A T to C mutation in the polypyrimidine tract of the exon 9 splicing site of the RB1 gene responsible for low penetrance hereditary retinoblastoma

Inactivation of both alleles of the retinoblastoma susceptibility gene ( RB1 ), localised on chromosome band 13q14, is the crucial event for the development of retinoblastoma, a malignant tumour that originates from embryonal retinal cells.1, 2 Germinal mutation of one allele leads to a predisposition to retinoblastoma. Tumour development is initiated by inactivation of the second allele. In most families, the tumour predisposition segregates as an autosomal dominant trait with high (90%) penetrance3 and affected subjects usually develop bilateral multifocal tumours. Rare instances of familial retinoblastoma with low penetrance and variable expressivity have been described. In such families, patients develop retinoblastoma later than classical familial cases, there is a high rate of unilateral cases, and phenotypically normal obligate carriers are observed.4 A family with several cases of retinoblastoma has been identified (fig 1). Four members of the family were affected; three had unilateral retinoblastoma (III.5, IV.12, and IV.13), diagnosed at 12, 12, and 24 months, respectively, and one had bilateral retinoblastoma (IV-6), which developed at 11 months. Thus, with the exception of patient IV.13, the age of onset was not delayed compared to an average of less than 12 months in the majority of familial retinoblastoma. There were no cases of spontaneous osteosarcoma in this family, a secondary tumour recurrently found in patients with predisposition to retinoblastoma.5 However, the retinoblastoma of patient IV.6 was treated by radiotherapy (45 Gy) and 10 years later an osteosarcoma occurred in the irradiated field. It is well established that a germline mutation in the RB1 gene dramatically increases the probability of developing a radiation induced osteosarcoma.6 After ophthalmic examination of unaffected family members, no case of retinoma/retinocytoma, which may represent benign proliferation or tumour regression, was found. Altogether, these observations suggest the presence of a germline RB1 mutation linked to incomplete …