Patterns of risk of hereditary retinoblastoma and applications to genetic counselling

Abstract

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.

A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype

“…By contrast, individuals who present without a family history and have only unilateral, unifocal tumors are generally considered not to carry germline mutations. While this distinction holds true in the vast majority of cases there is some overlap since approximately 2% of unilateral cases have a family history (Draper et al, 1992) and we have shown recently that unilateral cases who have a particularly early age of onset may also carry germline mutations (Cowell and Cragg, 1996). Within the hereditary group it is now clear that both alleles of the RB1 gene must be inactivated for tumorigenesis, supporting Knudson's original two-hit hypothesis (Knudson, 1971).…”

“…Thus, within pedigrees where the majority of a ected individuals have multiple tumors in both eyes, there are, on rare occasions, individuals who only develop a single tumor in one eye or who, since they do not experience the second mutation at all, are una ected carriers of the germline mutation. This phenomenon is referred to as incomplete penetrance and occurs at an estimated frequency of 8 ± 10% (Draper et al, 1992). Typically these variant forms of the disease phenotype occur within families where the other a ected members have the more severe form of the disease.…”

Patterns of childhood cancer among siblings

“…The only welldocumented causes of childhood cancer are ionising radiation (particularly antenatal X-rays; see, for example, Bithell and Stewart, 1975) (Knudson, 1978). Draper et al (1992) estimated the risk of retinoblastoma in sibs of affected patients. For the five families in which one child has unilateral retinoblastoma and a second a different type of tumour there was no family history of the disease; these sib pairs could result from unrecognised familial retinoblastoma, since it is known that a wide variety of tumours may occur in individuals carrying the retinoblastoma gene (Sanders et al, 1989;Eng et al, 1993 (Breslow et al, 1988).…”

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

“…About 40% of RBs are hereditary, about 80% of which arise from de novo germline mutations in the absence of a known family history (6). The majority of hereditary cases have bilateral or multifocal ocular involvement, but about 10% to 15% of children with unilateral, unifocal RB also have hereditary disease (7).…”