Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006
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pigmentation of affected infants may be lighter than that of their siblings. Beginning usually between 6 and 12 months of age, signs of impaired renal tubular reabsorption (Fanconi’s syndrome) develop, with excessive urinary losses of water, glucose, amino acids, calcium, phosphorus, sodium, potassium, bicarbonate, and other metabolites. Affected infants may be fussy, feed poorly, urinate and drink excessively, vomit, and suffer episodes of acidosis, dehydration, and electrolyte imbalances. They fail to grow and gain weight. They develop rickets, sometimes tetany, arrhythmias, and muscle weakness. Untreated, the natural course is one of progressive glomerular damage with renal failure and uremia, requiring dialysis or kidney transplantation usually by age 6 to 12 years; in some cases renal failure occurs as early as 1 to 3 years of age. Accumulation of cystine in other tissues and organs produces a variety of additional clinical manifestations. Primary hypothyroidism is common. Some patients develop insulin-dependent diabetes mellitus. Males may exhibit hypogonadism, delayed puberty. Some patients develop hepatomegaly, occasionally hypersplenism. Accumulation of cystine in the intestinal tract and appendix may contribute to nausea and vomiting. Continued accumulation in muscle can lead to impaired function; this may contribute to swallowing difficulties in older patients. There may be decreased ability to sweat. Neurological manifestations, such as seizures, tremor, or mental retardation, occur occasionally.
Involvement of the eye in cystinosis is extensive. Studies have documented accumulation of crystals within keratocytes; throughout subepithelial tissues of conjunctiva; in sclera and episclera; in epithelium and stroma of iris; in pigmented and nonpigmented epithelium and connective tissue of ciliary body; in choroid, mainly within fibrocytes and histiocytes; in retinal pigment epithelium; in meninges and fibrovascular pial septae of the optic nerves; and in extraocular muscles.48,90,142,222,287
Clinically, the pathognomonic ocular sign of cystinosis is a distinctive crystalline keratopathy (Fig. 7-9). Slit lamp examination reveals myriads of scintillating iridescent crystals within the corneal stroma, usually by age 1 year.286 Deposition of the corneal crystals appears to begin in the anterior stroma and progress posteriorly, and to advance from the periphery of the cornea to the center, in time involving the full extent of the stroma.172 Crystals may be found at or near the endothelial surface, but epithelium usually is spared.172 In time the cornea may become diffusely hazy.134 Punctate keratopathy, painful
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FIGURE 7-9. Iridescent corneal crystals of cystinosis.
recurrent corneal erosions, and band keratopathy may develop in time.134,214 Photophobia, an early and prominent symptom, and blepharospasm, can be significant problems.134,214 Glare disability has been documented.140 Corneal sensitivity may be reduced.139 On slit lamp examination, refractile crystals also can be detected within the conjunctiva, on the iris, and sometimes overlying the lens.134,286
Another major clinical ocular manifestation of cystinosis is progressive retinopathy, which is characterized by depigmentation and mottling of the fundus, often in a patchy distribution, involving predominantly the periphery, extending from the equatorial region to the ora serrata, often with fine to coarse pigment clumps distributed over the light background; there also may be granularity or fine pepper-like stippling of the posterior fundus (Fig. 7-10).213,288 Conspicuous yellow mottling of the macula in association with generalized disturbance of the retinal pigment epithelium also has been described.222 Retinal changes can be seen as early as infancy and can precede the development of corneal signs.222 Glistening crystal-like deposits may be evident on fundus examination.134,213 In young patients, visual function and ERG responses often are normal, but older surviving patients whose retinas have accumulated cystine for one to three decades commonly suffer progressive visual impair-
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ment, reduced acuity, color vision, dark adaptation, and ERG responses.94,134,288
Pupillary-block glaucoma, attributed to thickening and rigidity of the iris related to accumulation of crystals in iris stroma, can occur in childhood-onset cystinosis.277 Posterior synechiae may contribute.134 Narrowing of the anterior chamber angle and altered ciliary body configuration, which may contribute to the predisposition to glaucoma, has been demonstrated by ultrasound biomicroscopy.181 Primary open-angle glaucoma also has been reported in the benign adult form of cystinosis.285
The diagnosis of cystinosis is confirmed by demonstrating elevated cystine content in polymorphonuclear leukocytes or cultured fibroblasts. At birth, measurements can be made of placenta or white cells of cord blood. Prenatal diagnosis can be made using cultured amniocytes or chorionic villi.95 Heterozygote detection also is possible.95
Treatment of cystinosis includes management of renal losses, renal dialysis, and kidney transplantation for renal failure.95 Cystine accumulation does not occur in the donor kidney, but continues in other sites, contributing to extrarenal complications in long-term survivors. Chronic therapy with a
FIGURE 7-10. Pigmentary retinopathy of cystinosis.
