CONGENITAL AND GENETIC DISEASE

Congenital and Genetic Disease

COATS’ DISEASE, CONGENITAL RETINAL TELANGIECTASIAS Nonfamilial developmental vascular anomaly with intraand subretinal lipid leakage from telangiectatic vessels. Usually presents with leukocoria or strabismus. Ninety percent of cases are unilateral, and 80% are male patients who are usually otherwise healthy. Bimodal distribution: children (18 months to 10 years) and adult (after age 16, associated with hyperlipidemia). Exam shows dilated retinal arteries and veins with aneurysms that may cause circinate lipid exudation; exudative RD in two thirds of patients, with possible CME. FA shows capillary nonperfusion and ‘‘light bulb’’ microaneurysms. Limited form, called Leber’s miliary aneurysms, is frequently progressive. Treat early with cryotherapy or laser to obliterate leaking vessels in order to stabilize vision and prevent progression. RD usually needs buckle or vitrectomy.

CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM (CHRPE) Flat, black, well-delineated focal RPE hypertrophy present at birth with no malignant potential. Overlying depigmented lacunae may be present. Multifocal variant shows grouped lesions (‘‘bear tracks’’). Pathologically, cells have macromelanosomes (normally, RPE has moderate-size apical melanosomes).

Gardner’s syndrome: multiple, bilateral, variably shaped CHRPE-like pigmented ocular fundus lesions (POFLs) in patients with familial adenomatous polyposis (100% incidence of colon carcinoma by age 50). Patients also have associated benign soft tissue and bony tumors, jaw lesions, and increased risk of thyroid, adrenal, and liver CA. Defect of the adenomatous polyposis coli (APC) gene on chromosome 5q21–22 with a POFL-negative and positive phenotype. Four or more POFLs indicates >90% specific and 70 to 80% sensitive for familial adenomatous polyposis.

CYSTINOSIS Inability of lysosomes to excrete cystine; ranges from benign to nephrotic (renal failure and rickets) severity, with salt and pepper fundus and corneal crystals causing glare and photophobia.

INCONTINENTIA PIGMENTI, BLOCH-SULZBERGER SYNDROME X-linked syndrome at Xp28 in females that has unilateral peripheral retinal degeneration with RD (often presents with leukocoria that may mimic RB), with peripheral capillary nonperfusion, arteriovenous shunts, NV, and isolated cataract. Characteristic ‘‘splashed paint’’ hyperpigmented skin macules with eosinophilic skin infiltration on the trunk and skin erythema, bullae (filled with eosinophils), and verrucae. Patients often have seizure disorder, mental retardation, microcephaly, hydrocephalus, dwarfism, and skull, dental, and palate deformities.

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236 RETINA AND VITREOUS

MUCOPOLYSACCARIDOSES Retinal pigmentary degeneration seen in Hurler’s, Scheie’s, Hunter’s, and Sanfilippo’s syndromes.

NANOPHTHALMOS, UVEAL EFFUSION SYNDROME Characterized by ciliochoroidal detachment, recurrent choroidal effusions, short axial length, hypermetropia, and glaucoma from thickened sclera (disorder of collagen lamellae) that impedes vortex venous outflow. Treat with partial thickness scleral windows near vortex vein exits in at least three or four quadrants. May also develop uveal effusions with scleritis, hypotony, or postsurgically.

PERSISTENT HYPERPLASTIC PRIMARY VITREOUS (PHPV), PERSISTENT FETAL VASCULATURE (PFV) Caused by arrest in development, which causes a unilateral (75%) small eye. Patients often have leukocoria, cataracts (rare with RB), foveal hypoplasia, retinal folds, RD, and ACG. Observe; consider lensectomy for cataract, but may have hemorrhage from patent hyaloid vessel.

Anterior: most common presentation; 90% unilateral, with retrolental plaque of tissue (may be fibrous, adipose, muscle, or cartilage) that pulls ciliary processes centrally. Lens may be resorbed or have intralenticular lipid. Associated with leukocoria, secondary ACG, peripheral RD, microphthalmia, cataract, and microcornea. Nearly half of patients have VA 20/200 or worse.

Posterior: may have features of anterior PHPV plus retinal traction and a nasal retinal fold extending to the periphery, with primary vitreous fibers attached to the retina and potential for RD. Differential diagnosis includes toxocariasis.

