Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006

Wilson’s disease is an autosomal recessive disorder. It occurs worldwide with an incidence of approximately 1 in 30,000.60 The gene has been localized to chromosome 13q 14.3.60 Heterozygotes do not exhibit clinical manifestations; approximately 20% have decreased levels of ceruloplasmin. Prenatal diagnosis is possible, provided DNA is available from the index case.63

Laboratory confirmation of the diagnosis of Wilson’s disease involves demonstration of decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration.60

Wilson’s disease can be effectively treated with penicillamine, a chelating agent that reduces body stores of copper. Both the Kayser–Fleischer ring and sunflower cataract may regress with treatment.31,254,282 Changes in the eye can be used to monitor efficacy of treatment and compliance with treatment. Ocular complications of penicillamine therapy, particularly optic neuritis and retinal changes, have been reported.74,108 Treatment alternatives are trientene or orally administered zinc salts. Liver transplantation has a place in the treatment of patients with advanced liver disease and can be successful in fulminant cases. Disappearance of the Kayser–Fleischer ring after liver transplantation has been documented.227

Menkes’ Disease

In Menkes’s disease, there is widespread disturbance in the cellular transport of copper. There is defective intestinal absorption of copper, resulting in copper deficiency, and defective synthesis of copper enzymes, with severe neurological and connective tissue consequences.63 Major manifestations are abnormal hair, a distinctive facies, hypopigmentation, progressive neurological deterioration, lax skin, arterial degeneration, bone changes, urinary tract diverticulae, and hypothermia. Laboratory findings include very low levels of serum copper and ceruloplasmin, grossly reduced copper content in the liver, and greatly increased copper content in the intestinal mucosa.

The disorder is X-linked recessive, characteristically affecting hemizygous males; some heterozygous females show manifestations. The gene location is Xq 13.2–13.3.60 The estimated incidence of the disease is 1 in 250,000 live births.60 Prenatal diagnosis and heterozygote detection are possible.

Manifestations develop in infancy; some may be evident at birth. The hair is pale, lusterless, brittle, often stubby, giving rise

ganglion cells with loss of nerve fibers and atrophic changes of the optic nerve have been documented by light and electron microscopy.231,289 In addition, microcysts of the iris pigment epithelium and irregularity of melanin granules in the retinal pigment epithelium were found.231,289 Electroretinogram (ERG) and visual evoked potential (VEP) responses diminish.22,85,161,240,278 Nystagmus and strabismus are common. There may be blepharitis, dacryostenosis, and possibly tear deficiency.168 Aberrant lashes have been noted.85 In addition, cataracts, possibly incidental, have been reported.218

As yet there is no truly affective treatment for Menkes’ disease.60 Various forms of copper replacement therapy have been tried. Presymptomatic treatment with copper histidine injections can modify the disease, but no treatment has been found to significantly alter the course once brain damage has occurred.

THE MUCOPOLYSACCHARIDOSES

The group of syndromes generically referred to as the mucopolysaccharidoses (MPS) are caused by deficiency of specific lysosomal enzymes involved in the metabolic degradation of dermatan sulfate, heparan sulfate, and keratan sulfate, either singly or in combination; chondroitin sulfate also may be affected.185 Incompletely degraded mucopolysaccharides (glycosaminoglycans) accumulate in various tissues and organs throughout the body and are excreted in the urine.

The mucopolysaccharidoses are characterized by a rather distinctive spectrum of clinical manifestations. Bone abnormalities (dysostosis multiplex), joint contractures, skeletal deformity, and dwarfing are prominent features. There is a characteristic facies with coarse, often somewhat grotesque features. Visceromegaly, cardiovascular disease, respiratory problems, hearing impairment, and mental deficiency occur within the group. Hypertrichosis is common. The principal ocular manifestations of the various mucopolysaccharidoses are progressive corneal clouding, pigmentary retinal degeneration, optic atrophy, sometimes papilledema, and in certain cases glaucoma (Table 7-1). The familiar prototype of the mucopolysaccharidoses is Hurler syndrome (MPS I-H).

