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

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FIGURE 5-7B–C. (continued).

same gene that causes Stickler syndrome.310 It appears that Kniest dysplasia results from shorter type II collagen monomers and that alteration of a specific domain of COL2A1 that may span from exons 12 to 24 results in the Kniest phenotype.

Patients with Kniest dysplasia have a severe vitreoretinal degeneration that resulted in retinal detachment in five eyes of seven patients in one series.175 The retinal detachments

frequently result from giant tears or retinal dialysis. All patients in one series had congenital severe myopia averaging 15.25 diopters and oblique astigmatism averaging 3.00 diopters. The myopia did not progress with increasing age. Some patients developed cataracts in the first or second decade of life. Subluxation of the lens and glaucoma are rare findings.

Careful retinal examination should be performed at regular intervals with prophylactic cryotherapy of retinal breaks or vitrectomy as required. Cataract surgery should be carefully weighed against the high incidence of aphakic retinal detachment in these patients. No specific treatment is available for the bone dysplasia.

Chondrodysplasia Punctata

There are several genetically and clinically distinct types of chondrodysplasia punctata. Some are autosomal recessive while others are autosomal or X-linked dominant. These diseases share the radiologic appearance of punctate calcific stippling of the epiphyses.

The X-linked dominant forms of chondrodysplasia punctata (CDPX2, Conradi–Hunermann disease) is characterized by typical facial features with a saddle nose and a flat, sometimes grooved nasal tip, linear ichthyosiform skin changes, cataracts, scoliosis and leg length discrepancies.105,167,191,268 Skin lesions are present at birth in about 30% of cases and affect areas of flexion and moisture. Intelligence is normal. Progressive scoliosis is a prominent feature. Stippled epiphyses are characteristic, but the stippling may fade or disappear with age leaving areas of defective ossification. Sectoral or wedge-shaped cortical cataracts are usually present at birth or early in life. There is little or no progression, with good visual prognosis. The linear skin changes and the wedge-shaped lenticular changes are thought to be due to Lyonization.16,52 The gene for CDPX2 maps to Xp11.23–p11.22 and codes for the delta(8)-delta(7) sterol isomerase emopamilbinding protein.22 The X-linked recessive form, CDPX1, is due to mutations in the arylsulfatase E gene at Xp22.3 with significant variability of clinical manifestations in carrier males and females.252

In the autosomal dominant form of chondrodysplasia punctata (Conradi–Hunermann syndrome),47,120 limb shortening is not asymmetrical.251,265 The nose has a flattened tip with a short columella and a depressed nasal bridge. Although males and

is caused by an abnormality in peroxisomal function.111,203,298 Cataracts occur in all patients.65,284 The eyes are otherwise normal on histopathological examination (D. Wilson and R. Weleber, personal communications). The rhizomelic autosomal recessive form of chondrodysplasia punctata maps to 6q22–q24 and results from mutations in the PEX7 gene that encodes the peroxisomal type 2 targeting signal receptor PTS2.21

Cataract surgery is performed if lenticular opacities are visually significant in the dominant varieties of the disease. In the rhizomelic form, cataract surgery was withheld in the past because of poor prognosis for life, but with current survival of patients with this disease late into the first decade, we favor early surgery and visual rehabilitation. Life expectancy and mental development are normal in the dominant varieties. Orthopedic problems are frequent from the asymmetrical shortening of the limbs or scoliosis.

Spranger et al. concluded that the form of chondrodysplasia punctata to which the Conradi–Hunermann eponym is appropriately applied has predominantly epiphyseal, frequently asymmetrical calcifications and dysplastic skeletal changes, a relatively good prognosis, and autosomal dominant inheritance.268 They concluded that cataracts occur in only 17% of cases as compared with a frequency of 72% in the rhizomelic form, which is recessive and is usually lethal in the first year of life. Skin changes occur in about 28% of cases of both forms. Happle suggested that cataracts are consistently absent in the autosomal dominant form and present in about two-thirds of the rhizomelic and X-linked dominant forms.105

Conditions confused with chondrodysplasia punctata include Zellweger cerebrohepatorenal syndrome and multicentric epiphyseal ossification in multiple epiphyseal dysplasia.

Homocystinuria

Homocystinuria is an autosomal recessive disease characterized in the untreated state by mental retardation, coarse fair hair, malar flush, and a thromboembolic diathesis. Patients have a marfanoid body habitus and have lens dislocation, hence the clinical confusion with the Marfan syndrome. Two main categories of homocystinuria are recognized.190 The most common type or classical homocystinuria is caused by a deficiency of cystathionine -synthase, which catalyzes the transsulfuration of homocysteine to cystathionine in the presence of pyridoxine.

significance have been noted in the retinal periphery of some patients with the disease.

Lens fringe or ragged zonules have been described in some patients with homocystinuria.223,224 A characteristic thick periodic acid–Schiff- (PAS-) positive layer composed of short filaments of zonular origin is demonstrated histopathologically over the ciliary epithelium. The degree of zonular abnormality is related to the age of the patient.