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cystine-depleting agent, cysteanine ( -mercaptoethylamine), taken orally can forestall renal failure and improve growth but does not reverse the ocular changes.134 The use of cysteamine eyedrops can help prevent and reverse corneal crystal deposition.135,136
HOMOCYSTINURIA
The condition known as homocystinuria is caused by deficiency of cystathionine -synthase.179 Important in the complex scheme of methionine metabolism, this enzyme catalyzes conversion of homocysteine to cystathionine. The defect results in intracellular accumulation of homocysteine, increased serum levels of methionine, homocysteine, and homocystine, and excretion of these metabolites in urine. Cystathionine levels, particularly in brain, and cystine levels in urine, plasma, and red blood cells, are decreased.
The disorder affects predominantly the skeletal, vascular, and central nervous systems and the eye; other organs including liver, skin, and hair also may be involved.179 Major clinical manifestations are osteoporosis, thromboembolism, mental retardation, and ectopia lentis.
The locus for cystathionine -synthase has been mapped to 21q22.3.179 The enzyme deficiency is inherited as an autosomal recessive condition. Direct enzyme assay confirms the diagnosis of the disorder; liver biopsy specimens, cultured skin fibroblasts, phytohemagglutinin-stimulated lymphocytes, or long-term established lines of such cells can be used. Identification of heterozygotes can be difficult. Prenatal diagnosis is feasible.
Osteoporosis is the most consistent skeletal manifestation of homocystinuria, found in at least 50% of patients by the end of the second decade of life; it is most common in the spine, followed by the long bones.179 Scoliosis also is frequent. Other skeletal manifestations include increased length of long bones, arachnodactyly, biconcave “codfish” vertebrae, pes cavus, genu valgum, pectus carinatum or excavatum, various abnormalities of the metaphyses, epiphyses, carpal and metacarpal bones, and high arched palate.
Thromboembolism is a major cause of morbidity and the most frequent cause of death in patients with homocystinuria.179 Vascular occlusion can occur at any age, including infancy. The
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risk of thromboembolism appears to increase with age, with pregnancy and the postpartum state, and possibly in the postoperative state. Other vascular manifestations of homocystinuria are malar flush and livedo reticularis.
The principal neurological manifestations of homocystinuria are mental retardation and psychiatric disturbances.179 Seizures, EEG abnormalities, and extrapyramidal signs are less frequent. Focal neurological signs may occur with cerebrovascular occlusion.
Additional findings in patients with homocystinuria include fair brittle or sparse hair, thin skin, fatty liver changes, inguinal hernia, myopathy, endocrine abnormalities, and reduced clotting factors.179
The characteristic ocular manifestation of homocystinuria is ectopia lentis (Fig. 7-11).59,243 Partial or complete dislocation of the lens has been found in almost all cases59,243; it is usually evident by age 10 years.59,209 The dislocation is bilateral, progres-
FIGURE 7-11. Ectopia lentis with cataract in homocystinuria.
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sive, and commonly occurs in the inferior or nasal direction, although it may occur in any direction59,179,243; in some cases the lens may dislocate into the anterior chamber or vitreous.59 An important clinical sign of ectopia lentis is iridodenesis. The ectopia is attributed to progressive fraying and disruption of the zonular fibers.179 On slit lamp examination, a fringe of zonular remnants may be found attached to the anterior lens capsule.208 It has been postulated that an abnormality of zonular fibrillin, like that in Marfan syndrome, is responsible for the ectopia lentis in homocystinuria.179
Myopia commonly develops as the lens loosens and becomes more spherical.179 Significant myopia in the very young child should raise suspicion of ectopia lentis and the possibility of an underlying metabolic disorder such as homocystinuria.
Glaucoma, often pupillary block glaucoma, is a frequent complication in patients with homocystinuria.59,243 Cataracts have been noted in some cases.243 A variety of other ocular abnormalities including optic atrophy, cystic and pigmentary changes of the peripheral retina, retinal detachment, keratitis, iritis, and strabismus have been described in patients with homocystinuria.59,209,243 In many cases the iris stroma is lightly pigmented.243
Light and electron microscopic studies of the eye in homocystinuria have shown the zonular fibers to be deficient at the border of the lens and retracted to the surface of the ciliary body, forming a matted layer of filaments along a thickened basement membrane of the nonpigmented ciliary epithelium.209 Zonular remnants attached to the lens capsule also have been found to be composed of short filaments in disarray, with occasional bundles of normal-appearing fibers.208 In addition, peripheral degeneration of the retina has been documented on histopathological examination.209 Note: Investigation into the nature of zonules has documented certain characteristics, particularly their elasticity and propensity to recoil, and their cysteine content, of great interest with regard to the pathological findings in homocystinuria.251
Treatment of patients with homocystinuria involves (1) management of the biochemical abnormalities in an effort to prevent or ameliorate clinical manifestations of the disease, and
(2) management of complications that do occur as a result of the disease. Most patients detected in infancy are treated with a lowmethionine, cystine-supplemented diet. Early dietary management can be effective in preventing mental retardation and
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ectopia lentis, and may possibly reduce the occurrence of initial thromboembolic events and the incidence of seizures.179 In some patients, treatment with pyridoxine can be effective in reducing, but not completely normalizing, the biochemical abnormalities. In vitamin B6-responsive patients, pyridoxine may be used alone or in conjunction with less stringent methionine dietary restriction. B6-responsive patients generally have milder and more slowly developing manifestations that those who are not responsive to pyridoxine. Betaine can be useful for vitamin B6- nonresponsive patients for whom dietary management is unsatisfactory.
