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

Decreasing vision is often the presenting sign.211 In time there is progression to blindness. Maculopathy, frequently described as bull’s-eye maculopathy, is an important early finding.245 Other signs of retinal degeneration, including pigmentary changes (granularity, clumping, spicule formation), vascular attenuation, and optic atrophy, often develop.100,245 The ERG is reduced or extinguished early.100,211 Accumulation of lipopigments in the retina has been documented.100

The presence of vacuolated lymphocytes in peripheral blood is an important diagnostic finding in juvenile NCL.211 Battenin, a lysosomal membrane protein, is defective in juvenile NCL.124 Its function is unknown. The gene location for juvenile NCL is 16p12.124

Kufs’ Disease: Adult NCL

Mental and motor changes may appear in the second or third decade. Personality changes, ataxia, and myoclonus are common. Vision loss is not a prominent feature of adult NCL, but evidence of retinal degeneration and storage of lipopigment has been documented.76

ALBINISM

The term albinism describes a group of genetic disorders of melanin synthesis characterized by congenital hypopigmentation that can involve the skin, hair, and eyes (oculocutaneous albinism) or can be limited to the eye (ocular albinism) (Table 7- 6). Essential to the diagnosis of all forms of albinism are ocular abnormalities, particularly retinal hypopigmentation, foveal hypoplasia, and misrouting of optic nerve fibers at the chiasm, with altered visual function; other common features are iris hypopigmentation and translucency, photophobia, nystagmus, strabismus, and high refractive errors.145,148

The melanins, which account for virtually all visible pigmentation in the skin, hair, and eyes, are produced by subcellular organelles called melanosomes within melanocytes. The melanocytes are derived from two embryonic tissues, the neural crest and the optic cup. Melanocytes originating in the neural crest migrate to the skin (at the epidermal–dermal border), the eyes (in the choroid and iris stroma), and the hair follicles.

Melanocytes of the retinal pigment epithelium are derived from

TABLE 7-6. Forms of Albinism.

Oculocutaneous albinism (OCA)

OCA1: TYR gene mutations, tyrosinase deficient

OCA1A

•No tyrosinase activity

•Classic OCA phenotype with white hair, milky skin, pale irides OCA1B

•Some residual tyrosinase activity

•Minimal pigment, platinum or yellow OCA

OCA2: P gene mutations, tyrosinase positive

•Spectrum of pigmentation

•Includes brown OCA OCA3: TYR P1 gene mutations

•Rufous or red OCA

Ocular albinism (OA) OA1: X-linked

• Nettleship–Falls

neuroectoderm as cells originating from the outer layer of the optic vesicle. Two types of melanin can be produced: eumelanins, which are black or brown, and pheomelanins, which are yellow or red. Normal pigmentation requires a number of critical steps during development, and a large number of genes have been shown to participate in the process. The enzyme critical to melanin production is tyrosinase, although there are also a number of posttyrosinase factors and enzymes that regulate the quantity and quality of melanin produced.145

Oculocutaneous Albinism (OCA)

This condition is the most common inherited disorder of generalized hypopigmentation. It has been described in all ethnic groups. The estimated frequency is 1 in 20,000 in most populations.145

The classification of oculocutaneous albinism includes three major genetic types, designated OCA 1, OCA 2, and OCA 3. All are autosomal recessive. Also important in the classification of OCA is a related syndrome, the Hermansky-Pudlak syndrome.

OCA 1 is tyrosinase-related (or tyrosinase-deficient) oculocutaneous albinism, resulting from mutations of the tyrosinase (TYR) gene, which has been mapped to chromosome 11q14–q21.145 Two subtypes occur: in OCA 1A, there is no tyrosinase activity; in OCA 1B there is some residual tyrosinase

the amount of iris pigmentation. In African or AfricanAmerican individuals with OCA 2, the hair is yellow at birth and remains yellow or may turn darker. The skin is creamywhite at birth, changes little with time, and usually does not tan. The irides are blue-gray or lightly pigmented, appearing hazel or tan. This is the common “tyrosinase-positive” OCA phenotype. Tyrosinase-negative and tyrosinase-positive forms of albinism can be distinguished by a hair bulb incubation test.147

Another variant of OCA 2 caused by mutation of the P gene is “brown OCA.”145,146 In this condition, the amount of eumelanin in the skin and hair is reduced but not absent. In African and African-American individuals with “brown OCA,” the hair and skin color are light brown, the irides gray-blue to tan or brown. In time the hair may turn darker and the irides may accumulate more pigment. There is iris translucency. The skin will tan on exposure to sun.

