Rudolph's Pediatrics, 22nd Ed.

CHAPTER 592. Genetic Eye Diseases

J. Bronwyn Bateman, John Roarty, Christina L. Butera, and Alex V. Levin

The development of techniques for identifying the genetic bases for disease has resulted in an increase in the understanding of eye diseases. The prevalence of genetic disease as a basis for significant visual loss is uncertain and dependent on the population, health care resources, and cultural values. Genetic factors may influence normal, stable development of the eye but may cause a progressive deterioration over time. Although a specific mutation of a gene may result in a consistent phenotype, variation is common and may reflect the effect of other genes or environmental factors. Complex diseases, such as myopia and strabismus, probably have both genetic and environmental bases. Population-based studies may be influenced by ascertainment bias, inconsistent data collection, or cultural factors. Autosomal recessive disorders are more common in consanguineous cultures such as occur in the Middle East or Asia. Other disorders, such as the group of diseases called retinitis pigmentosa, have a more uniform geographic prevalence rate of 20 to 40 per 100,000 worldwide. With the completion of the Human Genome Project ( and the rapid development of improved analytical tools, a new understanding of the genetic bases of eye diseases offers the hope of understanding causes and identifying cures.

Some ocular diseases are caused by mutations of genes that are expressed primarily or exclusively in the eye. Other disorders are multisystemic.1 A genetic basis should be identified for visual loss or malformations that are not attributable to infections or trauma to optimize both treatment of the patient and counseling of the family. The evaluation should be initiated with a careful family history and pedigree. The parents should be queried about consanguinity. It is helpful to identify the anomalies commonly encountered in genetic eye diseases and syndromes (eg, kidney abnormalities and general dysmorphic features such as abnormal interpupillary distance, epicanthal folds, and palpebral fissure slant). The ophthalmologist increasingly depends on the primary care physician to make an accurate diagnosis, and the primary care physician/geneticist depends upon the ophthalmologist for information that may be helpful in rendering a diagnosis and prognosis. Consultation with a geneticist for many conditions is wise.

This chapter will deal with some genetic diseases of the eye. Cataract, glaucoma, and corneal diseases often have a genetic basis and are discussed in Chapter 590, as are those multisystem genetic disorders that have ocular manifestations (eg, neurofibromatosis).


Major structural anomalies occur in 2% to 3% of all newborns, and minor anomalies occur in 15%.2 The eye begins as a groove in the forebrain at 22 days gestation. Histologically, the lens placode is seen by 4 weeks with a lens vesicle in the optic cups by 5 weeks. The groove on the ventral surface of the optic cup closes by 7 weeks, closing the optic nerve and completing the pupil. A major regulatory gene for eye development is PAX6 (paired box gene 6), a transcription factor; other important regulatory genes are the PAX2 (paired box gene 2) and SHH (sonic hedgehog) genes. Multiple gene products function in pathways downstream of each of these genes.2 Mutations in these and other genes can lead to eye disease.


Most chromosomal disorders are associated with abnormal eye findings, and virtually all involve other organ systems. Infants with chromosomal disorders often have multiple congenital anomalies, growth retardation, and developmental delay in addition to the ocular abnormalities. All microscopically identifiable chromosomal deletions, duplications, or aneuploidies (disorders of chromosomal numbers) are associated with some element of mental retardation, with the exception of some X-chromosomal anomalies. The ocular manifestations of chromosomal aberrations are numerous, varied, and beyond the scope of this chapter.3 Some examples of eye findings in chromosomal aberrations are listed in Table 592-1.


Monogenic disorders are caused by a mutation in a single gene. Some syndromes can be caused by mutations in more than one gene (genetic heterogeneity), each resulting in a similar syndromic phenotype, and may have variable inheritance patterns. Increasingly, known genes can be sequenced if the clinical diagnosis suggests a particular disease, thus allowing for a molecular diagnosis. Table 592-2 lists eye findings for many syndromic disorders. Table 592-3 provides a list of eye findings for metabolic disorders that share a similar genetic pathogenesis as the syndromes. For further discussion of inborn errors of metabolism such as the mucopolysaccharidoses, sphingolipidoses, and mucolipidoses, refer to Section 11.