Surgery for ectopia lentis can be complicated by vitreous loss and adhesions.59 Visual results from removal of the lens vary.59 It should be noted that some patients with homocystinuria have died of thromboembolism following ocular surgery.59,179
GALACTOSEMIA
Galactose is an essential source of energy in infants. Although some galactose is produced by endogenous synthesis from glucose, the main source of galactose is ingested milk and milk products containing lactose. Under normal circumstances, ingested galactose, a disaccharide, is hydrolyzed into its constituent monosaccharides, galactose and glucose; these monosaccharides are rapidly absorbed from the intestine, and galactose is then converted to glucose. The enzymes involved in the principal metabolic pathway for conversion of galactose to glucose are
(1) galactokinase (GALK), (2) galactose-1-phosphate uridyltransferase (GALT), and (3) uridine diphosphate galactose-4 epimerase (GALE).126 The enzymes are found in many cell types and tissues, although the liver is the major organ of galactose metabolism. Genetic defects in galactose metabolism result in abnormally high concentrations of galactose and its metabolites in body tissues and fluids, with a variety of clinical manifestations, including cataracts. Prenatal screening for all three enzyme defects is available. All are autosomal recessive.
GALT Deficiency
Classical galactosemia results from deficiency of galactose-1- phosphate uridyltransferase (GALT). The gene encoding this
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enzyme has been localized to the short arm of chromosome 9 in the 9p13 region.126 The disorder presents in the first weeks of life with poor feeding, vomiting, diarrhea, weight loss, lethargy, and hypotonia. There may be signs of liver dysfunction, including jaundice and hepatomegaly, with elevated liver transaminases and elevated plasma amino acids, coagulopathy, and hemolytic anemia, and there may be signs of renal tubular disease, including metabolic acidosis, galactosuria, glycosuria, albuminuria, and aminoaciduria. Septicemia is not uncommon.
The characteristic ocular manifestation of galactosemia is cataract. Galactosemic cataracts typically are bilateral and develop in the first weeks or months of life55; pathological changes of the lens have even been found in a fetus.270 The clinical appearance of the galactosemic cataract in its early stages is often likened to that of an oil droplet within the lens; the nucleus is sharply demarcated from the surrounding perinuclear zone by a difference in refractive state.270 In other cases there may be a distinct zonular opacity, lamellar cataract, or dense nuclear cataract, sometimes with fine punctate opacities in the periphery of the lens, or dense cortical or subcapsular opacities270 (Fig. 7-12). The cataract formation has been attributed to accumulation of
FIGURE 7-12. Nuclear and concentric lamellar cataract formation in galactosemia.
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galactitol (dulcitol) in the lens.126,269 There may be secondary nystagmus and strabismus.55
A less well recognized ocular manifestation of galactosemia is vitreous hemorrhage, probably related to coagulopathy.160 Retinal scarring and pigmentary changes may follow. There may be significant visual impairment.
With early diagnosis of galactosemia and timely treatment with a galactose restricted diet, the systemic effects of galactosemia can be reversed, even prevented. However, even with early dietary treatment there may be long-term effects, including impaired cognitive development, speech and language defects, verbal apraxia, visual perceptual dysfunction, ataxic neurological disease, and ovarian failure.126 Neuroimaging of the brain in patients with neurological manifestation has shown abnormal white matter, cortical atrophy and ventricular enlargement, cerebellar atrophy, and involvement of basal ganglia and brainstem.126 Cataract formation also can be reversed, or even prevented, with early diagnosis and prompt dietary treatment.28,55
GALK Deficiency
In patients with deficiency of galactokinase (GALK), the only consistent clinical finding is cataract.162 The cataracts are bilateral and morphologically like those of classic galactosemia (GALT deficiency).162,192 They may be seen in the first weeks of life162 and may be reversible with early diagnosis and timely treatment with a galactose-restricted diet.162
Pseudotumor cerebri has been found in some patients with GALK deficiency.126 Other reported abnormalities such as macular deposits, mild retardation, complement deficiency, and seizures with neurological deterioration may be coincidental.126 The gene encoding galactokinase has been localized to chro-
mosome 17p24.126
It is of interest that in studies of adult patients with idiopathic cataracts, some had diminished galactokinase levels.79,241 Reduced galactokinase activity may increase the risk of developing presenile cataracts requiring surgery by the fourth decade.
GALE Deficiency
In most cases of uridine diphosphate galactose-4 epimerase deficiency, the enzyme defect is confined to the erythrocytes; most patients are asymptomatic and require no treatment.126
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Cataracts are not a feature of this disorder. Generalized GALE deficiency is rare; a few patients with GALE deficiency have presented with manifestations similar to those of classic galactosemia and may have long-term complications.126 These patients respond to galactose-restricted diets. The enzyme encoding uridine diphosphate galactose-4 epimerase has been localized to the short arm of chromosome 1 at 1p36.126
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