4 Retinoblastoma – Genetic Counseling and Molecular Diagnosis Claude Houdayer 1,4 , Marion Gauthier-Villars 1 , Laurent Castéra 1 , Laurence Desjardins 2 , François Doz 3,4 and Dominique Stoppa-Lyonnet 1,4,5 1 Genetics Department, Institut Curie, Paris 2 Ophtalmology Department, Institut Curie, Paris 3 Pediatrics Department, Institut Curie, Paris 4 Université Paris Descartes, Paris 5 INSERM U830, Pathologie Moléculaire des Cancers, Institut Curie, Paris France 1. Introduction Retinoblastoma is a malignant embryonal tumour of childhood arising at the expense of retinal cones. It has an incidence of 1 per 15,000 to 20,000 births. In 90% of cases, it is diagnosed before the age of 3 years. The possibility of conservative management depends on early diagnosis (Moll et al., 1996). However, although treatment strategies have advanced considerably, the visual prognosis is still a major source of concern, especially central vision when the tumour is situated at or close to the macula. In two-thirds of cases, the lesion is unilateral and the median age of diagnosis is 2 years. In the other third, the lesion is bilateral and the disease is diagnosed earlier, possibly even during the neonatal period, with a median age of diagnosis of 1 year. Most cases of unilateral and bilateral retinoblastoma are sporadic, with no family history. However, 10 to 15% of all cases of retinoblastoma present a family history. The distribution of cases within the family is compatible with the existence of a tumour susceptibility gene transmitted according to an autosomal dominant mode with high penetrance. In this case, the lesion is usually bilateral and diagnosed at an early age. 1.1 Diagnosis The most frequent presenting signs are leukocoria (white pupillary reflex) and strabismus. Retinoblastoma may also be discovered on routine ocular fundus examination performed in a child from a high-risk family. The diagnosis is essentially based on the ocular fundus examination under general anaesthesia, completed by ultrasound and CT. Tumour growth may be endophytic with invasion of the vitreous cavity or, more rarely, exophytic with retinal detachment. A precise description of the lesions based on fundoscopy findings allows the lesion to be classified according to the 5 stages of the Reese-Ellsworth classification, associated with an increasingly severe prognosis. Ultrasound and orbital CT demonstrate tumour calcifications