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Attitudes of von Hippel-Lindau disease patients towards presymptomatic genetic diagnosis in children and prenatal diagnosis
  2. STÉPHANE RICHARD (on behalf of the french vhl study group)
  1. * Unité 535 INSERM, Bâtiment INSERM Gregory Pincus, 80 rue du Général Leclerc, 94276 le Kremlin Bicêtre cedex, France
  2. Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, 94276 Le Kremlin Bicêtre et Service de Néphrologie, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France
  1. Dr Levy, mlevy{at}

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Editor—Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterised by a predisposition to develop a wide variety of benign tumours and malignant neoplasms, most frequently haemangioblastomas of the cerebellum and spinal cord, retinal haemangioblastomas, phaeochromocytomas, renal cysts, and clear cell carcinomas, pancreatic cysts and tumours, epididymal cystadenomas, and endolymphatic sac tumours.1-3 The combination of affected organs and the sequence of organ involvement vary considerably among families and even among individual patients in a family. Two types of families may, however, be distinguished according to the presence or absence of phaeochromocytoma.4 Central nervous system haemangioblastoma remains the main cause of death although renal cell carcinoma could represent a major problem in the future.5 Recent progress in research methods will render possible the identification of VHL gene mutations in virtually all families.6

Between 1995 and 1997, we have evaluated the views of 24 women aged 20 to 41 and 17 men aged 20 to 50 with VHL about presymptomatic genetic diagnosis in their children as well as prenatal diagnosis and termination of pregnancy. All were informed of the hereditary nature of their disease. Patients, having previously agreed over the telephone, were interviewed in the French VHL Care Centre (Necker Hospital in Paris and Kremlin-Bicêtre Hospital) where they were currently being followed. It was decided to have a full discussion with each subject after completion of the questionnaire, but not to interrupt its completion or correct erroneous answers immediately. The oral discussion allowed us not to ask a specific question, or even to interrupt the interview, if the patient showed a strong emotional reaction. All were included in the national French VHL register which includes 650 patients to date. Family pedigrees and medical records were reviewed.

The participants belonged to 34 families. In 28 families, one subject was interviewed. In the remaining six families, two or three sibs (two brothers in two families, a brother and sister in three families, and two sisters and a brother in one family) were interviewed. At the time of interview, 31 patients (76%) had developed central nervous system haemangioblastoma, 25 (61%) pancreatic cysts, 19 (46%) retinal haemangioblastoma (one woman was blind, another was amblyopic, and three had unilateral blindness), 14 (34%) renal cell carcinoma (one brother-sister pair being treated by dialysis because of bilateral nephrectomy and another man showing chronic renal failure), and seven (17%) phaeochromocytoma (one man and four women requiring substitutive treatment because of bilateral adrenalectomy). Differences between men and women were not significant. Percentages of retinal haemangioblastoma were, however, higher in women. According to a personal medical score (evaluating the severity of the disease considering the harm possibly resulting from symptoms, periodic examination, treatment, and residual disabilities), VHL disease was considered mild in five patients, moderate in 15, intense in 17, and severe in four. During the interview, 75% of women and 47% of men declared that their lives were modified by manifestations directly linked to the illness and treatments and/or to psychological distress, that is, anxiety or depression, sometimes prominent and requiring specific treatment. When comparing the patient's personal perception of burden with personal medical score, it appears that life modifications were acknowledged by many, but not all patients who had severe or intense disease and also by patients (especially women) who had moderate or mild disease and mainly suffered from psychiatric symptoms.

In studying family structures, it appears that VHL disease had an impact on the patients' reproductive intentions. Only three men and 11 women (34%) have had children. There were more childless men than women (82% v 54%). Most patients had only one child, but one woman had two children, two others have had three children, and a fourth woman with two children was pregnant at the time of interview. Two thirds of the pregnancies had occurred either when the parent was not ill or when he (or she) did not know that the disease was hereditary and that children would be at risk. Furthermore, four patients (three women and one man) who already have children and six childless patients (three women and three men) have decided not to have children in the future because of the potential risk for them. Although all patients claimed that they had heard of inheritance of the disease, half of them did not correctly remember the genetic risks (table 1). This misunderstanding was not influenced by educational background. One part of the discussion we had with each subject after completion of the questionnaire focused on helping them to understand the present state of medical and genetic knowledge so as to be able to make better informed decisions in the future.

Table 1

Knowledge about transmission and risk for children to be affected at the time of interview

Before the recent progress in DNA based testing, the diagnosis of VHL led to recommending screening of at risk members throughout their lifetime to determine whether they had manifestations of the disease. This recommendation imposed a considerable burden on asymptomatic family members.1 On the one hand, it is not known at what age screening can be discontinued for at risk members, assuming that they do not have the disease. On the other hand, it is not known at what age screening should begin. It may be guided by the possible age at onset of symptoms since each lesion has its own onset age.1 2 7 In this series, disease onset occurred between 10 and 15 years in six patients. Arterial hypertension related to a phaeochromocytoma was discovered in a 10 year old boy and neurological symptoms related to a cerebellar haemangioblastoma occurred in a 9 year old boy. A 12 year old girl and two 13 and 15 year old boys presented with ocular symptoms. In addition, visual field loss was discovered at school in a 12 year old girl. Similarly, there are several other published reports of childhood onset. For example, retinal haemangioblastoma, phaeochromocytoma, and cerebellar haemangioblastoma have been detected in children as young as 4,8 5,9 and 10 years,10respectively. Furthermore, renal cell carcinoma was discovered in a 12 year old child included in the French VHL register (Richard, personal communication). Consequently it could be recommended to start regular screening of asymptomatic patients for retinal lesions and phaeochromocytoma at the age of 5, for renal cell carcinoma at the age of 10, and for central nervous system haemangioblastomas at the age of 15.

