Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition

Ocular Manifestations of Systemic Disease



Alex V. Levin

Thomas W. Wilson

  1. Raymond Buncic

Diseases of metabolism are classified according to the type of substance accumulated or absent due to an error in enzyme production or function, including amino acids (cystinosis, homocystinuria, phenylketonuria, and tyrosinemia), organic acids (glutaric aciduria and alkaptonuria), cholesterol (Smith-Lemli-Opitz), sugars (diabetes mellitus, galactosemia, and carbohydrate-deficient glycoprotein syndrome), lipids (abetalipoproteinemia, hyperlipoproteinemia, and lecithin acyltransferase deficiency), neural components (Fabry, galactosialidosis, mucopolysaccharidosis, mucolipidosis, and sphingolipidosis), peroxisomal (Zellweger, neonatal adrenoleukodystrophy, Refsum, and hyperoxaluria), and metals (Menkes and Wilson disease).

Ocular abnormalities in the sphingolipidosis are caused by accumulation of products of metabolic degradation of cerebral tissue. A cherry red spot is seen in Tay-Sachs, Niemann-Pick, Sandhoff, Farber, metachromatic leukodystrophy, and GM1 gangliosidosis. Optic atrophy is a manifestation of metachromatic leukodystrophy, Krabbe, Zellweger, and all mucopolysaccharidoses. Corneal abnormalities are common in Fabry (corneal verticillata) and corneal cloudiness in Lowe, metachromatic leukodystrophy, Zellweger, mucolipidoses, and mucopolysaccharidoses.

Kayser-Fleischer rings can be located in the peripheral cornea of patients with the copper metabolism abnormality Wilson disease. Cataracts are common in diabetes mellitus, mannosidosis (spoke-wheel cataract), Lowe, Fabry (spoke-wheel cataract), and Niemann-Pick (brown anterior lens changes).



Figure 20.1 Cystinosis—Cornea

Cystinosis is a group of metabolic disorders that results in excess cystine in the tissues throughout the body. Patients present with photophobia due to deposition of corneal crystals (left image). The crystals are deposited in the peripheral cornea and then progress centrally. Their highest concentration is in the anterior stroma. Patients can also have deposition of cysteine in other ocular tissues, and crystals have been observed in the anterior lens capsule, iris (right image), and retina. Oral cysteamine can decrease extracellular levels of cysteine. Clinical trials are currently in progress to determine the effect of cysteamine applied topically to decrease the corneal crystals. Renal failure is the major cause of nonocular morbidity.


Figure 20.2 Cystinosis—Retina

Pigment retinopathy is concentrated in the periphery and is characterized by pigment clumps and areas of atrophy. The macula may also be involved. Retinal crystals of cystinosis can be deposited with the layers of the retina. Cystinosis can lead to retinal dysfunction as demonstrated on electroretinogram and dark adaptation. Progressive vision loss is common. Systemic manifestations include renal failure from a deposition of cystine. Patients will often present with dehydration because of the decreased reabsorption of water. The deposition of cystine within body tissue confirms the diagnosis of cystinosis. Treatment of renal failure requires transplantation.


Figure 20.3 Homocystinuria

Homocystinuria involves the abnormal metabolism of sulfur-containing amino acids. The most common enzyme deficiency is cystathionine β-synthase. Homocystinuria is inherited as an autosomal recessive trait and has been linked to chromosome 21. Patients will have increased levels of homocysteine and methionine. Ocular features include ectopia lentis and retinal detachment. Patients with homocystinuria are at increased risk of developing thromboembolic events and vascular occlusions. Patients often have skeletal changes similar to Marfan syndrome (arachnodactyly, scoliosis, and increased limb length [Marfanoid habitus]) but also often have mental retardation of learning delays not seen in Marfan syndrome. Treatment includes supplemental pyridoxine and cystine and a methionine-free diet.




Figure 20.4 Galactosemia

Galactosemia is a group of metabolic disorders with defects in galactose metabolism. Different enzyme deficiencies will lead to specific clinical features. Newborns with galactose-1-phosphate uridylyl transferase deficiency will commonly present as a newborn with jaundice, difficulty feeding, irritability, and hepatomegaly. Permanent damage to the brain and liver are inevitable without an early diagnosis. Classic cataract of galactosemia is an oil droplet located in the nucleus. Other causes of galactosemia include galactokinase deficiency. Diagnosis of galactosemia is demonstrated by increased levels of reducing substance in the urine. Treatment includes avoiding milk products and foods containing galactose.


Figure 20.5 Mucopolysaccharidosis

Mucopolysaccharidosis type 1H, or Hurler syndrome, is a disorder of abnormal degradation and storage of glycosaminoglycans. The enzyme deficiency of Hurler syndrome is α-L-iduronidase with accumulation of dermatan and heparin sulfate within body tissues. Clinical features include the characteristic of facies (left image). The head is enlarged with frontal bossing. The nasal bridge is depressed and the nose is wide and flat. There is also deposition in the subcutaneous tissues resulting in thickening and decreased flexibility (right image).


Figure 20.6 Mucopolysaccharidosis—Cornea

Ocular manifestations include cloudy corneas, retinal pigment degeneration, and optic atrophy. Adverse systemic features include hepatosplenomegaly, mental retardation, and cardiac abnormalities. Umbilical and inguinal hernias are more common than in the normal population. Mucopolysaccharidosis type 1S, or Scheie syndrome, is secondary to accumulation of dermatan sulfate within the body tissues. The clinical manifestations are milder than in Hurler syndrome and include a normal level of intelligence with similar facial appearance.




