X-linked juvenile retinoschisis

DEFINITION/OVERVIEW

X-linked juvenile retinoschisis (XLRS) is an inherited disorder that causes abnormal splitting (schisis) of retinal layers within the macula at a young age. This separation of the retinal layers causes an absolute scotoma in the involved area, which in most cases causes significant visual impairment. The disease occurs mostly in young male patients, and is said to be the most common macular degenerative disease in that population. The incidence of XLRS is approximately 1 in 15,000–30,000.19

ETIOLOGY

The RS1 gene, which codes for a protein known as retinoschisin, is located on chromosome Xp22.1. Retinoschisin has been demonstrated to be involved in secretory pathways that are involved in retinal cell adhesion, which may be important in retinal differentiation and development. The details of how retinoschisin helps to maintain retinal architecture are not yet understood; however, interactions with specific intracellular proteins, beta-2-laminin and alpha-B-crystallin, are currently being examined.

XLRS is a congenital dysfunction of the retinal cell architecture which allows the inner retinal layers (inner limiting membrane, nerve fiber layer, Muller’s cell fragments, and some blood vessels) to separate from the remainder of the underlying retina. Pathologic studies have shown thinning of the ganglion cell layer and degeneration of the photoreceptor layers. The schisis that occurs results in a cavity within the retina and an elevation of the inner layer. While many patients (50%) show peripheral (most commonly inferotemporal) involvement, the vast majority of patients show schisis cavities which involve the fovea (96–100%). An X- linked inheritance pattern can often be demonstrated on review of the family history. AR and AD patterns have also been reported in the literature.

CLINICAL PRESENTATION

The age of onset and presenting features of XLRS can be quite varied. XLRS is a congenital disorder, and has been seen in infants as young as 3 months. This may be discovered by a diminished red reflex from hemorrhage resulting from the schisis, or by strabismus. It may also present in children of school age, who are noted to develop decreased vision over a period of days to weeks. Patients often retain good vision until the 4th decade of life, but final visual acuity in most patients ranges from 20/60–20/200.

On funduscopic examination, the inner layer of the retina is visibly elevated and a clear dry schisis cavity is seen within the macula, involving the fovea (foveal schisis) (182, 183). Large peripheral retinoschisis cavities may also be present in infancy, but these often regress over time, leaving pigmented lines that are seen in adulthood.

Because the inner retinal layers contain blood vessels, vitreous hemorrhage is a common occurrence, seen in 30% of patients. In rare cases, the vitreous may contract due to the presence of resorbing blood, and cause traction on the retina. Such complications have presented as a white pupillary reflex (leukocoria) and raised concern for disease such as retinoblastoma and cataracts. Full thickness retinal detachment may later occur in 20% of older patients, due to degeneration of the inner and outer layers of the retina, which creates a full thickness retinal hole.

DIFFERENTIAL DIAGNOSIS

An important distinction between cystic lesions involving the fovea is that of a dry schisis cavity (no fluid) or a wet schisis cavity (containing serous fluid, blood, exudate, deposits). This distinction is simple when the intervening fluid is colored, but may be difficult to visualize if clear serous fluid is present. Dry foveal retinoschisis may occur in RP, a relatively common rod-cone dystrophy, and other rare diseases such as Goldmann–Favre disease and niacin-induced cystic maculopathy.

Wet foveal retinoschisis is seen in a variety of diseases that are rare in children and rarer still in infants. These include central serous chorioretinopathy, central retinal vein occlusion, diabetic maculopathy, uveitis, infectious retinopathies, and AD cystoid

macular edema. Each of these conditions has other characteristic findings that help differentiate them from XLRS.

DIAGNOSIS

XLRS is best diagnosed in infants with indirect ophthalmoscopy, which allows for direct visual examination of the retina. In older children, newer modalities such as optical coherence tomography (OCT) can demonstrate the dry cystic nature of the cavity.

ERG typically shows a reduced amplitude of the b-wave (bipolar cell activation), which indicates lack of communication between the inner and outer retinal layers. However, some studies have shown remarkably normal responses in patients with limited retinal involvement (due to the localized nature of foveal schisis).

MANAGEMENT/TREATMENT AND PROGNOSIS

XLRS is a genetic disorder with remarkably variable phenotypic expression, therefore educating patients about the disease process and progression is an important aspect of proper management. The complications of vitreous hemorrhage, vitreoretinal traction, and retinal detachment may be treated surgically if indicated. Advances in cell research and gene replacement therapy have given hope to the idea of replacing the defective retinoschisin gene. These studies have been in animal phase testing only as of 2007.

