Offspring Of Survivors Research Articles

Prevalence of Adult-Onset Multifactorial Disease among Offspring of Atomic Bomb Survivors

The first study to examine whether parental radiation exposure leads to increased heritable risk of common adult-onset multifactorial diseases (i.e., hypertension, diabetes mellitus, hypercholesterolemia, ischemic heart disease, and stroke) was conducted among 11,951 participants in the clinical examination program out of a potential of 24,673 mail survey subjects who were offspring of survivors born from May 1946 through December 1984. Logistic regression analyses demonstrated no evidence of an association between the prevalence of multifactorial diseases in the offspring and parental radiation exposure, after adjusting for age, city, gender and various risk factors. The odds ratio (OR) for a paternal dose of 1 Gy was 0.91 [95% confidence interval (CI) 0.81-1.01, P = 0.08], and that for a maternal dose of 1 Gy was 0.98 (95% CI 0.86-1.10, P = 0.71). There was no apparent effect of parental age at exposure or of elapsed time between parental exposure and birth, but male offspring had a low odds ratio (OR = 0.76 at 1 Gy) for paternal exposure, but cautious interpretation is needed for this finding. The clinical assessment of nearly 12,000 offspring of A-bomb survivors who have reached a median age of about 50 years provided no evidence for an increased prevalence of adult-onset multifactorial diseases in relation to parental radiation exposure.

Genetic consequences of cancer treatment

Although radiation is a well established mutagen in germ and somatic cells, to date epidemiological studies have demonstrated no convincing or consistent evidence for radiation-induced germ cell mutations resulting in genetic disease in offspring The Genetic Consequences of Cancer Treatment (GCCT) study is a large-scale retrospective cohort study of the offspring of survivors of childhood and early-onset cancer, the objective of which is to determine the extent to which curative therapies, including radiation, contribute to adverse health outcomes or other inherited effects i.e. cancer, birth defects, stillbirths, neonatal and all other premature deaths. The study is unique in that it examines risk in relation to well established testes and ovarian doses. Gonadal doses cover a wide range and approach the maximum possible without causing infertility. Good outcome ascertainment is possible using the extensive Danish and Finnish registries. Approximately 19000 children of cancer survivors and 50000 children of the survivors’ siblings are being evaluated for adverse pregnancy outcomes. 100 families are providing blood samples for storage of DNA and viable lymphocytes. These are being used to study genetic markers of cancer susceptibility and the induction of minisatellite mutations. Because of the wide dose range, results from this study will provide valuable information on radiation genetic risk and cancer susceptibility for counseling cancer survivors as well as relevant information for those encountering occupational radiation. The project is supported by grant Number 1 R01 CA104666 from the US National Institutes of Health, National Cancer Institute through Vanderbilt Medical Center. www.gcct.org

Genetic Effects of Radiation in Atomic-bomb Survivors and Their Children: Past, Present and Future

Genetic studies in the offspring of atomic bomb survivors have been conducted since 1948 at the Atomic Bomb Casualty Commission and its successor, the Radiation Effects Research Foundation, in Hiroshima and Nagasaki. Past studies include analysis of birth defects (untoward pregnancy outcome; namely, malformation, stillbirth, and perinatal death), chromosome aberrations, alterations of plasma and erythrocyte proteins as well as epidemiologic study on mortality (any cause) and cancer incidence (the latter study is still ongoing). There is, thus far, no indication of genetic effects in the offspring of survivors. Recently, the development of molecular biological techniques and human genome sequence databases made it possible to analyze DNA from parents and their offspring (trio-analysis). In addition, a clinical program is underway to establish the frequency of adult-onset multi-factorial diseases (diabetes mellitus, high blood pressure, and cardiovascular disease etc) in the offspring. The complementary kinds of data that will emerge from this three-pronged approach (clinical, epidemiologic, and molecular aspects) promise to shed light on health effects in the offspring of radiation-exposed people.

