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Challenges in the genetic testing of children for familial cancers

Angus J Clarke and Clara Gaff Arch Dis Child 2008 93: 911-914

doi: 10.1136/adc.2006.113381

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Perspectives

Challenges in the genetic testing of children for familial cancers

Angus J Clarke,1 Clara Gaff2,3
The genetic testing of children is a topic that has generated much disagreement and debate. When a child has an illness that may be genetic in origin, and genetic testing is a straightforward way of achieving a diagnosis, then genetic testing is clearly appropriate. When the child is healthy but at risk of the familys inherited disorder, however, the situation may be very different. In cases where predictive genetic information is of clear practical value in decision making about future medical intervention, then the question comes down to a matter of timing: when, all things considered, will it be most helpful to determine the childs genetic constitution? Internationally, guidelines encourage decisions about testing be left to the child once s/he is older if no medical intervention is available during childhood and adolescence for those at risk of disease.1 Nonetheless, in clinical practice, counselling parents who are seeking predictive genetic testing of their child for an adult onset condition is often more complex than simply citing guidelines as a reason for declining testing and expecting the family to deal with the consequences. These requests can raise complex issues for health professionals, bringing into play potentially conflicting commitments of genetics professionals, such as client-centred counselling (with the family as client), providing advocacy (for the child) and the need to consider the professionals long term relationship with the family. Here we discuss four scenarios that exemplify issues that arise not infrequently in practice. We have altered some case details to ensure anonymity. The man had a subtotal colectomy performed at the age of 20 years with a good result and attends regularly for screening of his rectum. The parents request testing for their son, who is at 50% (1 in 2) risk of developing this condition, to see if he has inherited the familys (known) mutation in the APC gene. The genetic counsellor discusses the best timing for this test with the parents. Many professionals prefer to carry out such a test over the months immediately before the information is required, before screening would begin for colonic tumours by colonoscopy or flexible sigmoidoscopy at around 1112 years of age.2 They would involve the child in discussions about the genetic test and its implications at perhaps 10 or 11 years of age. This avoids a lengthy period when the family knows the results of the test but, if the child has the mutation, there is no action to be taken on the basis of the information. Where requests for testing are made at a younger age, the clinician encourages the parents to reflect on the recommended course of action, that is not testing in early childhood, as well as the alternative, namely testing in early childhood and then subsequently presenting the results of testing and the need for surveillance to the child as a fait accompli (if the test result proves mutation positive) at a later age. In this family, as is most common, the parents decided to accept the professionals slowly slowly approach to testing, so as to have the childs active participation in the process, as they were primarily motivated by a desire to ensure their child had access to the relevant services. Professionals often prefer the deferred course in the hope that involving the child in the decision about genetic testing may help him subsequently to accept screening, if that proves necessary. If the parents had been especially insistent on having the test performed immediately, this would have reduced the boys degree of engagement in the testing process. The extent to which this would impact on his subsequent understanding of his condition (if mutation positive) and on family interactions can only be surmised.

SCENARIO 1: FAMILIAL ADENOMATOUS POLYPOSIS

A man affected by familial adenomatous polyposis (FAP) attends the genetics clinic with his wife and their 2-year-old son.
Department of Medical Genetics, School of Medicine, Cardiff University, Cardiff, Wales, UK; 2 Genetic Health Services Victoria, Melbourne, Australia; 3 Departments of Medicine and Paediatrics, The University of Melbourne, Melbourne, Australia Correspondence to: Professor Angus Clarke, Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, Wales, UK; clarkeaj@cardiff.ac. uk Arch Dis Child November 2008 Vol 93 No 11
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From an ethical standpoint as he would in any case be tested as a minor testing early would not breach his autonomy as a future adult or challenge his right to privacy (confidentiality) in the way that would occur if he were being tested for Huntingtons disease (HD) or a similar late-onset disease for which no useful medical intervention is (yet) available before the onset of symptoms. It is also worth noting that only a minority of adults at risk of HD choose to have predictive genetic testing, whereas a large majority of those at risk of FAP make this decision at some stage. Where it is known that a young child is at risk of FAP, we are constrained by the need to begin colonoscopies at around 11 12 years of age and cannot defer testing until the child has a more mature understanding; the best explanation available in practice for each child has to accompany the genetic testing and, where necessary, the colonoscopies too. Every stage of life has its difficulties and there is no good time at which to give a child or adolescent such unwelcome information. We think that the parallel with adoption can be very helpful as an aid to reflecting on the issues. It is usual for professionals to encourage disclosure to a young child of the fact that they have been adopted, not as a single revelation but in an occasional and gradual conversation conducted over the years as the child slowly becomes able to understand what this means. Then, when the child is older and able to make important decisions, they can decide whether and/or when to find out more about, or to make contact with, their birth parents. Similarly in relation to genetic information, we would in general encourage parents to raise their child in the knowledge that there is a genetic condition in the family and that it may be relevant to them in the future. When they are older, they will be able to make their own decisions about genetic tests, except in cases such as FAP, where the decisions need to be made rather sooner.