Microphthalmia is a small eye (as differentiated from isolated microcornea). Anophthalmia refers to the complete absence of the eye; true anophthalmia is rare and can be confirmed only after the contents of the orbit have been examined histologically. Anophthalmia results when the optic vesicle fails to form. Primary anophthalmia may occur in an otherwise normal child or in association with a multisystem disorder such as trisomy 13, deletion of the short arm of chromosome 18, or other cerebral maldevelopment disorders. Isolated anophthalmia usually occurs sporadically and may be due to autosomal dominant, autosomal recessive, and X-linked recessive mutations.


The term aniridia is a misnomer, because a small stump of iris tissue is almost always present; the disorder is rarely limited to the iris malformation (Fig. 592-1). As with most autosomal dominant disorders, expression can be extremely variable even within a family. Nystagmus (wandering or shaking eye movements), cataracts, ectopia lentis (dislocated lens), glaucoma, macular hypoplasia, optic nerve hypoplasia, and retinal dystrophy also may occur. The corneal epithelial stem cells may be abnormal, resulting in progressive vascularization of the cornea (pannus), which is associated with an increased risk of transplant rejection. Studies with stem cell transplantation and autologous serum eyedrops are ongoing. Lubrication with artificial tear preparations also may be helpful.

The “sporadic” form accounts for one third of all cases and may be associated with a deletion of the short arm of 11p13. This region includes the PAX6 and Wilms tumor genes (WT1), and absence of the intervening genes may result in genitourinary anomalies and mental retardation (WAGR syndrome—Wilms tumor; aniridia; genitourinary anomalies, usually tumors of the gonads; and mental retardation). Glaucoma frequently develops before adolescence in approximately 50% of patients. Visually significant cataracts are common. About 30% of patients with the chromosomal deletion form of aniridia develop a Wilms tumor before 3 years of age; this cancer is diagnosed before age 5 years in 80% of cases. Conversely, less than 2% of patients with Wilms tumor have aniridia. All patients with sporadic aniridia should have a karyotype, including assessment for a microdeletion using FISH or other molecular genetics techniques. Renal ultrasound study should be performed every 3 to 6 months to assess the possibility of Wilms tumor in all infants/children with sporadic aniridia, and every 3 months in those with deletions of chromosome 11.

Table 592-1. Chromosomal Aberrations and Their Eye Deformities

Two thirds of aniridia cases are familial, caused by mutations in the PAX6 gene and exhibit an autosomal dominant mode of transmission. Aniridia has not been reported in families with autosomal dominant Wilms tumor.

Table 592-2. Ocular Findings in Multisystem Syndromes

A rare autosomal recessive form of aniridia (Gillespie syndrome) has a different iris appearance and is associated with other systemic abnormalities not seen in typical dominant aniridia.

Table 592-3. Systemic Disease Associations with Retinitis Pigmentosa

Autosomal Dominant

Alagille syndrome (arteriohepatic dysplasia)

Charcot-Marie-Tooth disease

Flynn-Aird syndrome

Oculodentodigital dysplasia syndrome

Olivopontocerebellar atrophy

Paget disease

Pierre Robin syndrome

Steinert disease (myotonic dystrophy)

Stickler syndrome

Waardenburg syndrome

Wagner disease

Autosomal Recessive

Albers-Schönberg disease (osteoporosis)

Alström disease

Bardet-Biedl syndrome

Bassen Kornzweig disease (abetalipoproteinemia)

Batten disease

Cockayne syndrome

Friedreich ataxia

Grönblad-Strandberg syndrome

Hallgren syndrome


Hurler syndrome (MPS 1-H)

Jeune syndrome

Juvenile Paget disease (hyperostosis corticalis deformans juvenilis)

Kearns-Sayre syndrome


Marinesco-Sjögren syndrome

Refsum disease

Sanfilippo syndrome (MPS III)

Scheie syndrome (MPS 1-S)

Usher syndrome

Wolfram syndrome

Zellweger syndrome (cerebrohepatorenal syndrome)


Bloch-Sulzberger syndrome (incontinentia pigmenti)

Hunter syndrome (MPS II)

Pelizaeus-Meizbacher disease


Retinitis pigmentosa is a general term for a group of hereditary retinal degenerative diseases and, depending on the author, may include all genetic forms of retinal dystrophies/degenerations.