Chromosomal Abnormalities among Offspring of Childhood-Cancer Survivors in Denmark: A Population-Based Study

Ionizing radiation and many cancer drugs have the potential to produce germ-cell mutations that might lead to genetic disease in the next generation. In a population-based study, we identified, from records in the Danish Cancer Registry, 4,676 children treated for cancer. Their 6,441 siblings provided a comparison cohort. The results of a search of the Central Population Register identified 2,630 live-born offspring of the survivors and 5,504 live-born offspring of their siblings. The occurrence of abnormal karyotypes diagnosed in these offspring and also in any pregnancies terminated following prenatal diagnosis of a chromosome abnormality was determined from the Danish Cytogenetic Registry. After exclusion of hereditary cases and inclusion of the prenatal cases, after correction for expected viability, the adjusted proportion of live-born children in survivor families with abnormal karyotypes (5.5/2,631.5 [0.21%]) was the same as that among the comparison sibling families (11.8/5,505.8 [0.21%]). There were no significant differences in the occurrence of Down syndrome (relative risk [RR]=1.07; 95% CI 0.16-5.47) or Turner syndrome (RR=1.32; 95% CI 0.17-7.96) among the children of cancer survivors, compared with the children of their siblings. These reassuring results are of importance to the survivors, to their families, and to genetic counselors.

Transmission of Response to Trauma? Second-Generation Holocaust Survivors’ Reaction to Cancer

Opinions differ about the effects of the Holocaust on the adult offspring of survivors. The authors studied cancer patients who were second-generation Holocaust survivors in an attempt to determine whether they react to their illness with the high distress found to be a characteristic of Holocaust survivors. In a study population of women with breast cancer, 106 second-generation Holocaust survivors were compared to 102 women whose parents were not in the Holocaust. Background information was obtained by interviews. In addition, all patients completed three self-reports: the Mental Attitude to Cancer Scale, the Brief Symptom Inventory, and the Impact of Event Scale. The two groups had identical mean scores on the Mental Attitude to Cancer Scale. The offspring of Holocaust survivors had scores on the Brief Symptom Inventory and the Impact of Event Scale that were substantially and significantly higher and in the range of psychopathology. Within the group, married women and women whose mothers were still alive were even more distressed. Other independent variables shed little light on why the second-generation Holocaust survivors suffered from extreme distress. Second-generation Holocaust survivors are particularly vulnerable to psychological distress and, when faced with a trauma such as breast cancer, react with extreme psychological distress.

Having children after cancer. A pilot survey of survivors' attitudes and experiences.

Although the prevalence of infertility after cancer treatment and the health of the offspring of survivors have been studied, little information has been available about survivors' attitudes, emotions, and choices with regard to having children. A questionnaire was received by 283 patients from the Cleveland Clinic Foundation tumor registry who were diagnosed before age 35 years, were age 18 years or older at the time of the survey, and were free of disease. The SF-36, a measure of health-related quality of life, was included, as well as questions about demographic and medical background, reproductive and fertility history, and a variety of concerns about having children after cancer. The response rate to the survey was 47%, yielding a sample of 43 men and 89 women who had had cancer at various sites. Their mean age at diagnosis was 26 years and the mean time since diagnosis was 5 years. Before cancer, 35% had at least 1 child, compared with 46% currently. Of those currently childless, 76% want children in the future. Although about half of the entire sample view themselves as having impaired fertility, only 6% have undergone infertility treatment. Nineteen percent have significant anxiety that their cancer treatment could impact negatively on their children's future health. Of women, 18% fear that a pregnancy could trigger a cancer recurrence. Only 57% received information from their health care providers about infertility after cancer. Other reproductive concerns were discussed less often. Only 24% of childless men banked sperm before treatment. SF-36 scores were very similar to normative data for healthy Americans of similar age. About 80% of the sample viewed themselves positively as actual or potential parents. Feeling healthy enough to be a good parent after cancer was the strongest predictor (P < 0.001) of emotional well-being as measured by the Mental Component Score of the SF-36. The great majority of younger cancer survivors see their cancer experience as potentially making them better parents. Those who are childless want to have children in the future. Many, however, are left with significant anxieties and insufficient information about reproductive issues.

Risk of cancer among offspring of childhood-cancer survivors. Association of the Nordic Cancer Registries and the Nordic Society of Paediatric Haematology and Oncology.