OCA 3, also called rufous or red OCA, results from mutations of the tyrosinase-related protein-1 (TYRP1) gene.145 Occurring in African or African-American individuals, the phenotype of OCA 3 includes individuals with red or reddish-brown skin, ginger or reddish hair, and hazel or brown irides. All ocular features of albinism, however, are not always present; many do not have iris translucency, foveal hypoplasia, or misrouting of optic nerve fibers, raising some questions of definition and classification.145,155

Hermansky–Pudlak syndrome (HPS) is a complex autosomal recessive disorder characterized by the triad of OCA, a bleeding diathesis, and a ceroid storage disease.145,252 It occurs more often in Puerto Rican than non-Puerto Rican individuals; its frequency in Puerto Rico is approximately 1 in 1,800.284 The gene responsible for most HPS in Puerto Rico maps to 10q24.145

Hypopigmentation of the skin and hair in HPS varies from marked to moderate. Freckles may be present is sun-exposed areas, but tanning does not occur. Iris color varies from blue to brown; there is iris translucency. Other ocular features of albinism including retinal hypopigmentation and foveal hypoplasia are present; nystagmus and strabismus are frequent; acuity varies from 20/400 to 20/60.252

The bleeding diathesis in HPS is related to deficiency of storage granules (dense bodies) in platelets, and associated deficiency of serotonin, adenine nucleotides, and calcium in the platelets.145 Platelets do not show irreversible secondary aggregation in response to stimulation. Manifestations include easy

bruiseability, epistaxis, hemoptysis, gingival bleeding; sometimes major, even life-threatening, hemorrhages occur.

The third component of the HPS triad is production of autofluorescent ceroid material, a yellow waxy substance that can be found in urine and many tissues throughout the body, particularly in the lung and gastrointestinal tract, and also in kidney and heart.145 Manifestations include pulmonary fibrosis and granulomatous colitis, which can be severe.

Ocular Albinism (OA)

In ocular albinism (OA), hypopigmentation clinically is limited to the eye, although changes in the cutaneous pigment system also may be present when the ultrastructure of these tissues is examined.145

The OA 1 phenotype, also known as the Nettleship–Falls type of ocular albinism, is X-linked recessive. It is produced by the OA 1 gene on Xp22.145 In OA 1, melanocytes are normal, but cutaneous and ocular melanocytes contain both normal-sized and giant or macro-melanosomes. Histopathological study of the skin is useful in the diagnosis in both the affected and carrier state.195,259 Variable expression has been documented in both affected males and Caucasian females.259 Affected Caucasian males have blue to brown irides with variable translucency, and the other ocular abnormalities of albinism are present. The skin and hair are normally pigmented. In African-American males, the iris color is usually brown, with little translucency. Many African-American males have scattered hypopigmented maculae of the skin.

Heterozygous females often have ocular pigment changes of mosaicism from X-inactivation. Many have a variegated pattern of retinal pigmentation and punctate areas of iris translucency. Some have ocular abnormalities of albinism, including reduced acuity and nystagmus. Occasionally unilateral changes are observed. Detection of the carrier state can be difficult, affecting reliable genetic counseling.38

Ocular Features of Albinism: Summary

The ocular abnormalities essential to the definition and diagnosis of all forms of albinism appear to be related to the reduction in melanin during embryonic development and postnatal life.145,238 Reduction of melanin in the stroma and in the poste-

FIGURE 7-8. Fundus hypopigmentation in oculocutaneous albinism.

rior epithelial layer of the iris results in translucency of the iris.148,252 Reduction of melanin in the retinal pigment epithelium results in varying degrees of hypopigmentation and translucency of the retina, sometimes frank transparency of the macula, allowing increased visibility of the choroidal vessels (Fig. 7-8).148,252 The fovea in albinism is hypoplastic with a reduced or absent foveal reflex.93,252 The cone density of the central retina is reduced.283 Retinal vessels may course into the macular area.246,252 The optic nerve may appear hypoplastic.246 Visual acuity is subnormal, ranging from 20/400 to 20/40, commonly 20/200 to 20/100.88,145 Color vision, however, usually is normal.148 The ERG in most cases is normal or near normal.274