Figure 20.7 Mucopolysaccharidosis— Hunter Syndrome

Mucopolysaccharidosis type 2, or Hunter syndrome, is secondary to a deficiency of iduronate sulfatase. Clinical manifestations include coarse facial features, joint stiffness, and dwarfism. Patients develop severe mental retardation and a progressive decline of their mentation. Ophthalmic features include retinal and optic nerve degeneration. The corneas are typically clear. Hunter syndrome is inherited as an X-linked recessive disorder with the gene location at Xq28.


Figure 20.8 Mucopolysaccharidosis—Maroteaux-Lamy Disease

Maroteaux-Lamy disease, or type 6 mucopolysaccharidosis, is a systemic disease with similar features to Hurler disease. Patients have coarse facies and short stature. Contractures of the hands (as shown here) and knees are common. Patients have an increased risk of umbilical and inguinal hernias. There is an increased risk of cardiac valve abnormalities, including mitral insufficiency and aortic regurgitation. Ocular manifestations include mild cloudy cornea and optic atrophy. Patients typically have a normal level of intelligence. Patients have increased levels of tissue dermatan sulphate. The enzyme deficiency is N-acetylgalactosamine-4-sulphatase.


Figure 20.9 Niemann-Pick Disease

Niemann-Pick disease is a deficiency of sphingomyelinase and has increased accumulations of sphingomyelin. It is inherited as an autosomal recessive trait and is more common in Ashkenazi Jews. Patients present with hepatosplenomegaly and infiltration of the lungs with sphingomyelin. Bone marrow biopsy demonstrates foam cells. Several subtypes have been described with different times of onset and severity of disease. Type A Niemann-Pick disease has a continued deterioration of mental status and physical development, with death by age 3. Ophthalmic features include corneal opacities and a brownish hue to the anterior lens capsule. A cherry red spot in the macula secondary to accumulation of sphingomyelin within the nerve fiber layer is common. There can be a cystoid halo around the fovea.




Figure 20.10 Gaucher Disease

Gaucher disease is a type of sphingolipidosis secondary to a deficiency of the enzyme glucocerebroside with accumulations of glucosyl ceramide. It is most commonly found in the Eastern European Jewish population and is inherited as an autosomal recessive trait. Clinical features include hepatosplenomegaly and pancytopenia secondary to Gaucher cells in the bone marrow. The skin has a yellowish-brown tint. Ophthalmic manifestations include accumulations of Gaucher cells, which are seen as white patches in the retina and choroid. Macular changes may lead to a lesion similar to a cherry red spot (Fig. 20.15) but often less striking and more grey. There is a web-shaped area of thickening of the limbal conjunctiva, which probably represents a pinguecula.


Figure 20.11 Infantile Refsum Disease

Infantile Refsum disease is secondary to abnormal peroxisomes. Clinical features include increased phytanic acid levels. Patients have dysmorphic features, mental retardation, and associated hearing loss. Patients with infantile Refsum have a retinal pigmentary degeneration.


Figure 20.12 Lowe Syndrome

Lowe oculocerebrorenal syndrome is a metabolic defect inherited as an X-linked recessive trait. Patients present with hypotonia, decreased tendon reflexes, and mental retardation. Patients progress to renal tubular acidosis and secondary renal failure with rickets and proteinuria. Carriers of Lowe syndrome can have punctate lenticular opacities within the cortex.




Figure 20.13 Lowe Syndrome—Cataract

Lowe oculocerebrorenal syndrome has several associated ocular manifestations. This is one of a few disorders that have the combination of congenital cataract and congenital glaucoma. This rare combination is also caused by rubella syndrome. The anterior lens capsule is thicker than normal and the posterior capsule is thinner than normal. Opacities of different sizes and morphology have been reported. Other findings of Lowe oculocerebrorenal syndrome include corneal keloids and pupillary abnormalities. The female carriers of this X-linked recessive disorder may demonstrate a characteristic pattern of radiating lens opacities (right image).


Figure 20.14 Tyrosinemia Type 2 (Richner-Hanhart syndrome)

There are several disorders of tyrosine metabolism, of which Richner-Hanhart syndrome is of ophthalmic significance. In this autosomal recessive disorder, deficiency of hepatic tyrosine aminotransferase leads to elevated blood tyrosine. The classic clinical triad consists of pseudodendritic keratitis, shown here, sometimes painful hyperkeratosis of the palms and soles, and developmental delay. Ocular symptoms may be seen as early as 3 months old. Unlike herpes, the corneal findings are bilateral. Cataract has been observed infrequently. Conjunctival biopsy with staining for tyrosine crystals can be diagnostic.


Figure 20.15 Tay-Sachs Disease (GM2 Gangliosidosis Type 1)—Cherry Red Spot

Tay-Sachs disease is due to a deficiency of the enzyme hexosaminidase A. This autosomal recessive neurodegenerative disorder usually results in death before 4 years of age. The classic cherry red spot shown here is due to GM2 ganglioside lipid-laden ganglion cells. As there are no ganglion cell bodies in the fovea, no opacity results and the underlying retinal pigmented epithelium and reddish choroid are visible. Other metabolic causes of a cherry red spot include GM1 gangliosidosis, Niemann-Pick disease, metachromatic leukodystrophy, Farber disease, Sandhoff disease (GM2 gangliosidosis type 2), Gaucher disease, and others.