Balmer and Munier Figure 1 (a) Left leukocoria in a 1 year-old boy with unilateral retinoblastoma. (b) Exophytic retinoblastoma with total retinal detachment. First signs The primary sign is leukocoria. The term leukocoria, also known as “amaurotic cat’s eye”, literally means “white pupil” from the greek “leucos” (white) and “korê” (pupil) and is created by the reﬂection of incident light off the retinal lesion within the pupillary area when the fundus is directly illuminated (Figures 1a and 1b). Leukocoria is the most frequent sign (60%) and is associated with retinoblastoma in almost half of all infants presenting with a white pupil (Howard and Ellsworth 1965b). A white pupil is most often initially noticed by close family members (Abramson et al 2003) or on ﬂash photography, this often the primary reason for consultation. It is, however, a late manifestation, the vital prognosis still good (88% at 5 years) but that for globe salvage uncertain. A number of other conditions, however, may also present with leukocoria as a ﬁrst sign. These include persistent hyperplastic primary vitreous (PHPV), Coats’ disease, ocular toxocariasis, retinopathy of prematu- rity, retinal hamartomas (Bourneville’s tuberous sclerosis, von Recklinhausen’s disease), congenital falciform fold 432 or organized vitreous hemorrhage (Howard and Ellsworth 1965a; Shields, Shields et al 1991). The second most frequent primary manifestation is stra- bismus (20%), an affection thus not to be taken lightly and requiring immediate ophthalmological examination com- prising full fundus examination with a dilated pupil, under anesthesia if necessary. Strabismus is usually secondary to macular involvement and an invaluable early sign carrying an excellent life prognosis and every chance of preserving the globe. Finally, in 20% of cases the ﬁrst manifestation is atypical, often inﬂammatory or hypertensive, and common to both retinoblastoma and certain pseudo-retinoblastomas. Atypical signs can cause major problems in diagnosis (Binder 1974; Balmer et al 1994; de Leon et al 2005) and include red eye, uveitis, hypopyon, hyphema, heterochromia, rubeosis, glau- coma or phthisis bulbi, in particular as ultimate complications of unchecked disease. These are very late signs carrying a far more reserved vital and functional prognosis. Differential diagnosis Depending on the clarity of the media, ﬁrst signs, stage of disease, frequency, the type and gravity of complications associated with spontaneous evolution, the approach to differential diagnosis will be made according to whether diagnosis is simple, difﬁcult or concerns rare diseases. Simple diagnosis With clear media, diagnosis is generally simple and can be made at ﬁrst glance, such as in most cases of retinoblastoma, choroidal or optic nerve coloboma, falciform retinal fold, myelinated ﬁbers, “Morning Glory Syndrome”, cataract, congenital toxoplasmosis or retinal capillary hemangioma. Asymmetrical pupillary reﬂexes, even leukocoria, may be associated with common strabismus or anisometropia. With strabismus, the reﬂex may be darker in the ﬁxating eye due to a greater pigmentation of the macular area (Brückner’s phenomenon) (Brückner 1962). Other, more serious conditions, are also easily identifiable when of typical presentation, in particular Coats’ disease, persistent hyperplastic primary vitreous (PHPV), astrocytic hamartoma (Bourneville’s tuberous sclerosis) or retinopathy or prematurity. Difﬁcult diagnosis Diagnosis of retinoblastoma or pseudo-retinoblastoma is much more difﬁcult with opaque media or with atypical features. Clinical Ophthalmology 2007:1(4)