All the mucopolysaccharidoses are autosomal recessive disorders with the exception of Hunter syndrome (MPS II), which

is an X-linked recessive disorder.185 Diagnosis of the various mucopolysaccharidoses is made on the basis of the distinguishing clinical features, the presence of excessive mucopolysaccharide substances in tissue and urine, and demonstration of the enzyme deficiency in fibroblasts, leukocytes, or serum. Prenatal diagnosis is possible by analysis of cultured amniotic fluid cells or chorionic villi. Identification of heterozygotes also is becoming increasingly available.

Enzyme replacement therapy is being investigated.186 There has been some success in altering the course of certain of the mucopolysaccharidoses with bone marrow and stem cell transplantation.186 Some improvement in the ocular findings after marrow transplantation has been documented.115,253

Hurler Syndrome: MPS IH

In Hurler syndrome, there is profound deficiency of -L- iduronidase with excessive urinary excretion of both dermatan sulfate and heparan sulfate. The gene encoding this enzyme has been mapped to chromosome 4p 16.3.186 There is accumulation of acid mucopolysaccharide in virtually every system of the body, producing marked somatic and visceral abnormalities beginning in infancy or early childhood, progressing with age, and leading to early death, usually by age 10 years.

The head tends to be large and misshapen; on radiologic examination the calvarium is thickened, there is premature closure of lamboid and sagittal sutures, the sella is enlarged and J-shaped, there is hypertelorism, the orbits are shallow, and the optic foramina may be enlarged. The facial features characteristically are coarse, the expression dull (Fig. 7-3). The eyes appear wide-set and prominent, the lids are puffy, the brows are prominent, and the lashes coarse. The nose is broad with wide nostrils and a flat bridge. The ears may be large and low-set. The lips usually are patulous, the tongue large and protuberant. The teeth generally are small, stubby, and widely spaced, the gums hyperplastic. The skin tends to be thick. Generalized hypertrichosis is common.

Moderate dwarfism, short neck, kyphoscoliosis, and gibbus are typical. On X-ray, the vertebral bodies, particularly those of the lower dorsal and upper lumbar region, are wedge shaped with an anterior hooklike projection referred to as beaking. The extremities are short, the hands and feet are broad, the phalanges short and stubby. Radiologically, the tubular bones show expan-

FIGURE 7-3. Coarse facial features of Hurler syndrome.

sion of the medullary cavity and thinning of the cortex, and the terminal phalangeal bones commonly appear hypoplastic. The joints are stiff and flexion contractures develop; clawlike deformity of the hands is especially characteristic. The posture is semicrouching, the gait awkward. There is thoracic deformity; the chest appears wide and large, with flaring of the lower ribs over the abdomen. On X-ray, the ribs appear spatulate or saber shaped, and the medial end of the clavicle is widened. The constellation of skeletal abnormalities and radiologic findings in MPS is described by the term dysostosis multiplex.

The abdomen is protuberant owing to visceromegaly and abnormalities in supporting tissues. As a rule, there is enlargement of both liver and spleen. Diastasis recti, umbilical hernia, and inguinal hernias are common. Pathological changes in the heart due to mucopolysaccharide deposition can be extensive; the great vessels and peripheral vessels also are affected. Cardiac manifestations include murmur, angina, myocardial infarction, and congestive heart failure. Respiratory problems, particularly recurrent upper respiratory tract infection, bronchitis, and chronic nasal congestion are common. The patients almost

Slit lamp examination reveals fine granular opacities, often increasing in density from the anterior stroma and subepithelial region to the posterior stromal layers of the cornea.18,56 Corresponding histopathological and ultrastructural changes of mucopolysaccharide accumulation in the cornea have been well documented.18,128,188