SCENARIO 2: HEREDITARY NONPOLYPOSIS COLON CANCER

A boy of 12 years of age is referred to a general paediatrician for assessment of recurrent, non-specific abdominal pain. The boy has not enjoyed the transition from his village primary school to the large secondary comprehensive school in the market town some 10 miles away, and the paediatrician thinks this is the likely trigger for these complaints, most
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probably associated with school avoidance. However, the situation looks very different when his mother reveals that she was diagnosed with bowel cancer at 18 years of age and has a mutation in one of the hereditary non-polyposis colon cancer (HNPCC) loci, which encode proteins involved in the DNA mismatch repair pathways. She has been anxious for some time that her son may develop cancer and recent events have heightened her concern. The genetics team involved did not know the boys mother personally and had some doubts about her story, as colorectal cancer (CRC) is unusual at 18 years, even in an HNPCC family.3 They accessed the relevant cancer registry to confirm her diagnosis and, with her permission, also checked the molecular genetic investigations. These had been carried out at another centre on a research basis, but the genetics team did then confirm them in an accredited diagnostic laboratory. The extent to which genetic testing might assist the management of the childs essentially emotional problem was discussed at length, over the course of several consultations in the paediatric and genetic clinics and on several more occasions at team meetings of the two departments involved. If tests revealed that the boy did not have his mothers MSH2 gene mutation, then her anxiety might abate somewhat, which could be helpful for him. On the other hand, if he did carry his mothers mutation, then the emotional charge in the family seemed likely to worsen. Despite the reservations of several of the professionals, it was ultimately agreed simultaneously to investigate the boy as if for CRC while also testing for his mothers MSH2 mutation. No anomaly was found on colonoscopy at all, and the mother was greatly relieved. The genetic test result was then obtained a few weeks later, which showed that the boy did indeed share his mothers HNPCC-associated mutation. On the one hand, it may seem that no great harm was done because bowel screening by colonoscopy would have been recommended anyway for this boy from some point in his later teenage years instead of the more usual age of 25 years because his mother had had a malignancy at such a young age. On the other hand, the emotional disturbance generated by this test result may prove to have some persistent negative consequences. Whereas the normal colonoscopy result appeared to be settling the family (both
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mother and son), the genetic result rekindled the mothers anxiety about her sons uncertain future. Investigations to exclude a tumour as the cause of his abdominal pain might well have been sufficient at that stage. It is still too early to tell how the abdominal pain is going to progress and whether school avoidance will become a more serious problem in the long term.

SCENARIO 3: LI-FRAUMENI SYNDROME

A previously healthy 5-year-old girl was found to have an adrenocortical tumour. Her paediatric oncologist suspected she might have Li-Fraumeni syndrome (LFS) and arranged for molecular genetic testing of her p53 gene. This did indeed demonstrate a pathogenic mutation and she was consequently referred for a clinical genetics assessment. On taking the family history, it became clear that her 25-yearold mother was an obligate carrier as she had a paternal family history consistent with LFS. As she was at particular risk of breast cancer, in addition to many other types of tumour for which screening is unhelpful, annual breast imaging by MRI was recommended because this avoids the radiation-related hazards of conventional mammography in LFS. The question of the most appropriate surveillance for tumours in at risk children is a vexed one: for the 3-year-old brother of the affected girl, however, the consensus is that surveillance for Li-Fraumeni related tumours would not be of benefit.4 The parents anxiety about both their children, and their feelings of helplessness, led them to argue forcefully in favour of genetic testing for their son. The parents felt that not knowing his status would be unbearable and that their understandable anxiety would cause them to over-react to any minor episode of illness for fear that it was caused by a malignancy associated with LFS. They felt this would not be fair to the child or themselves. While knowing that he carried the mutation would not change anything, they felt that the relief provided by a mutation negative result would be helpful. The professionals involved in this case could not, on medical grounds, see any medical benefit to testing at this age. The test results would not change management and the condition is not fully penetrant (especially in males).5 Nonetheless, the genetic counsellor and clinical geneticist both had some sympathy for the parents arguments and appreciated that this request provided an outlet for the grief and anger they felt in their predicament and a desire for some

kind of certainty in the midst of turbulence. Weighing against this, however, was the possibility that the testing would be unhelpful and might not provide the degree of certainty the parents sought if their son did in fact carry the mutation. The professionals consulted colleagues and discussed the situation in their clinical meetings. The consensus among the full team was opposed to testing in these circumstances, so they declined the request.

