Late stages of PHPV and Coats’ disease are the most common conditions to mimic retinoblastoma (Balmer et al 1988; Shields, Parsons, et al 1991). In the absence of the classical clinical triad or with atypical retinal lesions, diagnosis of retinal astrocytic hamartoma may also be problematic. Inﬂammatory conditions, in particular ocular toxocaria- sis, can lead to complex clinical features requiring a whole battery of investigations, including serology, ultrasonogra- phy, and neuro-diagnostic tools. Severe vitreous hemorrhage following trauma may trans- form into a massive retinal gliosis and even develop calciﬁca- tions (Yanoff et al 1971). The history may be confused, the trauma unrecognized or prenatal or, conversely, be wrongly held responsible for the clinical situation. Primary or secondary retinal detachment may further complicate the assessment. Rare diseases Sheer rarity of a disease can make diagnosis more difﬁcult, such as in medulloepithelioma, optic nerve glioma, familial exudative vitreoretinopathy, X-linked retinoschisis, Norrie’s disease, or incontinentia pigmenti. Table 1 gives a classiﬁcation by system and by frequency of diseases involved in the differential diagnosis of retino- blastoma. Genetics Retinoblastoma (Augsburger et al 1995; Abramson et al 1998; Balmer and Munier 2002a; Aerts et al 2006; Bornfeld et al 2006) is a malignant tumor of the retina resulting from a double oncogenic mutation between the beginning of the 3rd month of gestation and 4 years of age in an immature retinal cell, most likely a multipotent retinoblast (Munier 2002), precursor cone cell. Onset of the disease may thus occur in utero (Maat-Kievit et al 1993) and up to 4 years of age, with a mean age of appear- ance of ﬁrst signs of 7 months for bilateral cases, 24 months in unilateral disease (Balmer and Munier 2002a). Retinoblastoma may be non hereditary (60%) or heredi- tary (40%), the hereditary form showing a classic autosomal dominance pattern with 90% penetration at birth. The RB1 gene belongs to the group of anti-oncogenes, also called tumor-suppressor genes. According to the literature, the mean frequency of reti- noblastoma is one in 20,000 live births (Balmer and Munier 2002b) with no sex, race or geographic predilection and no known exogenous risk factors apart from the age of the parents, in particular that of the father (DerKinderen et al 1990; Matsunaga et al 1990). Clinical Ophthalmology 2007:1(4) Differential diagnosis of leukocoria and strabismus Table I Differential diagnosis in infantile leukocoria 1.Tumors Retinoblastoma Medulloepithelioma Naevoxanthome juvenile Glioneuroma Leukemia Choroidal hemangioma Combined retinal hamartoma 2. Phakomatoses Astrocytic hamartoma (Bourneville’s tuberous sclerosis) Retinal capillary hemangioma (von Hippel-Lindau) Encephalotrigeminal syndrome (Sturge-Weber) Neuroﬁbromatosis (von Recklinhausen) (NF–1) 3. Congenital malformations Persistent Hyperplastic Fetal Vasculature (PHFV) Posterior coloboma Retinal fold Myelinated nerve ﬁbres Morning Glory Syndrome X-linked retinoschisis Retinal dysplasia Norrie’s disease Incontinentia pigmenti 4.Vascular diseases Retinopathy of prematurity Coats’ disease Familial exudative vitreoretinopathy 5. Inﬂammatory diseases Ocular toxocariasis Congenital toxoplasmosis Congenital cytomegalovirus retinitis Herpes simplex retinitis Other types of fetal iridochoroiditis Pseudo-uveitis Endophthalmitis 6.Trauma Contusion of the globe Intraocular foreign body Shaken baby syndrome 7. Divers Vitreous hemorrhage Retinal detachment Strabismus (Brückner’s phenomenon) Stickler syndrome Clinical presentation The clinical presentation of retinoblastoma varies according to the type of growth of the tumor and duration, the degree of vascularization and presence of calciﬁcations, vitreous seeding, retinal detachment or hemorrhage. The initial tumoral cell divisions may occur in different internal retinal layers, a tumor developing on the surface of the retina and into the vitreous cavity being called an endo- 433