A critical abnormality of the visual system in albinism is abnormal decussation and misrouting of optic nerve fibers at the chiasm.114 In normal individuals, nerve fibers of the nasal retina cross in the chiasm to terminate in the contralateral geniculate body, and nerve fibers of the temporal retina remain uncrossed to terminate in the ipsilateral geniculate body; in albinism, however, the nerve fibers of the temporal retina project to the contralateral geniculate body. In normal individuals, the ratio of crossed to uncrossed fibers is approximately 55:45; in albinism, the proportion of crossed fibers probably exceeds 90%.145 Corre-

sponding abnormalities in the size and configuration of the afferent visual pathways have not been documented by magnetic resonance imaging.25 The visual evoked response is asymmetrical and distinctively diagnostic.9,10,87,116,153 Stereopsis usually is reduced.116,159 Nystagmus is present in most individuals with albinism, and many exhibit compensatory posturing.1,2,148,252 Strabismus is common.148 Many individuals with albinism have high refractive errors88,252; there is some evidence that the type of refractive error is reflective of the type of albinism.138 Also, image quality may affect refractive development.72 Compounding the effect of the neuroanatomic abnormalities of the afferent visual pathways, the nystagmus, high refractive errors, and light scatter all adversely affect retinal image quality.1

Axenfeld anomaly, other signs of anterior segment dysgenesis, and developmental glaucoma have been reported in patients with albinism.156,252

In the management of patients with albinism, all efforts should be made to improve visual function with appropriate refractive correction and whatever low-vision aids are found to be helpful and acceptable to the patient. Tinted lenses can provide relief from glare. Protection from ultraviolet effects must be advised. Extraocular muscle surgery for nystagmus may improve vision and compensatory posturing.65 When strabismus presents a cosmetic problem, surgical correction can be offered.

When assessing an albino child’s visual function for educational purposes, it is important to measure acuity binocularly at both distance and near, allowing compensatory posturing, in addition to testing acuity monocularly, as the measurements may vary in the presence of nystagmus. Young albino patients also should be allowed and encouraged to hold things close for maximal performance. As might be expected, intellectual capabilities and educational attainment in patients with albinism vary.92

TYROSINEMIA

A semiessential amino acid, tyrosine is derived from dietary sources and from hydroxylation of phenylalanine. It is incorporated into protein, and it is important in the synthetic pathways leading to catecholamines, thyroid hormone, and melanin pigments. Its degradation occurs primarily in hepatocytes, and under most circumstances the rate of its degradation is determined by

TABLE 7-7. Disorders of Tyrosine Metabolism.

Fumarylacetoacetate hydrolase (FAH) deficiency Hepatorenal tyrosinemia (tyrosinemia type 1)

Variable symptoms, including acute liver failure, cirrhosis, hepatocellular carcinoma, Fanconi’s syndrome, peripheral neuropathy

Tyrosine aminotransferase (TAT) deficiency Oculocutaneous tyrosinemia (tyrosinemia type II) Palmoplantar keratoses and keratopathy

4-Hydroxyphenylpyruvate dioxygenase (4-HPPD) Dysfunction Hereditary 4-HPPD deficiency (tyrosinemia type III) Neurological signs, mental retardation, ataxia

Hawkinsinuria

Metabolic acidosis and failure to thrive in infancy Transient tyrosinemia of the newborn

In most cases, no symptomatology

In some infants, lethargy, reduced motor activity Possibly adverse developmental effects

the activity of tyrosine aminotransferase.176 One of the least soluble of the amino acids, tyrosine at high concentration forms characteristic crystals.

A number of inherited and acquired disorders can cause hypertyrosinemia (Table 7-7).176 Of these, tyrosinemia type II, referred to as oculocutaneous tyrosinemia, is of special importance in pediatric ophthalmology.

Oculocutaneous Tyrosinemia

Commonly known as Richner–Hanhart syndrome, this disorder is characterized by painful keratopathy, palmoplantar keratoses, and mental retardation.176 It is caused by autosomal recessive deficiency of cytoplasmic tyrosine aminotransferase (TAT), the first enzyme of the tyrosine catabolic pathway.176 In humans, this enzyme is located on chromosome 16q22.1–q22.3.176