The rapid development in genetic technology is changing the practice of medicine. Once the VHL gene mutation has been identified for a given family, at risk members can be tested. If no mutation is identified, it is not necessary to subject a person to periodic medical testing. If a mutation is identified, that person should be periodically examined for manifestations of the disease, taking the specific mutation into account, as well as the age specific incidence of VHL tumours. As indicated by the American Society for Clinical Oncology, genetic testing constitutes a help for families presenting with syndromes predisposing to cancer (for example, familial adenomatous polyposis, multiple endocrine neoplasia type 2, retinoblastoma, and VHL disease) for which either a positive or negative result will change medical care, and for which it may be considered part of the standard management of affected families.11 Various situations have to be distinguished, however. Whereas presymptomatic surgical treatment is proposed for patients with familial adenomatous polyposis and multiple endocrine neoplasia type 2, preventive treatment cannot be offered for VHL. Carriers with a mutant gene causing VHL syndrome are treated only after expression of the disease. However, identification of the mutation may have implications for guiding specific screening for phaeochromocytoma and renal cell carcinoma.12-14

In our group of 14 VHL patients with children, most, but not all, were willing to have their children tested as soon as possible or had already asked for testing (table 2). In six of these families, nine children aged between 3 and 18 years had already been clinically tested (no abnormality had been detected). However, there was a discrepancy between attitudes regarding themselves and their children since three of the 10 patients with onset after 20 years declared that they would not have appreciated knowing earlier that they were affected and three others did not know whether they would have appreciated it. Asked if they would tell the truth to their children in the case of a positive test, all answered yes, except one woman with three children (aged 15, 13, and 10 years), who had already refused presymptomatic clinical testing. Finally, asked when they would tell the truth, they could not specify the age. Although all authors agree on the need for testing at risk children for VHL, the age at which they should be tested is still under discussion. As shown by the reports of an international consensus meeting, answers vary. Fifty six percent of the participants from different disciplines favoured DNA analysis in VHL before the age of 5 and 5% prenatally, 15% between the ages of 5 and 10, and 18% at an age when children can make their own choice.15

Table 2

Attitudes of the 14 patients with children towards genetic testing for their children

With the use of genetic testing, the child and his family will be informed on the carrier state probably years before the initial clinical manifestations. Many authors recommend careful weighing of potential benefits and psychological harm to the child or adolescent and his family before making a decision about genetic testing.16-19 They mentioned the impact of testing on the child's own development as well as the emotional reactions of both the affected and the unaffected parent. Moreover, in large families, the reactions of the non-carrier sib(s) should also be considered. As mentioned by Fanos,18 psychosocial support should be provided to at risk families before making a decision. This view is strengthened by our observation of a high frequency of psychological distress in our patients (47% of the men and 67% of the women).

The use of DNA studies introduces new options for couples who may have to consider whether the abortion of an affected fetus is morally acceptable given the partially treatable nature of VHL disease. Most reports on patients' attitudes towards prenatal diagnosis have focused on autosomal recessive diseases where unaffected parents are grieving the loss of an affected child. Few have dealt with dominant diseases such as VHL disease where one parent is affected. In our series, 22 of the 31 VHL patients who wished to have children intended to use prenatal diagnosis in the case of a pregnancy (table 3). However, half of this group either disapproved of the idea of termination of an affected pregnancy or were undecided. The other 11 patients considered abortion of a fetus with the VHL disease acceptable. When studying Alport syndrome, an X linked dominant condition, we have already pointed out the discordant attitudes existing between the choice of prenatal testing and termination of pregnancy.20 Of the 21 VHL patients in favour of termination in the case of severe malformations (independent of VHL), 10 considered abortion of a VHL fetus as acceptable. The eleventh patient, a woman, who would choose abortion in the case of a VHL fetus, was reluctant to terminate a pregnancy for severe malformations. This patient presented with the highest score of severity, but denied any modifications in life style. Neither the VHL patient's own perception of the illness (that is, the associated physical, psychological, social, and financial problems) nor the patient's own attitude towards termination of pregnancy appeared to influence the decision making process. As indicated by the discordant sibs' answers, attitudes appear to depend upon personal motivation, independent of a common cultural and religious environment. Decisions of VHL patients appear to be quite individual and difficult to predict. Most patients who were against termination of pregnancy should prenatal diagnosis show an affected fetus based their feeling on the hope that progress in treatment would prevent symptoms as severe as their own in their children.

Table 3

Attitudes of the 31 patients wishing to have children towards prenatal diagnosis and termination of pregnancy


We wish to thank the VHL patients for their cooperation in this study. This work was supported by the Ligue Nationale contre le Cancer.


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