XLRS often stabilizes and allows for good visual acuity until the 4th decade of life. The rate of progression and severity of vision loss may vary tremendously even amongst family members with the same mutation.

182

182 X-linked retinoschisis:retinal photograph showing a subtle finding of retinoschisis in the right eye.Note the light reflexes (arrowheads) to the right of the fovea which form a radial pattern,suggesting a focal circular elevation of the inner layers of the retina.

183

183 X-linked retinoschisis: retinal photograph showing a subtle finding of retinoschisis in the left eye. Note the light reflexes (arrowhead) that encircle the fovea,suggesting a focal circular elevation of the inner layers of the retina involving the entire fovea.This finding was seen in both eyes of this patient.

Albinism

DEFINITION/OVERVIEW

Albinsim is a well described condition of melanin or melanocyte deficiency that causes hypopigmentation of affected structures. This condition may affect both the skin and eyes (oculocutaneous albinism) or only the eyes (ocular albinism). When the skin is involved, the diagnosis is fairly evident in most cases, but ocular albinism without skin involvement may be subtle and difficult to diagnose in a young infant.

ETIOLOGY

All forms of oculocutaneous albinism are AR inherited, with variable phenotypic expression. Oculocutaneous albinism has been linked to four known genes: OCA1, OCA2, OCA3, and OCA4.20 Ocular albinism is an X-linked disorder that has been linked to OA1. The activity of the enzyme tyrosinase appears to be involved in the metabolism of melanin, and its presence within the hair bulb of affected patients has been used to categorize subtypes of albinism (tyrosinase positive vs. tyrosinase negative). Since the isolation of the human tyrosinase gene in 1987, over 100 mutations in the gene have been discovered.

The decreased pigmentation of skin and ocular structures in oculocutaneous albinism is the result of a decreased production of melanin within normal melanocytes. In contrast, ocular albinism is thought to be due to a decreased number of melanocytes within ocular structures; however, giant melanocytes have been seen on histopathologic studies.

CLINICAL PRESENTATION

Patients with oculocutaneous albinism often have significant hypopigmentation of their skin, hair, and eyes, relative to their family members. Patients without skin involvement may simply present with signs of poor vision such as visual inattention or congenital nystagmus in infancy. The effect of oculocutaneous and ocular albinism on visual acuity is highly varied and may range from 20/30–20/200. On slit-lamp examination, the iris may be lightly pigmented (blue, gray, or pink) or of darker shades but show reflections of light on retroillumination (iris transillumination defects) (184).

184

184 Ocular albinism:retinal photograph of a patient with ocular albinism showing the extensive network of underlying choroidal blood vessels (arrowheads) that are easily seen because of absent retinal pigmentation (RPE).

The other important ocular findings associated with albinism include iris transillumination, foveal hypoplasia, nystagmus, strabismus, amblyopia, and increased crossing (decussation) of optic nerve fibers (185). Iris hypoplasia is caused by decreased melanocytes within the pigmented epithelium of the iris. The term foveal hypoplasia describes a limited development and differentiation of the foveal retinal cell layers, which may be caused by poor metabolic function of the retinal pigment epithelium that underlies the fovea. Nystagmus and strabismus are linked to poor vision in infants, but may also be the result of abnormal visual pathways within the cerebral cortex.21 Amblyopia is frequently due to strabismus in albinism.

DIAGNOSIS

Both oculocutaneous albinism and ocular albinism may be diagnosed with clinical findings on dermatologic and ophthalmologic examination if several classic features of hypopigmentation are present. When the diagnosis is less evident, ancillary testing including genetic evaluation for OCA genes 1–4 or OA1 may be helpful. Increased crossing of optic nerve fibers is an interesting and

185

185 Ocular albinism:retinal photograph showing foveal hypoplasia. The lack of a foveal light reflex and absent foveal pigmentation (arrowheads) are suggestive of an underdeveloped central macula, which clinically results in poor central vision and subsequent sensory nystagmus.

potentially useful diagnostic feature in subtle phenotypic expressions of albinism. VEP may be helpful in discerning the percentage of nerve fibers that cross within the chiasm, and aid in the diagnosis of ocular albinsim.

Two important and potentially life-threaten- ing systemic conditions are well associated with albinism, and should be evaluated in every patient with the oculocutaneous form of albinism. Hermansky–Pudlak syndrome is characterized by platelet dysfunction and bleeding diathesis. Chediak–Higashi syndrome is an immunodeficiency disorder that predisposes patients to certain bacterial infections.

