ADRENAL HYPER PLASIA

Transcription

1 DR TREVOR COLE CONSULTANT CLINICAL GENETICIST BIRMINGHAM WOMEN S HOSPITAL EDGBASTON, BIRMINGHAM GENETICS OF CONGENITAL ADRENAL HYPER PLASIA Transcript prepared by Aarn & Vanessa Huisoon, edited by Sue Elford and checked for accuracy by Dr Cole CAHG 2007

2 THE GENETICS OF CAH Chromosomes, DNA, and Genes Cell Nucleus Chromosomes Gene Protein Adapted from Understanding Gene Testing, NIH, 1995 Geneticists now tend to be more proactive in the approach to counselling in diseases such as CAH. While the majority of the audience had undergone blood testing to identify the genetic abnormality causing their or their child s condition, only about half had seen a clinical geneticist. Dr Cole gave an overview of the principles of genetic inheritance and the genetics of CAH. Everyone carries on average two or three genetic abnormalities of some sort. In recessive conditions these do not cause a problem unless you have a child by a partner who has a similar abnormality. This is called autosomal recessive inheritance. Autosomal means that the condition can affect both sexes, while recessive means that both copies of the genes (for example in CAH) are affected, and a faulty gene is inherited from each parent. In autosomal recessive inheritance, there is a one in four chance of a child suffering from deficiency of this gene if both parents are unaffected carriers. In the UK about one in 35 to one in 50 people carries an abnormal gene for CAH.

3 Autosomal Recessive Inheritance Noncarrier individual Non-affected carrier Affected individual! Two germline mutations (one from each parent) to develop disease! Equally transmitted by men and women Once it is known that both parents are carriers of an abnormal gene, every child they have has this one in four chance of being affected. This is random, so that it is possible for a couple of carriers to have all normal children or all affected children or any combination of affected and unaffected children. Before considering a further pregnancy, it is important to know exactly what the parents gene abnormalities as this makes it possible to test for the disease in the foetus at a very early stage (by chorionic villus biopsy at about 11 weeks). CAH can also be detected by an amniocentesis, although this is not usually performed until the pregnancy is further developed (at about weeks). However, as both tests are associated with a small risk of miscarriage, many parents decide they do not want prenatal testing, especially if it would not change any decisions they make about the pregnancy. Prenatal Diagnosis : - CVS versus Amniocentesis! CVS! Amniocenetesis! Early result 11 to 12 weeks (fetal sex 24 hours)! Lower miscarriage rate (about 1 in 150)! Higher miscarriage rate ( about 1 in 75)! Late result - after 20 weeks

4 One of the possible decisions in early pregnancy is whether to take dexamathasone to reduce virilisation of a CAH female foetus. This needs to be started as soon as possible in pregnancy, but only 1 in 8 foetuses will actually need it. This is not known until the diagnosis is made; by chorionic villus biopsy. Dexamethasone treatment is controversial. It is not predictable how much it will reduce virilisation in any one pregnancy, and has potential for side effects for mother: hypertension, diabetes, proteinuria and headaches, weight gain (cushingoid face), odema, striae and mood fluctuations. However, to date all these effects have proved to be reversible. There is also speculation that dexamethasone treatment could cause unwanted foetal concerns, such as; it may reduce birth size and the sudden withdrawal could cause foetal loss and it is not 100% effective. There is also a possibility that cardiovascular disease, diabetes and behaviour patterns may affect the baby in later life, although there is no proof to date of these effects. The slide below shows the results of an 8 year study by Dr Maria New in the USA on the effects of dexamethasone treatment in CAH. DEXAMETHASONE THERAPY NEW ET AL 1995 (8 YEARS EXPERIENCE)! 239 PRENATAL TESTS! 37 / 239 AFFECTED PREGNANCIES! 21 / 37 FEMALE! 13 / 21 FEMALES TREATED! TREATED CASES NO OR LESS VIRILISED A parent affected with CAH will always pass on one copy of the abnormal CAH gene to their child. That child will only have CAH if their other parent also carries an abnormal copy of the CAH gene and passes it on to the child. Because about 1 in 50 people carry this abnormal gene, the risk of a CAH child having an affected baby themselves is about one in 100. Because carriers of abnormal genes are relatively common, partners of CAH patients are offered screening for the four common CAH mutations. This reduces the risk of an affected child being born, but it is not possible to completely exclude this risk.

5 CAH RISK TO THE NEXT GENERATION (slightly higher risk if use 1 in 35 carrier risk) AFFECTED CHILD 1 x 1/50 X 1/2 = 1/100 ( OR 1%) SIBLING OF AN AFFECTED CHILD 2/3 X 1/50 X 1/4 = 1/300 (OR 0.3%) UNCLE OR AUNT OF AFFECTED CHILD 1/2 X 1/50 X 1/4 = 1 / 400 (OR 0.25%) A sibling of an affected child has about a one in 300 chance of having an affected child themselves. This again can be reduced by testing the sibling for the abnormal genes that the parents carry (preferably when they are old enough to understand the consequences of this test). If they are positive, their partners can also be tested. In discussion, the distant prospect of gene therapy was highlighted. While widely publicised, gene therapy has not to date cured any genetic disease. The situation with CAH is similar to that with cystic fibrosis, where gene therapy has been promised for years but is still a long way from being a reality. The main problem is getting the replacement normal gene into the correct cells (i.e. the adrenal cortex), which has not been possible.