The relevance of understanding the genetics and the pattern of inheritance of DSD for patients and members of the extended family

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1 The relevance of understanding the genetics and the pattern of inheritance of DSD for patients and members of the extended family Trevor Cole, Clinical Geneticist, Birmingham Introduction Part of the investigation of any child or adult with a disorder of sexual development (DSD) is to try and identify the precise underlying diagnosis. There are many different causes of DSD and knowing the correct one is important to ensure the appropriate information and treatment is given to individual patients. The correct diagnosis is also vital when providing guidance on the genetic basis of a DSD. Without this information it is not possible to accurately advise on the likelihood of the condition recurring in the family. As the mechanisms behind DSD are complex it is very important that any individual with a DSD has the necessary investigations to confirm the underlying cause even where a clinical diagnosis is possible. In some instances this may be part of the initial investigation and management. In other settings it would be important to ask for a referral to a Clinical Geneticist with a particular understanding of the basis of the different types DSD's. As families with experience of DSD's will know, it is much too simplistic to identify the gender of an individual purely on the basis of the X or Y chromosome pattern alone. Within the womb embryos initially have much of the potential to follow a male or female pattern of development, irrespective of whether they have 2 X chromosomes or an X and a Y chromosome. Which pathway is subsequently followed is controlled by a whole series of genes and hormones which interact with each other. A helpful starting point is to imagine the development of the genital tract analogous to two different processes like a series of steps in a chain reaction. The two chain reactions are not identical but do have some similarities and individuals will have the genetic steps for both of the pathways. Which is ultimately followed is determined by a series of choices driven by genes or hormones as the process progresses through these steps. These choices are controlled by many different genes or hormones and therefore may have entirely different causes (and hence patterns of inheritance) in different families. You can find a more detailed description of genetic inheritance patterns on this website: Androgen Insensitivity Syndrome (AIS) due to X linked recessive inheritance (XLR) One of the commonest causes of a DSD is the androgen insensitivity syndrome (AIS). The androgen receptor is necessary for an individual to respond to androgen hormones. A helpful illustration is to imagine the androgen receptor is a lock and the androgen hormone is the key. The key only works if it fits into the correct lock. The androgen receptor gene (which makes the androgen receptor protein) is present on the X chromosome and a single non function copy of the receptor gene can be carried without affect by individuals with two X chromosomes. In this situation the androgen hormone (like the key) can fit into the second normal receptor (ie analogous to fitting into the correct

2 lock). However, individuals who carry the altered X chromosome but do not have a second X chromosome to balance it out (i.e. they will have the pattern XY) will not respond to the androgen and therefore will have androgen insensitivity because they have only one copy of the gene on their single X chromosome. This is known as an X linked recessive pattern of inheritance. If a mother carries an altered gene on one X chromosome but not the second X chromosome she will be unaffected but can pass the altered gene onto the next generation. One in 4 of her children will be daughters who carry the gene like their mother with an XX chromosome pattern and will have no apparent symptoms. One in 4 of her children will be daughters affected by androgen insensitivity with a XY chromosome pattern. The other half of children will be boys and girls who are unaffected and do not carry the altered gene. Each of these 4 different possibilities are equally likely in any one pregnancy as the chance of which X chromosome is passed on is completely random. Autosomal Recessive inheritance and DSD While AIS is one of the most frequently recognised DSD there are other causes which are cumulatively much more frequent. These have a different pattern of inheritance, the commonest single pattern of inheritance, is known as autosomal recessive inheritance. The commonest potential DSD condition is congenital adrenal hyperplasia (CAH) and other steroid hormone disorders. The genes which cause these conditions are on the other 22 pairs of chromosomes and not on the X or Y chromosome at all. When the inheritance pattern is autosomal recessive the condition will only occur when individuals inherit two altered copies of a gene one from each parent. In some instances it will only result in a DSD if a fetus has 2 XX chromosomes and in others only if a fetus carries an XY chromosome pattern. As both parents have to be carriers of recessive genes to result in the condition in most circumstances it only occurs within a single sibship in the family and not in distant branches of the family. There can be exceptions to this and therefore it is important to discuss this with your clinical geneticist. Autosomal Dominant Inheritance Finally, there can be patterns of inheritance which follow an autosomal dominant pattern. In these disorders there may be a 50% chance of passing on the altered gene. The clinical presentation however, is limited depending upon whether an individual has either two X chromosomes or and X and a Y chromosome. Therefore these disorders may be passed from generation to generation as fertility may only be impaired in either 46XX or 46XY individuals. Take Home message A more detailed investigation is needed to confirm which of the above explanations are correct before advice can be given on the chance of recurrence within family members and what options for testing may be possible. Possible Prenatal Options to Consider Once the precise genetic explanation is known for a DSD, individuals should be offered the opportunity to discuss with their doctors the different reproductive options that are available.