MANAGEMENT/TREATMENT AND PROGNOSIS

There are no known treatments that improve the vision in patients with albinism. Sunglasses and brimmed hats may help with photophobic symptoms. An important intervention that can be very helpful for patients with albinism and their families is low-vision therapy and social services referrals for the blind if vision is as low as 20/200.

Vision remains stable in patients with albinism. Many children will develop strabismus.

Retinal dystrophies with systemic disorders (ciliopathies)

DEFINITION/OVERVIEW

Many of the retinal dystrophies that have been described over the past decades have recently been linked by new genetic discoveries. Many of these diseases also have systemic disorders, which result from the same genetic mutation that causes the retinopathy. The theory of dysfunctional cilia (ciliopathies) within the retinal photoreceptors and other structures has moved to the forefront of hypotheses that unify these many diseases.

The conditions that have been described as ciliopathies include Bardet–Biedl syndrome, Laurence–Moon syndrome, RP, macular degeneration, cone-dystrophy, cone-rod dystrophy, LCA, Usher syndrome, primary ciliary dyskinesia, Senior–Loken syndrome, Joubert syndrome, McKusick–Kaufman syndrome, and Biemond syndrome. Other syndromes that may be due to ciliopathies are Alstrom, Edwards–Sethi, Ellis–van Creveld, Jeune, Meckel–Gruber, orofaciodigital Type 9, and Gurrieri syndromes.22

ETIOLOGY

The concept of ciliopathies originated from the observation that patients with RP and Usher syndrome were found also to have ciliary disorders causing motility abnormalities within their spermatozoa. It is known that the retinal photoreceptors also have cilia that connect their outer and inner segments. The cilia in both the spermatozoa and photoreceptors are similar in ultrastructure, with microtubules of alphaand beta-tubulin dimers in a 9+0 (nonmotile) or a 9+2 (motile) configuration. Further investigation revealed that almost all cells within the human body contain cilia (rare exceptions include bone marrow-derived cells and kidney collecting duct cells).

CLINICAL PRESENTATION

The most common diseases of retinal dystrophy with systemic findings include RP and its many variants (Usher, Senior–Loken, and Joubert syndromes), Bardet–Biedl syndrome, and Laurence–Moon syndrome, and present with characteristic clinical findings.

186

186 Ciliopathies: peripheral retinal photograph of the right eye of a patient with Bardet–Biedl syndrome.Note the pale optic nerve head, attenuated retinal vessels (both arterioles and venules are significantly narrowed) and the peripheral pigmentary changes seen here superiorly.

187

187 Ciliopathies: central retinal photograph of the right eye of a patient with Bardet–Biedl syndrome. Note the pale optic nerve head and mottled pigmentary changes in the central macula.

The ophthalmologic examination may reveal optic nerve pallor, foveal hypoplasia, and pigment changes in the peripheral retina (186, 187).

DIFFERENTIAL DIAGNOSIS

Many of the ciliopathies initially present with poor visual acuity and minimal retinal changes in infancy. They therefore should be differentiated from other retinal diseases with limited funduscopic anomalies such as LCA, achromatopsia, and CSNB. An extensive evaluation of other organ systemics and a genetic evaluation often reveal a constellation of findings which corresponds to known syndromes.

DIAGNOSIS

The diagnosis of retinal dystrophies with systemic findings relies heavily on medical evaluations for other organ dysfunction. Patients with poor vision in infancy should undergo exhaustive investigations for other anomalies, specifically kidney disease, cerebellar and cerebral abnormalities, and neurosensory hearing loss.

MANAGEMENT/TREATMENT AND PROGNOSIS

The treatment of RP may include high-dose vitamin A or dietary restrictions of arginine (Refsum disease) and this topic is discussed in Chapter 8. Other ciliopathies including Bardet–Biedl syndrome, Laurence–Moon syndrome, RP, macular degeneration, conedystrophy, cone-rod dystrophy, LCA, Usher syndrome, primary ciliary dyskinesia, Senior–Loken syndrome, and Joubert syndrome may have treatments and dietary restrictions that may limit dysfunction of the affected systems such as the kidneys and liver. There are no known treatments that improve the vision in patients with retinopathy and vision loss. An important intervention that can be very helpful for patients with these retinal dystrophies and their families is low-vision therapy and social services referrals for the blind if vision falls below 20/200.

Many of the conditions will behave like RP with progressive loss of vision.