PHAKOMATOSES See Chapter 9.

von Hippel-Lindau disease (VHL): retinal capillary hemangiomas, cerebellar hemangioblastoma; 25% of patients have renal cell carcinoma, pheochromocytomas, and pancreatic and renal cysts.

Neurofibromatosis (NF) II: choroidal hamartomas (51%)

Tuberous sclerosis (Bourneville’s syndrome): retinal and brain astrocytic hamartomas (50%)

Sturge-Weber syndrome: choroidal cavernous hemangioma (‘‘tomato catsup’’ fundus)

Wyburn-Mason’s syndrome (racemose hemangioma): direct AV communication

RETINOPATHY OF PREMATURITY (ROP) Ischemic immature retina in premature infants that leads to proliferative vitreoretinopathy. In normal development, the retina does not have blood vessels until 4 months gestation, when they grow in from the ON toward the ora, reaching the nasal retina edge by 8 months and the temporal retina after birth. Delayed vascularization of especially the temporal retina makes it susceptible to NV,

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and coincidental O2 treatment results in vasoconstriction and may compound the ischemia. Differential diagnosis includes FEVR that looks like ROP in an adult.

Risk factors: primary risk is prematurity (especially birth <32 weeks); also <1500 g (25–35% incidence if <1250 g), poor growth, hypoxia, and sepsis.

Examine at 4 to 6 weeks of age if birth weight is <1300 g or <30 weeks’ gestation (recommendation from the American Academy of Pediatrics). If no ROP, examine every 2 weeks; if avascular zone, examine every week; ROP usually appears at a median conceptive age of 37 weeks. Describe stage, zone, clock hours, and the presence of Plus disease or not.

Stages of ROP: 85% of Stage 1 and 2 ROP cases regress spontaneously, and only 6% overall reach threshold. Plus disease is dilated tortuous vessels in the posterior pole from AV shunting, poor iris dilation from vessel engorgement and rigidity, and vitreous haze (‘‘Rush’’ disease).

Stage 1: thin white line, demarcating mature and immature retina.

Stage 2: wide white line, which is ridge of dilated elevated vessels that do not leak.

Stage 3: ridge with neovascular vessels and crossing of this ‘‘ragged ridge’’ shunt area by retinal vessels.

Stage 4: tractional detachment. Stage 4a if extrafoveal or stage 4b if macula is involved.

Stage 5: funnel RD (10% will recover fix-and-follow visual acuity [F/F]).

Zones of ROP: anatomic zones are centered on the disk.

Zone I: posterior pole, radius 2 disk to fovea (6 mm); more posterior ROP has worse prognosis.

Zone II: peripherally from zone I, with radius from disk to nasal ora (cryo-ROP study: a multicenter, randomized prospective trial that studied cryotherapy retinal ablation for ROP; found that cryo-ROP study was a zone II study).

Zone III: remaining temporal crescent; most common zone for ROP.

Treatment: observe prethreshold disease (only 8% progress).

Threshold disease: 5 continuous or 8 cumulative clock hours of stage 3 disease (mnemonic: 3 þ 5 ¼ 8) in zone I or II with Plus disease. Treat as soon as detected: obliterate the immature retina with cryotherapy or laser. Apply laser with hot, white, confluent burns anterior to the ridge (use a 28 D lens to get 400 mm spot size).

Reexamine 10 days after laser to look for decreased Plus and vessels growing into the avascular retina. Zone I follow-up 1 week, zone II follow-up 2 weeks. Follow patient until maturation is complete to the ora.

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238RETINA AND VITREOUS

Usually treat stage 4a with lens-sparing vitrectomy, and stage 4b and possibly stage 5 with vitrectomy with or without a buckle.

Cryo-ROP study: cryotherapy to all areas of nonperfused retina in eyes with threshold disease caused 50% decrease in progression and unfavorable outcomes (22% treated vs. 42% untreated).

Treatment was cryotherapy for all retina anterior to ridge with contiguous freezes in two or three rows for 360 degrees at 55 C. However, both groups had about the same VA at 5 years (mainly from amblyopia).

Goal of treatment is anatomic success, but for visual success, patients will need lifelong care.

Complications: strabismus, pseudoexotropia (macular dragging, positive angle kappa), retinal fold in macula, progressive myopia in 80% (axial myopia and from forward movement of the lens–iris diaphragm), anisometropia, amblyopia, nystagmus, angle-closure glaucoma (usually at age 10 to 20), RD (may be late-onset), and cataract from laser treatment.