Although corneal clouding may impair visualization of the fundus, signs of retinal degeneration, nerve head swelling, and optic atrophy are found in Hurler syndrome.54,98 The ERG usually is markedly reduced.35,98 Related histopathological and ultrastructural changes, including the presence of inclusions in retinal pigment epithelium, retinal ganglion cells, and optic nerve astrocytes, have been well documented.37,188 Pathological evidence of mucopolysaccharide accumulation in virtually all ocular tissues has been found.37,143

Megalocornea has been described in many reports; in most cases the intraocular pressure has been normal, but glaucoma has been documented in some patients with Hurler syndrome.18,56,78,188,191,247 Involvement of the trabecular meshwork has been found.247 Normalization of ocular pressure after marrow transplantation for MPS IH has been reported.41

Progressive impairment of vision is usual, due to corneal clouding, retinal degeneration, and optic atrophy, singly or in combination; glaucoma, cerebral mucopolysaccharide accumulation, and hydrocephalus also may contribute. Considering all factors, corneal transplantation in an effort to improve vision has not generally been recommended in the past. Now, however, the possibility of altering the course of Hurler syndrome with treatment may alter the prospects for keratoplasty.186

Scheie Syndrome: MPS IS

In Scheie syndrome, there is deficiency of -L-iduronidase and urinary excretion of both dermatan sulfate and heparan sulfate as in Hurler syndrome, but the clinical picture is somewhat different. The major manifestations are corneal clouding, joint stiffness, claw-hand deformity, carpal tunnel syndrome, and aortic valve disease, principally aortic stenosis and regurgitation. The facial features are coarse; the mouth is broad. Other somatic and visceral changes tend to be minimal. Stature is normal. The intellect is normal or nearly normal, although psychiatric disturbances have been reported. There may be hearing impairment. The lifespan is relatively normal.

Corneal clouding is a prominent feature of Scheie syndrome.225 Evident early in life, sometimes at birth, the corneal clouding usually worsens with age and may ultimately interfere with vision. It is diffuse but tends to be most dense peripherally. The hazy cornea may appear enlarged, edematous, and thickened, initially raising suspicion of glaucoma, particularly when somatic signs of MPS are minimal. Reported histopathological and ultrastructural findings in cornea and conjunctiva are similar to those of Hurler syndrome.143,225 Corneal transplants have been tried with little success in the past.225 Glaucoma has been documented in some patients with Scheie syndrome.152,205

Although retinal changes have not been found in all cases,225 retinal degeneration is a recognized feature of Scheie syndrome.35,98,205 Manifestations include vision impairment, particularly progressive night blindness, field changes such as ring scotoma, retinal pigmentary changes, and diminished or extinguished ERG responses.

Hurler–Scheie Syndrome: MPS IH/S

Patients having features intermediate between those of the Hurler and Scheie syndrome have been described. They show deficiency of -L-iduronidase and urinary excretion of dermatan sulfate and heparan sulfate. The prominent clinical manifestations are skeletal, with dwarfing and progressive joint stiffness, scaphocephaly, hypertelorism, and progressive coarsening of facial features. In addition, a receding chin or micognathia appears to be a distinctive feature. Other significant manifestations include hepatosplenomegaly, pulmonary and cardiovascular involvement, mental retardation, and hearing impairment. Destruction of the sella, cerebrospinal fluid rhinorrhea, and loss of vision related to the presence of arachnoid cysts have also been reported. Patients with Hurler–Scheie syndrome may survive into their teens or twenties.

Corneal clouding occurs in MPS IH/S.137,250 The haze is diffuse, sometimes more dense peripherally, and progressive; it may be evident in childhood and in time may interfere with vision. Keratoplasty has been tried with some success.137

Retinal degeneration also occurs in MPS IH/S. There may be decreased acuity, night blindness, field constriction, retinal pigmentary changes, and ERG changes.40,98 Optic nerve head swelling and optic atrophy have been reported.54