Increasing numbers of children with cancer survive and reach reproductive age. However, the risk of cancer (other than retinoblastoma) in the offspring of survivors of childhood and adolescent cancer is uncertain. Using data from national cancer and birth registries, we assessed the risk of cancer among 5847 offspring of 14,652 survivors of cancer in childhood or adolescence diagnosed since the 1940s and 1950s in Denmark, Finland, Iceland, Norway, and Sweden. The offspring were followed up for a diagnosis of cancer for 86,780 person-years, and standardized incidence ratios were calculated. Among the 5847 offspring, 44 malignant neoplasms were diagnosed (standardized incidence ratio, 2.6; 95 percent confidence interval, 1.9 to 3.5). There were 17 retinoblastomas, yielding a standardized incidence ratio of 37. There were 27 neoplasms other than retinoblastoma (standardized incidence ratio, 1.6; 95 percent confidence interval, 1.1 to 2.4). The second most common primary site of cancer among the offspring was the brain and nervous system, in which eight tumors were observed (standardized incidence ratio, 2.0; 95 percent confidence interval, 0.9 to 3.9.) There were between zero and four apparently sporadic cases of cancer in other primary sites among the offspring. Excluding 4 likely cases of hereditary cancer and 2 subsequent cancers among the offspring with hereditary retinoblastoma, there were 22 sporadic cancers, for a standardized incidence ratio of 1.3 (95 percent confidence interval, 0.8 to 2.0). There is no evidence of a significantly increased risk of nonhereditary cancer among the offspring of survivors of cancer in childhood.

Genetic Disease in Offspring of Long-Term Survivors of Childhood and Adolescent Cancer

Numerous case series have addressed the concern that cancer therapy may damage germ cells, leading to clinical disease in offspring of survivors. None has documented an increased risk. However, the methodological problems of small series make it difficult to draw firm conclusions regarding the potential of cancer treatments to damage the health of future offspring. We conducted a large interview study of adult survivors of childhood cancer treated before 1976. Genetic disease occurred in 3.4% of 2,198 offspring of survivors, compared with 3.1% of 4,544 offspring of controls (P=.33; not significant); there were no statistically significant differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. A comparison of survivors treated with potentially mutagenic therapy with survivors not so treated showed no association with sporadic genetic disease (P=.49). The present study provides reassurance that cancer treatment using older protocols does not carry a large risk for genetic disease in offspring conceived many years after treatment. With 80% power to detect an increase as small as 40% in the rate of genetic disease in offspring, this study did not do so. However, we cannot rule out the possibility that new therapeutic agents or specific combinations of agents at high doses may damage germ cells.

Differential survival of fathead minnows, Pimephales promelas, as affected by copper exposure, prior population stress, and allozyme genotypes

AbstractTwo populations of fathead minnows (F1, offspring of survivors of an acute fluoranthene exposure; N1, naive hatchery fish born in outdoor ponds) were concurrently exposed to approximately 850 μg/L of copper for 132 h. During the exposure, 49% of the F1 and 85% of the N1 minnows died. A curled operculum deformity, detected in 54% of the F1 population, was significantly related to mortality. A failure time regression model, combining both the F1 and N1 populations together, was fit to examine the relationship between population type (F1 or N1), body condition (weight/length3), presence of an operculum deformity, and different allozymes on time to death (TTD). The model indicated that type of population, body condition, the presence of an operculum deformity, and three loci (GPI‐1*, IDHP‐1*, and MDH‐2*) were significantly related to TTD. The F1 minnows had a higher survival rate and longer average TTD compared to N1 minnows. In comparison to the N1 population, the F1 population possessed a higher frequency of genotypes associated with increased survivorship at the IDHP‐1* and MDH‐2* loci. Weight (and body condition) was negatively correlated with survivorship. Minnows with a severe operculum deformity, believed to be a result of parental exposure to fluoranthene, had a 100% mortality rate and exhibited a considerably reduced TTD compared to nondeformed minnows. Multilocus heterozygosity was not related to TTD for either population. This study indicates that genetic factors may exhibit stronger effects on survivorship than other factors (e.g., weight/body condition) commonly associated with fitness.

Birth defects and childhood cancer in offspring of survivors of childhood cancer.

To determine the effect of chemotherapy for cancer during childhood and adolescence on subsequent pregnancy outcome and the occurrence of cancer in the offspring. We reviewed the history of 405 former patients with pediatric cancer. A self-administered questionnaire was completed by members of a cohort of consecutively treated patients who were aged 18 years or older at the most recent follow-up visit and who were at least 5 years beyond the initial diagnosis of their cancer. Department of Pediatrics of a National Cancer Institute-designated comprehensive cancer center. One hundred forty-eight patients reported 280 pregnancies. Ninety-one of the patients who reported 1 or more liveborn or stillborn infants following the completion of treatment had received 1 or more chemotherapeutic agents as part of their treatment of cancer. The frequency of congenital anomalies was 3.3% among the liveborn offspring of the treated women and 3.3% among the liveborn offspring of the spouses or female companions of the treated men. No cases of childhood cancer have been diagnosed among the offspring. The present data suggest that prior treatment with mutagenic chemotherapeutic agents, in the dosage ranges examined, does not increase the frequency of congenital anomalies in the offspring of former pediatric and adolescent patients with cancer. Although no cases of childhood cancer have been observed thus far among the offspring, additional follow-up is necessary to adequately assess their risk of childhood cancer.

Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia: A Childrens Cancer Group/National Institutes of Health report

BACKGROUND It is not known if therapy for acute lymphoblastic leukemia (ALL) during childhood increases the risk of birth defects in the offspring of adult survivors. The Childrens Cancer Group (CCG), in collaboration with the National Institutes of Health (NIH), conducted a retrospective cohort study of adults successfully treated for childhood ALL to determine if their offspring had an increased incidence of birth defects compared with the offspring of their sibling controls. METHODS Study subjects were patients who had been enrolled on CCG ALL protocols, who were treated for ALL prior to age 20, who survived at least 2 years, and who were at least age 18. Survivors (N = 593) and sibling controls (N = 409) were interviewed by telephone. RESULTS The mean age of survivors was 22.6 years; the mean age of controls was 25.2 years. Among survivors, 93 (15.7%) had given birth to or fathered a total of 140 live-born offspring, (mean age, 3.4 years), and 122 (29.8%) sibling controls had given birth to or fathered a total of 228 live-born offspring (mean age, 5.9 years). There was no difference in the rate of birth defects between offspring of survivors and offspring of controls (3.6% [5 of 140] vs. 3.5% [8 of 228]; relative risk, 1.02; 95% confidence interval, 0.34, 3.05). No specific ALL therapy was associated with an increased rate of birth defects. Only female survivors reported offspring with birth defects (P = 0.0735). CONCLUSIONS Adult survivors of childhood ALL in our study were not at greater risk for having offspring with birth defects compared with sibling controls. Although this is the largest group of ALL survivors studied to date, the number of offspring is still not large enough to detect small but significant differences in rare events such as birth defects. Studies following this cohort into later adulthood and studies of additional ALL survivors are necessary to adequately quantify the risks. Cancer 1996;78:169-76.

Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report.

It is not known if therapy for acute lymphoblastic leukemia (ALL) during childhood increases the risk of birth defects in the offspring of adult survivors. The Childrens Cancer Group (CCG), in collaboration with the National Institutes of Health (NIH), conducted a retrospective cohort study of adults successfully treated for childhood ALL to determine if their offspring had an increased incidence of birth defects compared with the offspring of their sibling controls. Study subjects were patients who had been enrolled on CCG ALL protocols, who were treated for ALL prior to age 20, who survived at least 2 years, and who were at least age 18. Survivors (N=593) and sibling controls (N=409) were interviewed by telephone. The mean age of survivors was 22.6 years; the mean age of controls was 25.2 years. Among survivors, 93 (15.7%) had given birth to or fathered a total of 140 live-born offspring, (mean age, 3.4 years), and 122 (29.8%) sibling controls had given birth to or fathered a total of 228 live-born offspring (mean age, 5.9 years). There was no difference in the rate of birth defects between offspring of survivors and offspring of controls (3.6% [5 of 140] vs. 3.5% [8 of 228]; relative risk, 1.02; 95% confidence interval, 0.34, 3.05). No specific ALL therapy was associated with an increased rate of birth defects. Only female survivors reported offspring with birth defects (P=0.0735). Adult survivors of childhood ALL in our study were not at greater risk for having offspring with birth defects compared with sibling controls. Although this is the largest group of ALL survivors studied to date, the number of offspring is still not large enough to detect small but significant differences in rare events such as birth defects. Studies following this cohort into later adulthood and studies of additional ALL survivors are necessary to adequately quantify the risks.

Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin lymphomas

Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin lymphomas

Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin lymphomas

Understanding the extent to which childhood leukaemia and non-Hodgkin lymphomas are heritable is important to the survivors of these diseases, their families and clinicians who provide genetic counselling. Such understanding is also relevant to the possibility raised by Gardner et al. (1990, Br. Med. J., 300, 423-429) that paternal preconception irradiation may be an aetiological factor in these diseases. No malignant neoplasm was diagnosed among 382 offspring of survivors of childhood leukaemia and non-Hodgkin lymphoma followed up for a median period of 5.8 years, the largest available cohort of such offspring. These data indicate that it is unlikely that the risk of a malignant neoplasm occurring in the offspring exceeds eight times that expected in the general population. Similarly, the risk of leukaemia and non-Hodgkin lymphoma among offspring is unlikely to exceed 21 times that expected. The proportion of survivors of childhood leukaemia and non-Hodgkin lymphoma with the heritable form of these diseases is unlikely to exceed 5%, assuming an autosomal dominant pattern of transmission, with penetrance of at least 70% and that all heritable cases develop by age 15 years. The best (i.e. at present most likely) estimates of these risks are of course much lower. There was no evidence of an excess of congenital abnormalities among the offspring and the sex ratio was similar to that expected from the general population.