SCENARIO 4: FAMILIAL ADENOMATOUS POLYPOSIS

A couple have three children at 50% risk of familial adenomatous polyposis (FAP) because the mother carries a de novo mutation. Her diagnosis and treatment had been experienced as traumatic by the family. She is having treatment for polyps but has resisted surgery to date. The parents appreciate the risk to their 12year-old son and the need for management of this risk but do not want him to be seen for discussion prior to testing. They decline to attend the clinic and, in phone conversations between the parents and genetics team, it becomes apparent that they want the test to be performed without his explicit knowledge, with the results being used to assist in his management but without burdening him with bad news. The boy is intellectually able and is not recognised as requiring any particular support in the classroom. At one point, the mother rings to inform the genetic counsellor that she is in her car, one hour into a two hour journey to the clinic, and wishes to drop by for collection of a blood sample from the boy but not for counselling and not even simply for information. The counsellor experiences the mother as controlling and somewhat manipulative and makes it plain that she will not collude with the parents in such deception. The woman and her son do not arrive and, while the counsellor is pleased that she has escaped having to deal with a very challenging consultation at short notice, this does not provide a resolution to the problem. The counsellor feels an obligation to maintain a working relationship with these parents as this may be the only way of ensuring that the 12-year-old child and his younger siblings have the opportunity to benefit from genetic testing to clarify their risk of disease and their possible future need for colonoscopy and surgery. It is very difficult for the professionals to challenge the parents assertion that the boy is emotionally too immature
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or too sensitive to cope with the type of information that could be generated by genetic testing: his parents know him intimately, the professionals do not. On the other hand, the professionals may have a clearer idea about what is at stake for the boy than do the parents, who may have a bleaker understanding of the prognosis of this condition than is actually warranted by the outcomes of current medical and surgical practice. The counsellor will continue to work with the family and will attempt to persuade them to involve the boy in discussions. Although not optimistic that it would be accepted, she may also suggest a referral to an independent clinical psychologist because the womans difficulty in dealing with her own condition and its management seems to be projected by her onto her son, thereby interfering with the medical management appropriate for his situation.
decisions that appear to be the best available course of action at the time but which we later have cause to regret. Genetics professionals will often be thinking about the long term effect of decisions taken today on the child concerned and the parents, and indeed on other family members too. A clinical genetics unit may have a long term relationship with multiple family members of several generations and a decision that seems reasonable for one family members situation may have repercussions in other branches of the same family; consistency is of great importance. Two beliefs that we share, although they do not always apply, appear to us to be valuable guides to thinking around these issues and discussing them with parents. First, we think that the value of deferring a test until the child can participate in the discussion and perhaps make the decision for him- or herself, lies not so much in the abstract notion that their autonomy is preserved but rather more in that the active involvement of the adolescent in the decision about genetic testing may help them gradually to take over responsibility for managing their risk of cancer better than if they feel that they have been tested as a child with responsibility for decisions relating to future health being taken by others. Some parents express the wish to have the test performed so that their responsibilities have been discharged, perhaps in case their child makes the wrong decision. While this approach is understandable, it does not necessarily help the child in their acceptance of responsibility as they move towards adulthood; involvement in decision making about testing is an opportunity to foster that process. Second, although there is little evidence that labelling a child from a young age, as being likely to develop a genetic disorder in adult life, is harmful, we are nevertheless