Ocular manifestations usually develop in the first years of life, often in infancy, but can begin later.29,105,220,221 Key signs and symptoms are photophobia, lacrimation, pain and redness of the eyes, often with exacerbations and partial remissions. On slit lamp examination the typical ocular lesion is a dendritiform or pseudodendritic opacity of the central or paracentral cornea, involving primarily epithelium, sometimes the subepithelial region, Bowman’s layer, or anterior stroma.7,39 The corneal changes characteristically are bilateral, although often asymmetrical.7 Superficial punctate keratopathy, painful corneal

erosions and ulcerations occur.29,39 Neovascularization and corneal scarring may develop.29,106 The hypothesis is that tyrosine crystalizes in the corneal epithelial cells, disrupting the lysosomes and initiating an inflammatory response.7 Light microscopy of a corneal specimen showed some birefringent crystals in the corneal stroma, and on electron microscopy vacuolar degeneration of keartocytes with electron-dense particles in the vacuoles was found.224 It is known that patients who have undergone keratoplasty can develop recurrent lesions in the graft.12,224 There may also be conjunctival involvement including thickening, papillary hypertrophy, and microfollicular conjunctivitis; vacuoles and inclusion bodies have been found on pathological examination.21,105 Subcapsular lens opacities have been noted in some cases.29,106 Long-term consequences of oculocutaneous tyrosinemia include cornea plana, vision loss, associated nystagmus, and strabismus.176

It should be emphasized that affected children may be symptomatic before significant corneal changes can be detected, and the diagnosis of tyrosinemia type II should be considered in patients with unexplained photophobia, tearing, pain, and redness of the eyes.206 Also, the ocular signs must be differentiated from those of herpetic infection.39 The corneal lesion of tyrosinemia is thicker and more plaquelike, lacking the fine branching pattern and club-shaped edges of a true herpetic dendrite, and usually stains poorly if at all with fluorescein or rose bengal; also, corneal sensation is intact and viral cultures are negative.39

Fortunately the corneal manifestations of tyrosinemia can be reversed, and often prevented, by dietary restriction of tyrosine and phenylalanine17,39,105,106,121; early diagnosis and treatment are key. Symptomatic treatment with topical lubricants can be helpful for patients with keratopathy.

Cutaneous manifestations usually begin after age 1 year, but may begin in infancy.176 Painful hyperkeratotic plaques develop in the soles, palms, and plantar surfaces of the digits.105 Other areas, such as elbows, knees, and ankles, occasionally are involved, and leukokeratosis of the tongue has been reported.176 The skin lesions improve with dietary treatment.105,129,176

Mental retardation occurs in less than 50% of patients.176 Other neurological findings including seizures, microcephaly, extinguished visual evoked potentials, and behavioral problems have been reported in some cases.7,176 Early dietary treatment may prevent mental retardation.106

CYSTINOSIS

Cystinosis is a rare metabolic disease characterized by intracellular lysosomal accumulation of free nonprotein cystine, with crystal formation in many tissues and organs, particularly kidney and eye. The underlying defect is impaired transport of the amino acid cystine across the lysosomal membrane.95

Several forms of cystinosis occur, ranging from a benign nonnephropathic variant presenting with corneal crystals, to classic early-onset nephropathic cystinosis characterized by lifethreatening progressive renal disease and potentially debilitating ocular involvement (Table 7-8).95 The most frequent is classic nephropathic cystinosis; its incidence in North America is approximately 1 in 100,000 to 1 in 200,000 live births. All forms are autosomal recessive. The cystinosis gene, CTNS, has been mapped to chromosome 17p; a number of mutations have been identified.95 Heterozygotes for cystinosis, regardless of type, are clinically normal.

Infants with classic nephropathic cystinosis appear normal at birth, although in Caucasian families, the hair and skin

TABLE 7-8. Forms of Cystinosis.

Nephropathic:

Infantile

•Classic form, presenting at 6 to 18 months

•Most common and devastating variant, with Fanconi syndrome, renal failure, and extrarenal complications

•Extensive ocular involvement, particularly crystalline keratopathy and progressive retinopathy, possibly glaucoma

Late onset

•Range of presentation from 2 to 26 years, most commonly 12 to 15 years (adolescent form)

•Usually not full Fanconi’s syndrome; possibly late-onset renal deterioration

•Cystine crystals in marrow aspirates

•Crystalline deposits in cornea and conjunctiva; variable retinal involvement

Nonnephropathic:

Ocular

•Formerly adult or benign form

•Crystalline deposits in cornea and conjunctiva, often discovered in teens to adult years

•No retinopathy

•Usually asymptomatic with possible exception of photophobia

•Crystalline deposits in marrow

•No renal disease