Fertility and pregnancy after treatment for cancer during childhood or adolescence

Because most children and adolescents with cancer now survive, issues regarding the late effects of therapy, including fertility and the health of offspring, are increasingly important. This article summarizes the literature regarding issues related to fertility in survivors of cancer, including actual fertility, gonadal function, menarche, menopause, and birth defects and cancer in the offspring. Radiation therapy to the gonads and alkylating agent chemotherapy, either alone or in combination, impair actual fertility in survivors of childhood and adolescent cancer. Males are particularly affected by alkylating agents, and females who have had radiation therapy to the abdomen have decreased fertility and an increased risk of adverse pregnancy outcomes. Consequently, these women should be followed up as high-risk obstetrical patients. Offspring of survivors of cancer appear to have little risk of childhood cancer or birth defects. Thus, in most instances, survivors of cancer should not be discouraged from having children and can expect a good outcome of pregnancy. This article concludes with advice to survivors and clinicians who counsel survivors.

Patterns of risk of hereditary retinoblastoma and applications to genetic counselling.

A registry including information about nearly 1,600 cases of retinoblastoma diagnosed in Britain has been created at the Childhood Cancer Research Group. Cases have been classified as 'old germ cell mutation', 'new germ cell mutation' or 'sporadic non-hereditary'. For a population-based group of 918 cases diagnosed between 1962 and 1985 we have calculated the proportions of unilateral/bilateral and hereditary/non-hereditary cases. Bilateral cases represent 40% of the total number over this period; the proportion known to be hereditary is 44%, a higher proportion than has been reported elsewhere. By following up selected groups of cases, an estimate has been made of the proportions of siblings of retinoblastoma patients and offspring of survivors from retinoblastoma who are themselves affected with the disease. Where there is no previous family history, the risk for siblings of retinoblastoma patients of developing the disease is approximately 2% if the disease in the affected child is bilateral and 1% if it is unilateral, assuming that there are no other siblings; if there are unaffected siblings the risks for subsequent children are lower. Children of patients with hereditary retinoblastoma have a one in two chance of carrying the germ cell mutation and for those who are carriers the probability of developing retinoblastoma is very close to the accepted figure of 90% if the parents have bilateral retinoblastoma but probably less if they have the unilateral form. For children of patients not known to be carriers, the probability of developing retinoblastoma is estimated to be about 1%, considerably lower than the previously accepted figure of about 5%. Retinoblastoma kindreds consist mainly of bilateral cases but there is evidence that some kindreds have a high proportion of unilateral cases. The ways in which these findings may be used in conjunction with modern techniques of molecular biology for prenatal and postnatal genetic counselling are discussed.

What is a mutation? Identifying heritable change in the offspring of survivors at Hiroshima and Nagasaki.

"Mutations" have been crucial to the science of genetics, to the construction of evolutionary theory, and to efforts to understand the biological effects of radiation. Scientists have localized the abstraction of a "gene" by studying how its (mutant) effect was inherited. While a trait common to an entire population could not be analyzed, a deviation, thanks to its visual accessibility, could be.' At the same time, "mutation" has been a remarkably plastic concept, interpreted differently depending on the problem being investigated, the organism of interest, or the consequences of the interpretation. This paper examines the working concept of "mutation" in the original genetics study of the Atomic Bomb Casualty Commission (ABCC), established in Japan to track the long-term medical effects (both somatic and genetic) of exposure to radiation on the survivors of the August 1945 bombings. The genetics work of this organization was guided by University of Michigan geneticist James V. Neel, who was part of the original study team of the ABCC in 1946, and his younger collaborator William J. Schull, who came to Japan to work as ABCC geneticist in the summer of 1949.2 Neel and Schull have continued to work together on the