GENERAL DISCUSSION
When parents come to realise that their children may have inherited a strong, predisposition to malignancy from one of them, they may feel a powerful and confusing mix of emotions including sadness, anger, anxiety, denial, blame and guilt. Past personal and family experiences with the condition are influential. It is therefore thoroughly understandable that the parents will sometimes wish to avoid looking into the frightening question, Has our child in fact inherited the familys predisposition to cancer or not? and will sometimes wish to gain a sense of control by confronting this possibility head-on, hoping that the results show the child has not in fact inherited the predisposition. In this paper, we present the perspective of the health provider who must respond to such requests, recognising that a parents or familys perspective on these scenarios may well be different. Usually, cancer genetic counselling is a process that incorporates engaging the family in thoughtful decision making.6 Scenarios such as those presented here illustrate the tensions that can arise when a familys expressed need is at odds with professional judgement. Interactions can move from seeming client centred to feeling persuasive, with decision making ultimately lying in the professional realm. We have given some indication of the various factors that may need to be considered in reaching a decision as to what to do, in particular the potential medical benefit and its immediacy; professionals will all be familiar with making
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sometimes concerned about parental requests to label a child when there is no practical reason for doing so at the time. Labelling may lead to the child being treated differently in many subtle ways; the evidence on this is simply unavailable, so we have to make the best judgments we can based on clinical experience. In most families, but not all, exploration of the issues involved in testing, with a gentle and patient explanation of the course of action preferred by the professionals, will be accepted by the parents and family once they have had time to think the issues through carefully. When parents make forceful and insistent requests for a genetic test to be carried out, that we think may have little benefit or may even be unhelpful, it can be useful to consider what is at stake and the implications of failure to go along with the request. In situations where the parents are annoyed by heavy-handed professionals (like us), who are telling them what to do in a paternalistic fashion, the professionals reluctance or refusal to test can become the major issue. Defusing the clash of perspectives may then be required. The insistence of some parents on testing may, however, have inappropriate motivations that really should be addressed in their own right. This group is not large but the children involved may become casualties, whatever decision is made about genetic testing. Referral for more expert psychology or counselling help may be the wisest course in this setting. This paper has specifically addressed parental requests for genetic testing. A test may also be requested by an adolescent on their own behalf, whether or not they have the support of their parents. Counselling adolescents and young adults has its own challenges,7 but we approach the counselling issues in a very similar way, attempting to build a relationship

Suggested further reading

c c

Clarke A, ed. The genetic testing of children. Oxford: Bios Scientific, 1998. Clinical Genetics Society. The genetic testing of children. Working Party of the Clinical Genetics Society (UK). J Med Genet 1994;31:78597. Also available from http://www. bshg.org.uk/documents/official_docs/testchil.htm (accessed 22 July 2008). Davis DS. Genetic dilemmas. Reproductive technology, parental choices and childrens futures. New York: Routledge, 2001. Jansen L, Friedman Ross L. The ethics of pre-adoption genetic testing. Am J Med Genet 2001;104:21428. McConkie-Rosell A, Spiridigliozzi GA. Family matters: a conceptual framework for genetic testing in children. J Genet Counsel 2004;13:929. Ross LF. Children, families and health care decision making. Oxford: Oxford University Press, 1998.

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with the client that assists them clarify their expectations of genetic testing and to explore the breadth of consequences of testing. This paper does not address the issues relating to carrier testing during adolescence, which has sufficiently different medical and possibly psychosocial implications to justify separate deliberation. We hope that this article will stimulate thought and discussion among paediatricians and dialogue between paediatricians and genetics specialists (both clinical geneticists and genetic counsellors). There is no single policy or guideline that will always show us the correct path to take we need to work out our

own understandings of what to do in the course of engaging with our patients and their families. But we are convinced that working out what to do jointly and in discussion with each other will help us and those for whom it is our privilege to care.
Competing interests: None. Arch Dis Child 2008;93:911914. doi:10.1136/adc.2006.113381

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3.

4. 5. 6.

REFERENCES
1. Borry P, Stultiens L, Nys H, et al. Presymptomatic and predictive genetic testing in minors: a systematic review of guidelines and position papers. Clin Genet 2006;70(5):37481. 7.

Vasen HFA, Bulow S, The Leeds Castle Polyposis Group. Guidelines for the surveillance and management of familial adenomatous polyposis (FAP): a world wide survey among 41 registries. Colorectal Dis 1999;1:21421. Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 2005;129:41521. Field M, Shanley S, Kirk J. Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 2007;43(4):21929. Wu CC, Shete S, Amos CI, et al. Joint effects of germline p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res 2006;66(16):828792. Trepanier A, Ahrens M, McKinnon W, et al. Genetic cancer risk assessment and counseling: recommendations of the National Society of Genetic Counselors. J Genet Couns 2004;13:83114. Gaff C, Lynch E, Spencer L. Predictive testing of eighteen year olds: counseling challenges. J Genet Couns 2006;15:24551.

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