SPHINGOLIPIDOSES Most cause cherry red spot. See Chapter 9.

Hereditary Macular Disorders

BEST’S VITELLIFORM MACULAR DYSTROPHY Autosomal dominant juvenile macular dystrophy that develops about age 4 to 10 years. Defect found on bestrophin gene on chromosome 11q13 that codes for a protein expressed solely in the RPE. Early on, the fundus is normal (previtelliform stage) but the EOG is abnormal. EOG diagnostically shows a diminished light peak (Lp) to dark trough (Dt) ratio <1.5 in affected patients, asymptomatic patients with normal fundi, and asymptomatic carriers. The ERG is normal. Ultimately, the VA is usually 20/100 or worse with no good treatment available.

Stage 1: subretinal, lipofuscin-like pigment collects in RPE cells and clinically looks like ‘‘egg yolk’’ yellow material in the macula; usually 1–5 DD in size, with good VA.

Stage 2: ‘‘yolk’’ breaks up and may have macular ‘‘pseudohypopyon.’’

Stage 3: slowly progresses to atrophy and looks like ‘‘scrambled egg.’’

Stage 4: AMD-like scarring and severe central loss of vision from subretinal hemorrhage or NV; serous detachment may occur.

CENTRAL AREOLAR CHOROIDAL DYSTROPHY (CACD) Autosomal dominant circular RPE and choriocapillaris atrophy in third decade with mild

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central vision loss, slow progression, and poor visual prognosis. FA may show zonal choriocapillaris defect. Chromosome 6q defect.

CENTRAL AREOLAR PIGMENT EPITHELIAL DYSTROPHY (CAPE) Autosomal dominant, fine, modeled depigmentation of the fovea in the first decade with good prognosis.

CONE DYSTROPHY Spectrum with rod dystrophies (RP) with early onset cone dysfunction and slowly progressive decreased central VA, photophobia, and defective color vision. Early on, the fundus is normal but later shows a bull’s-eye maculopathy, diffuse pigment stippling, and temporal optic nerve atrophy. Often patients later develop rod disease but rarely lose peripheral vision and are not night blind. Usually presents in the first or second decade. Characterized by abnormal photopic ERG with decreased single-flash and flicker and reduced flicker fusion frequency. Ultimately VA is about 20/60–400 and symmetric OU. Most cases are sporadic but when familial are autosomal dominant or X-linked.

DOMINANT DRUSEN, DOYNE’S HONEYCOMB RETINAL DYSTROPHY, MALATTIA LEVENTINESE, FAMILIAL DRUSEN Autosomal dominant chromosome 2p16–21 defect with early (age <55 years) numerous cuticular drusen nasal to disk, atrophy, and linear drusen (especially in ML, where the linear drusen are more peripheral). CNVM is common, and most patients are legally blind by age 70. Has a normal ERG but abnormal EOG. Defect in epidermal growth factor (EGF)–containing fibrillin-like extracellular matrix protein-1.

JUVENILE X-LINKED RETINOSCHISIS (JXLR) Vitreoretinal dystrophy from defective X-linked gene XLRS1 with high penetrance. Presents early in life with parafoveal spokewheel-like radiating retinal folds that progress to macular intraretinal cysts and foveal bullous schisis cavities in the NFL. (In contrast, senile retinoschisis is cleavage of the outer plexiform layer.) Macular degeneration is present in 95% of cases; VH may result from an exposed retinal vessel as the NFL is obliterated. Outer layer holes may lead to RRD; also may have liquefied vitreous, traction bands, and PVD. Fifty percent of patients have peripheral schisis and 100% have foveal schisis. CME shows no leakage on FA. ERG has reduced photopic and scotopic B wave (Mu¨ller cell pathology, which causes the NFL schisis) in proportion to the area of schisis with an intact A wave because the photoreceptors are unaffected. Some cases have Mizuo-Nakamura phenomenon (golden yellow sheen when light adapted but disappears when dark adapted), as in Oguchi’s disease. Typically, VA is reduced to 20/50–100 or worse.

PATTERN DYSTROPHY RPE dystrophy with yellow-orange deposits under the RPE in a variety of ‘‘patterns’’; patients are usually asymptomatic or have mildly decreased VA or metamorphopsia. Pathology shows hyperplastic

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