Genetic counseling of the cancer survivor

Each year, tens of thousands of persons are diagnosed with cancer, are treated, and become survivors while still in their reproductive years. Their concerns about possible germ-cell damage as a result of life-saving radiation, chemotherapy, or both are plausible, based on evidence from animal models and from somatic cell mutations in human beings. A 40-year follow-up of survivors of the atomic bomb blasts in Japan showed no detectable genetic damage and suggested that the human gonad is more resistant to radiogenic mutation than the laboratory mouse. The pooled results of studying 12 series of offspring of cancer patients showed a 4% rate of major birth defects (similar to that of the general population) and an excess of fetal loss and low birth weight in offspring of women who received abdominal radiotherapy. According to preliminary evaluation of a new National Cancer Institute collaboration with five cancer registries, offspring of survivors of childhood cancers had no more birth defects than expected and, beyond an increase in probably familial cancers in children younger than 5, no overall increase in childhood cancer. Ideally, genetic and reproductive counseling should take place as soon as cancer is diagnosed (before therapy starts) and again when pregnancy is contemplated.

Genetics of Wilms' tumor.

The analyses of published data for Wilms' tumor show the following results: 1) The mode of inheritance of familial cases, which constitute less than 1% of all Wilms' tumors, is autosomal dominant with variable penetrance and expressivity. The familial pattern reveals no evidence that this tumor is associated with a vertically transmitting tumor virus. 2) There is a significant correlation between the first-degree relatives affected with Wilms' tumor in regard to expressivity as measured by the proportion of bilaterally affected or by the age of the patients at diagnosis. In particular, expressivity in the children affected varies consistently with expressivity in the carrier parents, indicating that inherited host resistance plays an important role in the manifestation of the major gene. The average risk of developing Wilms' tumor for offspring of unaffected carriers, who may be regarded as inherently resistant to tumor formation, is estimated at about 0.30. Although the data are limited, the risk for offspring of survivors of hereditary unilateral or bilateral cases may be as high as 0.40 or more. The data from seven pairs of monozygotic twins, including the discordant one associated with del(11 p) and aniridia, are consistent with the host resistance model. 3) In sporadic cases, the proportion of bilateral involvement is about 3%, in contrast with 20% in the familial cases. For bilateral cases, however, the distribution of ages of the patients at diagnosis is virtually the same whether sporadic or familial, and in two-thirds of the cases the disease is already bilateral when the first tumor is noted. These findings suggest that bilateral cases are probably always hereditary. Ages of the patients at diagnosis of sporadic unilateral cases tend to be much higher than in the patients with familial unilateral cases, indicating that most sporadic unilateral cases are nonhereditary. The overall risk for survivors of sporadic unilateral Wilms' tumor to transmit the disease to children may be as low 2∼4%. 4) Thus, a number of parallels are found between Wilms' tumor and retinoblastoma. The rate of germinal mutation per locus per generation is estimated at 3∼8×10-6 for Wilms' tumor, which does not seem to differ from 8∼14×10-6 for retinoblastoma. However, the incidence of nonhereditary Wilms' tumor per newborn is 7∼11×10-5, which is about twice that (3∼5×10-5) of nonhereditary retinoblastoma. This difference is possibly due to the greater number of cell divisions, resulting in an increased frequency of somatic mutations, of the embryonic cells involved in morphogenesis of the kidney than in the case of retinal development. 5) With increasing success in therapeutic management, it is anticipated that more and more cases of Wilms' tumor inherited from the survivors are emerging. However, even if complete cure of the disease and full recovery of fertility could be achieved for all the patients, about 10 generations may be required to double the present incidence of Wilms' tumor in the population, provided that other conditions remained the same. 6) Some guidelines for genetic counseling in families affected by Wilms' tumor are given.

Bilateral retinoblastoma: a dominantly inherited affection.

Ten survivors of sporadic bilateral retinoblastoma had 14 offspring, of whom eight were affected, seven of them in both eyes. Other reports from the literature raise the total of similar unselected cases to 19 survivors with a total of 39 offspring, of whom 17 were affected in both eyes and three in one eye.The high incidence of the bilateral affection in dominantly inherited retinoblastoma-as recorded in the literature-and in the offspring of survivors from sporadic bilateral retinoblastoma, as reported in the present study, establish all cases of bilateral retinoblastoma as a dominant disorder either in transmission or as a new mutation. This disorder, though fully or almost fully penetrant, is not always fully expressed. A small proportion, probably about 5 to 10% of all cases of the much more common sporadic unilateral affection, are in fact incompletely expressed germinal mutations for bilateral retinoblastoma. There is some evidence that histological appearances may distinguish these potentially transmissible unilateral tumours from the mass of unilateral retinoblastoma which have no genetic significance.