mother and baby appeared to be thriving and they were allowed to go home.  At the end of the first week, however, things began to go badly wrong.  Gary had been feeding well but he soon began to be sick and became very listless.  When he became unresponsive Gemma and her husband John rushed him to hospital.  Doctors quickly noticed that Gary had a sunken fontanelle, dry eyes and a rapid, weak pulse.  After putting on a saline/dextrose drip a small blood sample was taken for analysis.

Results of blood test:

Na+     118 mEq/L
K+    12 mEq/L

What is your initial diagnosis?

2. Gary quickly recovered but was kept in hospital for observation.  Gemma stayed with him and fed him as required.  There was no sign of gastroenteritis and the drip was removed.  Serum Na+ and K+ levels were monitored and within 24 hours of the drip being removed, Lukes sodium levels began to fall and potassium levels rose.

What might the paediatrician suspect is wrong with Gary?  What further tests are required to confirm the diagnosis? 

3. Endocrinology test results

Serum aldosterone: 5ng/dL
17-hydroxyprogesterone (17-OHP): 38,543 ng/dL

What are the normal ranges for aldosterone and 17-OHP?  What do the test results suggest is wrong with Gary?  What other tests can be done?  What are the complexities in genetic testing for this disease?

4. Results of DNA tests

Results of CYP21A DNA tests
Gemma: Heterozygous Q318X/normal
John: Heterozygous Intron 2 splice site 656 G/normal C
Gary: Compound heterozygote Q318X/Intron 2 656 G

Following the tests the paediatrician prescribes an appropriate treatment regime for Gary (your text).  He also arranges an appointment with a geneticist who explains the results of the tests and why Gary has been affected (your text).  She goes on to explain the chances of having a second affected child and what is likely to happen if an affected baby is a girl (your text).

Gemma and John decide to try for another baby and when Gemma falls pregnant they arrange to see the obstetrician immediately.  What might they recommend?

5. Gemmas second pregnancy

The obstetrician recommends that Gemma takes dexamethasone at a dose of 1mg daily until she knows the sex of her baby (why?). 

What is the best way to test the sex of the foetus?

6. Results of tests

Non-invasive pre-natal diagnosis by real-time quantitative PCR indicated the absence of SRY sequences.  This shows that the foetus is a girl.  What is the probability that this girl will have CAH? Gemma subsequently agrees to have amniocentesis to check whether the foetus has CYP21A mutations.  The DNA tests show that she has the same combination of mutations as Gary.

What should Gemma do for the rest of the pregnancy and what are the long term prospects for her baby girl?

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