Nyctalopia is the term describing reduced visual function under low lighting conditions. The rod cells of the retina primarily influence peripheral and night vision, and the cone cells are responsible for central vision (20/20 to 20/200) under lighted conditions; the fovea is a specific portion of the macula that is rich in cones and is the retinal region for sharpest vision. Thus, a disease that is primarily in the rods will be characterized by greater symptoms under low lighting conditions and an abnormal electroretinogram under darkened (dark-adapted) conditions. A disease that is primarily in the cones will produce decreased central visual acuity and be associated with an abnormal electroretinogram under lighted conditions. Isolated disease of the rod cells ultimately may cause cone degeneration and visa versa.

FIGURE 592-1. Aniridia. Red reflex test fails to reveal the iris. Arrows indicate edges of natural lens, which is slightly off center (ectopia lentis). The tiny peripheral stub of residual iris is not visible in this view.

Retinitis Pigmentosa

FIGURE 592-2. Typical fundus appearance in retinitis pigmentosa. Note the “waxy pallor” of the optic nerve, vascular attenuation, and bone-spicule-like pigmentary clumping.

Classically, retinitis pigmentosa is characterized by progressive visual field loss, nyctalopia, and pigmentary retinopathy; on laboratory testing, a depressed or nonrecordable electroretinogram and delayed dark adaptation are evident. The typical, late-stage fundus appearance consists of optic atrophy, retinal blood vessel attenuation, and “bone-spicule” pigmentary clumping (Fig. 592-2). Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked recessive, with some proportional variation based on geography. Mutations in over 30 genes, with different functions, have been implicated in causing classic retinitis pigmentosa. Almost 150 genes have been identified for retinal diseases. The Web site is an excellent, up-to-date source for genes and mapped loci that cause retinal diseases. Approximately half of all affected individuals have no family history of the disease. Although early-onset forms do occur, most patients are not severely handicapped until adulthood. Autosomal recessive and X-linked forms tend to present at an earlier age than the autosomal dominant forms. Affected individuals should be screened regularly for ocular complications such as cataracts and edema of the macular region.

Retinitis pigmentosa may be limited to the eyes, or it may be associated with additional organ system involvement such as congenital hearing loss in Usher syndrome. Retinitis pigmentosa also may be part of mitochondrial diseases.

Nongenetic conditions may produce a pigmentary disturbance of the retina similar to retinitis pigmentosa; these include metastatic cancer, intrauterine and perinatal infections (syphilis, rubella, cytomegalic inclusion disease, influenza), and drug toxicity (phenothiazines, chloroquine). Most are not progressive and the electroretinogram is normal.

Congenital Stationary Night Blindness (CSNB)

Congenital stationary night blindness is characterized by nyctalopia (night blindness) that is evident in infancy. This genetically heterogeneous disorder may be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. The group of diseases underscores the variability of clinical features of different mutations of a specific gene. For example, an autosomal dominant form may be caused by mutations of the rhodopsin (RHO) gene that more commonly causes classic retinitis pigmentosa. Another autosomal dominant form is caused by mutations of the phosphodiesterase 6B, cGMP-specific, rod receptor, beta specific (PDE6B gene) that also causes retinitis pigmentosa. The autosomal recessive forms may be caused by mutations of the glutamate receptor metabotropic-6 (GRM6) and the calcium-binding protein-4 (CABP4) genes. The X-linked recessive varieties may be caused by mutations of the nyctalopin (NYZ) or the retina-specific calcium channel alpha-1-subunit (CACNA1F) genes. Oguchi disease, an autosomal recessive disorder, has similar symptoms and is caused by mutations of the arrestin (SAG) gene.

