Figure 25-13 Aicardi syndrome. Fundus photograph showing optic disc coloboma and chorioretinal lacunae.
Diagnosis The clinical picture provides the foundation for diagnosis.
Treatment No treatment is currently available.
Fruhman G, Eble TN, Gambhir N, Sutton VR, Van den Veyver IB, Lewis RA. Ophthalmologic findings in Aicardi syndrome. J AAPOS. 2012;16(3):238–241.
Hereditary Macular Dystrophies
Macular abnormalities are seen in a number of hereditary disorders. The abnormality can be associated with a hereditary systemic disease (eg, the cherry-red spot seen in generalized gangliosidosis) or can reflect a primary retinal disorder, such as Stargardt disease or Best disease. Only primary retinal disorders are discussed here.
Stargardt disease
Stargardt disease (juvenile macular degeneration) is the most common hereditary macular dystrophy. Inheritance is usually autosomal recessive; in rare cases, it is autosomal dominant. Most cases are caused by mutations in the retina-specific adenosine triphosphate–binding transporter gene (ABCA4). It usually presents between ages 8 and 15 years with a decrease in vision. It is a bilateral, symmetric, progressive condition; visual acuity levels off at approximately 20/50–20/200.
Diagnosis The disease often progresses through stages. Initially, the fundus appears normal even when vision is decreased, and the patient may be misdiagnosed as having functional vision loss. The first ophthalmoscopic changes observed are loss of foveal reflex, followed by development of a characteristic macular bull’s-eye atrophy with surrounding round or pisciform yellow flecks, which develop in the posterior pole at the level of the RPE. If the flecks are scattered throughout the fundus, the condition may be referred to as fundus flavimaculatus. Before the flecks develop, the macula often appears atrophic due to diseased RPE, inducing a peculiar light-reflecting quality that resembles that of beaten bronze (Fig 25-14).
Figure 25-14 Stargardt disease. The macula has an atrophic, beaten-metal appearance.
The “dark choroid” sign on fluorescein angiography is distinctive and helps confirm the diagnosis of Stargardt disease. This phenomenon is due to the accumulation of lipofuscin-like pigment throughout the RPE, which blocks the choroidal fluorescence on fluorescein angiography; it is present in 80% of patients with Stargardt disease.
ERGs are often normal in the early stages of Stargardt disease. Stargardt disease can be associated with a progressive cone–rod dystrophy that has a much worse visual prognosis and an extinguished ERG.
Genetic testing for ABCA4 mutations may be diagnostic.
Treatment Gene therapy for Stargardt disease has been used in animal models and is being studied in phase 1 clinical trials in humans.
Han Z, Conley SM, Makkia RS, Cooper MJ, Naash MI. DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice. J Clin Invest. 2012;122(9):3221–3226.
Best disease
Best disease, or juvenile-onset vitelliform macular dystrophy (VMD), is an autosomal dominant retinal disorder with variable penetrance and expressivity. The condition is caused by mutations in the BEST1 gene on chromosome 11, which encodes for the protein bestrophin. Patients usually present asymptomatically in childhood with the classic retinal appearance or later in life with decrease in vision.
Diagnosis The retina may appear normal at first, but between 4 and 10 years of age, the “egg yolk,” or vitelliform, stage begins. A yellow-orange cystlike structure is seen, usually in the macula; however, the lesion may occur elsewhere, and occasionally there are multiple lesions (Fig 25-15A). The lesions are usually 1.5–5.0 disc diameters in size. The egg yolk–like appearance is associated with good central vision. With time, the cystic material may become granular, giving rise to the “scrambled egg” stage (Fig 25-15B). At this stage, central vision usually remains good, with visual acuity often being roughly 20/30. The cyst may rupture and become partially resorbed; a pseudohypopyon may form from cystic contents. Subretinal neovascularization and serous detachment of the RPE develop in 20% of patients. Subretinal hemorrhage may occur, and visual acuity may deteriorate to 20/100 or worse.
Figure 25-15 Best disease. A, Early disease, or “yolk” stage. B, Advanced disease, or “scrambled egg” stage. (Part B courtesy
of Richard A. Lewis, MD.)
The EOG is usually abnormal in affected patients and carriers. This disorder is one of the few in which the EOG is abnormal and the ERG is normal. BEST1 gene mutations are found in 60%–83% of affected patients. Carriers can be identified by the presence of an abnormal EOG with a normal retina or a BEST1 gene mutation.
Treatment No treatment is indicated unless subretinal neovascularization occurs.
Meunier I, Sénéchal A, Dhaenens CM, et al. Systematic screening for BEST1 and PRPH2 in juvenile and adult vitelliform macular dystrophies: a rationale for molecular analysis. Ophthalmology. 2011;118(6):1130–1136.
Hereditary Vitreoretinopathies
Hereditary vitreoretinopathies include a broad range of disease entities. The ones discussed here characteristically present in childhood.
Juvenile retinoschisis
Juvenile retinoschisis (splitting of the retina) is an X-linked disease caused by mutations in the RS1 gene, which encodes for the retinal protein retinoschisin, an adhesion protein that is believed to be essential to the health of Müller cells. Males usually present in early childhood with decreased vision. Visual acuity varies but usually deteriorates to roughly 20/200.
Diagnosis Foveal retinoschisis is present in almost all cases. Approximately 50% of patients also have peripheral retinoschisis (Fig 25-16). The retinoschisis occurs in the nerve fiber layer. The fovea
has a star-shaped or spokelike configuration that may resemble cystoid macular edema; it becomes less distinct over time. Vitreous veils or strands are common, and vitreal syneresis, or liquefaction, is prominent. Complications include vitreous hemorrhage and retinal detachment. The ERG shows a reduction of the scotopic b-wave with preservation of the a-wave. Optical coherence tomography scans show schisis spaces in the middle layers of the macula.
Figure 25-16 Juvenile retinoschisis. Central (macular) schisis (A) and peripheral schisis (B) may be present. (Part A courtesy of
Richard A. Lewis, MD.)
Treatment Contact sports should be avoided since the retina is more susceptible to trauma. Gene replacement has had some success in mouse models.
Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res. 2012;31(3):195–212.
Stickler syndrome
Stickler syndrome is the most common of the hereditary hyaloideoretinopathies. A hallmark of all such conditions is vitreous liquefaction that results in an optically empty vitreous cavity, except for vitreous veils that may be attached to the retina. There are many types of Stickler syndrome, which may present with ocular findings only, systemic findings only, or both ocular and systemic findings. The most common type of Stickler syndrome is autosomal dominant, has ocular and systemic findings, and is caused by a mutation in COL2A1, the gene that encodes for type II procollagen.
Diagnosis The diagnosis is made based on the clinical features as well as the results of genetic testing. In addition to the optically empty vitreous, common ocular abnormalities include high myopia, a high incidence of retinal detachment secondary to retinal breaks, lattice degeneration, and proliferative vitreoretinopathy. Anterior chamber angle anomalies, ectopia lentis, cataracts, ptosis, and strabismus are less common.
The systemic abnormalities are characterized by a flat midface, progressive hearing loss, cleft palate, Pierre Robin sequence, mitral valve prolapse, and progressive arthropathy with spondyloepiphyseal dysplasia. Although the arthropathy may not be symptomatic initially, children with Stickler syndrome often show radiographic abnormalities of long bones and joints.
Treatment The retinal detachments are often difficult to repair because the patient may have large retinal breaks posteriorly and the incidence of proliferative vitreoretinopathy is high. The incidence of vitreous loss during cataract surgery is high, as is the rate of subsequent retinal detachment. Retinal