3 Many families who are known carriers continue to have children without any prenatal investigations or intervention. However, many others want to understand whether or not their baby will be affected, so that they can fully prepare and inform themselves about the choices and best care for their future child. The three most commonly considered options would include a preventative approach using pre-implantation genetic diagnosis, non invasive prenatal diagnosis and invasive prenatal diagnosis. Non-invasive Prenatal Diagnosis A. Ultrasound scans Ultrasound scans may be helpful in detecting whether a pregnancy is male or female. However, accurate results are unlikely to be available much before four months of a pregnancy. There is the additional complication that if there is a significant degree of over virilisation or under virilisation this may make determination of the fetal gender on scan unreliable. Whether the ultrasound scan can provide more diagnostic information will depend on the specific disorder being considered. For example if there appears to be normal male genital development in a pregnancy at risk of androgen insensitivity it is unlikely that the fetus is affected. However in the situation of an apparently normal female gender identity on scan, this may not help with diagnosis of a pregnancy at risk of complete androgen insensitivity. B Testing Free Fetal DNA In recent years it has been recognised that a small amount of the fetal DNA (i.e. fetus blood) will leak into mum s blood throughout the pregnancy. Although this DNA will only last for a few hours because the process is continually happening it is possible to test for baby s DNA from a sample of mum s blood. A test that could be undertaken would be to look for evidence of a Y chromosome. This test can usually be accurately undertaken from seven to eight weeks onwards in a pregnancy. This test would only be informative in a proportion of cases. Examples where this might be useful include the following. In a family with a 1 in 4 risk of having a child with CAH associated with significant chance of virilisation in affected females with the chromosome pattern 46XX, the identification of a Y chromosome genes utilising free fetal DNA would rule out virilisation of a female fetus. However the Y chromosome material would not exclude the presence of congenital adrenal hyperplasia in a male. The test might also be informative in combination with an ultrasound scan. In a pregnancy at risk of CAH the absence of any Y chromosome material in an apparently male fetus from ultrasound scan appearance (i.e. virilised 46XX pattern) would indicate an affected and virilised girl with CAH. The opposite of this scenario is a condition where the scan clearly showed a female pattern but the free fetal DNA identified the presence of fetal Y chromosome genes. This would indicate a potential disorder of sexual development. Before using these non- invasive processes it would be important to discuss with your Clinical Geneticist or fetal medicine consultant whether these tests could be relevant to your own situation.

4 Invasive Prenatal Diagnosis Invasive prenatal diagnosis can involve typically one of three different tests. The first test known as a chorionic villus biopsy or chorionic villus sample (shortened to CVB) involves passing a needle through the tummy wall at around eleven or twelve weeks of pregnancy. The second test available is an amniocentesis taken at around fifteen or sixteen weeks of pregnancy also involved with passing a needle through the tummy wall to collect some amniotic fluid. The advantage of the chorionic villus biopsy is that it potentially provides an earlier result and more rapid access to DNA for testing. The disadvantage of a chorionic villus biopsy is that there is a slightly higher rate of miscarriage (approximately one to two percent). Therefore the amniocentesis provides a later diagnosis but has a smaller risk of miscarriage. In rare situations where investigations are required more quickly towards the middle of the pregnancy it is possible to take a fetal blood sample from the umbilical cord. This again involves passing a needle through the tummy wall into the cord vessel. The same tests can be undertaken on all three samples. Each of these invasive tests will allow the chromosomes to be examined. A chromosome result (i.e. XX or XY pattern) can be compared with the appearance of the baby genitalia on scan. Again this may provide a diagnostic tool in DSD where there is a clear discrepancy between the chromosome result and the ultrasound scan appearance. However such conclusions would not always be possible because of the issues mentioned above. More precise prenatal diagnosis usually requires that the causative gene change or changes have been identified in a previously affected individual with a DSD in the family. If the precise genetic explanation is identified then the test can be discussed in more detail with your Clinical Geneticist. In some instances it may be possible to avoid an invasive prenatal test if the free fetal DNA can identify whether baby has a 46XX or 46XY pattern. This in some instances may make the invasive test not necessary. You can find further information on prenatal invasive and non-invasive diagnosis on this website: A Preventative Approach to DSD If the precise cause of the DSD is known it can be possible to utilise a technique known as pre-implantation genetic diagnosis. This involves conceiving an IVF pregnancy (test tube pregnancy) and after fertilisation but before the eggs are re-implanted into mothers womb a single cell is biopsied from the growing fertilised egg. The genetic tests are then undertaken on the single cell. Only those fertilised eggs which are identified as not having the DSD would then be re-implanted. While there are many features that make this an attractive preventative option it is important to also consider a number of potential downsides and limitations to this procedure. Firstly there is limited availability of PGD in many countries and it may not always be possible in individual situations. Secondly it is important to recognise that it is intensive treatment and is intrusive into the process of natural conception. This also needs to be weighed up against the individual couples views of the choices they would wish to

5 make. For this reason some individuals decide not to proceed down this avenue although it is appropriate to offer to organise a discussion, so parents can gather the facts at an early stage and make an informed decision. Finally, it is important to understand that at best only about one in every three cycles attempted is likely to be successful. Therefore individuals may make several attempts at conception utilising pre-implantation genetic diagnosis and even then may not be successful. You can find further information on PGD on this website: Additional Reproductive Options to Consider In some DSD's (for example autosomal recessive conditions) it is necessary to inherit both copies of an altered gene, one from each parent. Under such circumstances parents may want to consider the option of either egg or sperm donation to reduce the chances of an affected child. In conditions which are X linked only egg donation from a person known not to be a carrier would have a preventative affect. Adoption is an alternative consideration for some couples. Summary It is important that the precise genetic origin of a DSD is identified in all cases where this is possible. This provides the most information in terms of management and genetic recurrence. It also allows couples to consider what reproductive options might be available to them. The issues are briefly outlined above but we would recommend a fuller discussion with a Clinical Geneticist to take you through the diagnostic process, underlying genetics and the available options including the advantages and disadvantages of each of these.