Visual acuity is relatively good in the autosomal dominant forms but may be subnormal in the recessive and X-linked forms. Variable degrees of myopia with associated degenerative retinochoroidal changes may be detected. The clinical features of the disease may be progressive, especially in older adulthood. The X-linked form may be associated with visual acuities ranging from 20/25 to 20/400. Diagnosis is usually based on an electroretinogram.

Stargardt Disease and Fundus Flavimaculatus

Degenerative genetic disorders affecting primarily the central retina are referred to as macular dystrophies. These diseases are rare, with an estimated prevalence of 1:10,000. The most common form is Stargardt disease, which is usually transmitted as an autosomal recessive disorder. Autosomal dominant transmission may also occur. The genes that, when mutated, most often cause autosomal recessive Stargardt disease are ABCA4 (ATP-binding cassette, subfamily A, member 4) and ELOVL4 (elongation of very-long-chain fatty acid-like 4).

The disease is characterized by a bilateral, relatively symmetrical, progressive loss of central visual acuity, usually occurring between the ages of 6 and 20 years. Generally, the reduced vision antedates and is out of proportion to the initial ophthalmoscopic changes. Progressive atrophy of the macula is heralded by loss of the normal macular reflex and development of a “beaten bronze” appearance. Multiple pisciform (fish-shaped), yellowish subretinal flecks usually develop in the macular region (Fig. 592-3) and, in the variant fundus flavimaculatus, throughout the retina. Vision often decreases to legal blindness, which is 20/200 or less. Total loss of vision is rare, and night blindness (nyctalopia) is not a characteristic feature. The electroretinogram is typically normal but may be variably depressed. A dark choroid (hypofluorescence caused by the blockage of the normal choroidal fluorescence) may be noted on fluorescein angiography and is helpful diagnostically. This sign is not seen in other genetic retinal diseases, which have subretinal flecks such as fundus albipunctatus, retinitis punctata albescens, Kandori fleck retina, and vitamin A deficiency.

Cone Dystrophy

In contrast to classic retinitis pigmentosa, cone dystrophy is usually characterized by reduced central visual acuity, initially without changes in the rod system. The mode of inheritance may be autosomal dominant, autosomal recessive, or X-linked recessive. Complaints of poor visual acuity, poor color vision, and photophobia (sensitivity to light) usually occur late in childhood or early adulthood. Ophthalmoscopic findings of the macula are variable and may include a normal appearance, a mottled pattern, “bull’s-eye” atrophy (ringlike pigmentary changes around the foveal area), or localized atrophy. The electroretinogram shows a normal scotopic (dark-adapted, rod) response but an absent or severely depressed photopic (light adapted, cone) response. Over time, rod involvement may lead to a diagnosis of cone-rod dystrophy. Relief of photophobia may be achieved by Corning sunglasses or colored contact lenses.

If the rods eventually become involved, the disorder is termed a cone-rod dystrophy. There are autosomal recessive, autosomal dominant, and X-linked recessive forms of this condition.


Achromatopsia, also known as rod monochromatism, is a rare (3 in 100,000) autosomal recessive condition characterized by severe color blindness and photophobia with markedly decreased vision due to dysfunction of cone cells in the retina. Symptoms usually become apparent in infancy with the development of nystagmus. Vision is better in dim illumination. The condition is generally not progressive, and there are no associated neurological abnormalities. The fundus is typically normal in appearance but may include an abnormality, or the absence of, the foveal light reflex. The cone electroretinogram is markedly abnormal, whereas the rod waveforms are normal.

Vitelliform Dystrophy (Best Disease)

FIGURE 592-3. Stargardt disease. Note tiny yellow flecks throughout macula.

Best disease is usually an autosomal dominant dystrophy of the macula. An autosomal recessive form also has been documented. Variable penetrance and expressivity is common. Onset is typically between 3 and 15 years of age. In the early stage, Best disease is usually characterized by bilateral, symmetric, well-defined, round “egg yolk” (vitelliform) lesions in the maculae (Fig. 592-4). In most cases, visual acuity is initially good despite the distinctly abnormal retinal appearance. An atypical form with multifocal vitelliform lesions may occur. The homogeneous, yellow appearance of the macular lesions may “layer out” and fragment with time, ultimately leaving a mottled scrambled egg appearance that may simulate other types of macular degeneration. Although there usually is loss of visual acuity, the long-term visual prognosis is good, with 20/40 vision in at least one eye through age 50 years. The electroretinogram is normal, but the electro-oculogram is abnormal and confirms the diagnosis. Some affected individuals are clinically unaffected but also have an abnormal electro-oculogram. The abnormal gene (BEST1VND2) produces the protein bestrophin 1, a transmembrane protein of the retinal pigment epithelium involved in chloride transport.

Leber Congenital Amaurosis (LCA)

This retinal dystrophy presents early in infancy with nystagmus and is responsible for an estimated 10% to 18% of all infantile visual impairment. Visual acuity ranges from 20/80 to no perception of light. Other features include high hyperopia (farsightedness); keratoconus; and, rarely, cataracts. Oculodigital phenomenon (eg, self-stimulation by digital poking of the eye) is common. The fundus presentation varies from a normal appearance to macular coloboma (similar in appearance to a toxoplasmosis scar) or classic retinal degenerative changes of retinitis pigmentosa (see above). The clinical presentation may include a multisystem disease with associated neurological findings, including progressive loss of milestones and renal abnormalities. The electroretinogram is nonrecordable early in life and is essential for the diagnosis.

FIGURE 592-4. Best disease. Dark vertical line indicates central macular yellowish “egg yolk” lesion seen in the first stage of this disorder.

Leber congenital amaurosis usually is inherited in an autosomal recessive fashion. Mutations of multiple genes, which disrupt several key retinal pathways, have been identified ( Studies of gene therapy in the forms caused by mutations of RPE65 (retinal pigment epithelium-specific protein, 65-KD) have been initiated in humans.


Norrie Disease

Norrie disease is a rare, X-linked recessive, devastating disease that affects only males. Intrauterine or infantile retinal detachment, sometimes described by the term retinal dysplasia, is usually identified by the presence of leukocoria (white pupil) or nystagmus. Typically bilateral, the abnormality is a congenital or infantile detachment or nonattachment (ie, dysplastic retina) of the retina with secondary retinal scarring. There also may be associated shallow anterior chamber, microphthalmia, or glaucoma (with enlarged eye). Over time, corneal opacities or cataract develop, and the eyes atrophy (phthisis). Delayed development and sensorineural deafness also develop. The Norrie disease gene (NDP) encodes the protein norrin.

Familial Exudative Vitreoretinopathy (Familial Vitreoretinal Dysplasia)

Familial exudative vitreoretinopathy (FEVR) is similar to Norrie disease but is not associated with deafness or delayed development. X-linked recessive, autosomal dominant, or autosomal recessive patterns of inheritance have been documented. Typically, the affected infant has bilateral visual impairment with nystagmus. Abnormalities of the temporal retina or incomplete retinal vascularization may result in dragging of the retina and subsequent retinal detachment. Mutations in the Norrie disease gene (NDP) also may cause the clinical features of X-linked FEVR. An autosomal dominant form may be caused by mutations of the frizzled-4 gene (FZX4), a transmembrane receptor. Both autosomal recessive and dominant forms may be caused by mutations of the low-density lipoprotein receptor-related protein 5 (LRP5), a cell surface protein.

Retinal dysplasia may occur as an isolated ocular disorder or may be associated with chromosomal anomalies such as trisomy 13 or single gene multisystem disorders such as Meckel syndrome. The dysplastic retina results in nonattachment during embryogenesis and a very poor visual prognosis.


Juvenile Retinoschisis

X-linked juvenile retinoschisis is one of the most common reasons for unexplained visual loss in young male patients. This X-linked recessive disorder is characterized by a bilateral schisis (splitting) within the nerve fiber layer of the retina. Initially, vision may be reduced only mildly, but it can decrease gradually with age, ending in the 20/200 range or worse. The initial appearance of the foveal region is that of characteristic, radiating microcysts. With time, the macula becomes mottled and atrophic. In more than half of affected patients, the macular changes are the sole ophthalmoscopic finding. Schisis of the peripheral regions of the retina also may be evident. Vitreous hemorrhage resulting from torn retinal vessels bridging the area of schisis or retinal detachment with sudden deterioration of vision may complicate this disorder. The electroretinogram may be helpful in confirming the diagnosis.

Stickler Syndrome

Stickler syndrome is an autosomal dominant disease with variable penetrance and expressivity. The ocular findings may include high myopia, cataract, vitreoretinal degeneration, perivascular pigmentary retinopathy, and retinal detachment. Systemic features include progressive arthropathy, epiphyseal dysplasia, characteristic facies, cleft palate, and cardiac defects. Some patients have the Pierre Robin sequence. Because of the subtle, yet extensive, nature of the nonocular features of the syndrome, early diagnosis of the disease may depend on an eye evaluation. Patients with cleft palate, especially when they have or there is a family history of myopia, deserve an eye examination. Early diagnosis is critical because of the risk of peripheral vitreoretinal pathology and retinal detachment.

The primarily ocular form is caused by mutations of the collagen, type II, alpha-1 gene (COL2A1). The multisystem forms include different bone diseases and may be caused by mutations in several collagen genes, including the collagen, type XI, alpha-2 (COL11A2); the collagen, type XI, alpha-1 (COL11A1); and COL2A1 genes. An autosomal recessive form of the disease is caused by mutations of the collagen, type IX, alpha-1 (COL9A1) gene.


Mitochondrial deletions are associated with external ophthalmoplegia (progressive loss of eye movement) and a pigmentary retinopathy that may be similar to retinitis pigmentosa. The Kearns-Sayre syndrome is a specific form of the disease and consists of the triad of a pigmentary retinopathy, progressive external ophthalmoplegia, and cardiac arrhythmias. Onset of symptoms may occur in the first decade of life. The external ophthalmoplegia usually includes ptosis. Diplopia is uncommon. The pigmentary retinopathy may have little effect on the central vision and visual fields. The arteriolar attenuation and pallor of the optic nerve, commonly associated with retinitis pigmentosa, may be absent. Systemic findings include muscle weakness, ataxia, hearing loss, and dementia. An electrocardiogram is important in all cases of acquired ophthalmoplegia of unknown etiology.

Mitochondrial dysfunction can result from mutations in nuclear autosomal genes, the products of which are expressed in the mitochondria. The nuclear-encoded DNA polymerase-gamma gene (POLG) gene, if mutated, may cause autosomal recessive or autosomal dominant disease. Other nuclear genes that can predispose an individual to autosomal dominant mitochondrial deletions include the ADP/ATP translocator or adenine nucleotide translocator (ANT; solute carrier family 25, member 4 [SLC25A4]), the twinkle protein (C10ORF2), and the nuclear-encoded DNA polymerase gamma-2 gene (POLG2) genes.

Leber hereditary optic neuropathy was the first disorder recognized to be of mitochondrial etiology. The incidence ranges from 1:25,000 to 1:40,000. Typically, sudden visual loss occurs in the third decade but can occur as early as age 1 year and as late as the ninth decade. Although visual loss ranges from 20/50 to no light perception, it is typically profoundly reduced. Early in the disease, optic nerve edema and circumpapillary vessel dilation occurs but may not be recognized. Eventually, optic nerve pallor develops. The disease is a bilateral condition but is usually asynchronous in presentation. Recovery of some vision can occur. The disease occurs predominantly in Caucasians, and unlike other mitochondrial disorders, which affect both genders equally, males are more likely and more severely affected. The reason for the male preponderance is unknown. Both genetic and environmental modifiers have been proposed. Evidence suggests that cigarette smoking and alcohol consumption may worsen the prognosis. Over 90% of affected individuals have mutations at base pairs 11778, 3460, and 14484, with visual outcome the best with the 14484 mutation.