All patients with dislocated lenses without a clear history of trauma should have quantification of serum amino acids to rule out homocystinuria. An episode of anterior dislocation of the crystalline lens in a patient with presumed Marfan syndrome should suggest the diagnosis of homocystinuria. Patients with homocystinuria are initially supplemented with 50 to 1000 mg/day of oral vitamin B6; this leads to clinical and biochemical improvement in about 50% of patients. Nonresponders are started on a diet low in methionine and supplemented with cystine. Betaine facilitates the conversion of serum homocystine to methionine and significantly reduces the symptoms of homocystinuria. Recent studies have demonstrated that neonatal screening, detection of the disease at birth, and appropriate therapy prevent the development of mental retardation, myopia, and subluxation of the lens. Patients with homocystinuria are placed on platelet antiaggregation agents such as dipyridamole and acetylsalicylic acid to prevent vasoocclusive or thromboembolic events.

In patients who present with lens dislocation into the anterior chamber, dilation of the pupil and positional manipulation may be sufficient to return the lens to the posterior chamber. Patients are then placed on miotics and a peripheral laser iridotomy is performed. With time, however, the pupillary sphincter may infarct and the lens subluxates into the anterior chamber, necessitating surgical removal. Because of the risk of thromboembolic phenomena with general anesthesia and the complications of surgery, conservative management of the dislocated lens is preferred. Survival is good in vitamin B6 responders, and a normal lifespan is expected. Patients with other types have shortened survival depending on the type of mutation, severity of the disease at diagnosis, and the time of institution of therapy. The need for any surgery should be carefully evaluated. Death from general anesthesia has been reported on several occasions. Good hydration and medications that inhibit platelet aggregation should be given before surgery.

SKIN DISORDERS

Albinism

Albinism refers to the absence or reduction in the amount of melanin in the skin, eye, or both. Diseases featuring albinism are genetically determined and involve defects of melanogenesis. In tyrosinase-negative oculocutaneous albinism, the defect involves the enzyme tyrosinase, which catalyzes the conversion of tyrosine to dihydroxyphenylalanine (DOPA) and of DOPA to DOPA quinone.141 In type II or tyrosinase-positive albinism, as well as in autosomal recessive ocular albinism and in the Prader–Willi plus albinism syndrome, the defect lies in the P gene located on 15q11–q13.

Albinism has an overall prevalence of about 1 in 20,000 individuals. In the United States, the frequency of tyrosinasenegative albinism is 1 in 39,000 of the white population and 1 in 28,000 of the black population, with a gene frequency of 1%. The prevalence of X-linked ocular albinism is about 1 in 50,000.142 There are nine forms of oculocutaneous albinism, at least two forms of ocular albinism and a number of disorders with dermal hypopigmentation without ocular albinism. Clinically, patients who have no skin, hair, or ocular pigment and do not tan at all have tyrosinase-negative oculocutaneous albinism. Patients who have any amount of pigment, and those who develop a suntan, are classified as having type II or tyrosinasepositive albinism. The hairbulb incubation test is the definitive way to assign patients into one of these two categories, but is of no practical value as the diagnosis can be made with relative certainty based on clinical findings.138 Patients with the Chediak–Higashi syndrome have tyrosinase-positive oculocutaneous albinism and susceptibility to gram-positive infections and lymphoreticular malignancies. They have characteristic giant cytoplasmic inclusions in peripheral leukocytes.307 In the Hermanski–Pudlak syndrome,110 which is very common in Puerto Ricans, there is defective platelet aggregation and patients develop progressive restrictive lung disease and bowel disorders that may lead to death in the third and fourth decades of life (Fig. 5-10). The gene for tyrosinase has been mapped to 11q14–q22.8

Ocular albinism is X-linked recessive78 and has been mapped to the short arm of the X chromosome.14,210 Pedigree analysis and the presence of a mosaic pattern of retinal pigment epithelium

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FIGURE 5-10C. (continued).

(RPE) and choroidal pigmentation in carrier females allow diagnosis. Skin biopsies reveal macromelanosomes in melanocytes,200 a finding that indicates that the skin is involved as well. Black patients may retain a fair amount of uveal pigment, leading to the picture of ocular albinism cum pigmento.199 Rarely, patients appear to have autosomal recessive ocular albinism.188 Such patients have mutations in the P gene on chromosome 15q11–q13.157 The P protein is a transmembrane polypeptide that may transport small molecules such as tyrosine, the precursor of melanin. Ocular albinism is a leading cause of nystagmus in male infants and children. Slit lamp examination for iris transillumination and examination of the ocular fundus of carrier mothers are essential to rule out this condition in the child with nystagmus.

The ocular features of albinism include nystagmus, strabismus, macular hypoplasia, and absence of pigment in the retinal pigment epithelium and uveal tract with iris transillumination, prominence of choroidal vessels, and high astigmatic refractive errors.142 Although photophobia is generally believed to be a major symptom of albinos, this has not been a universal experience, and sunglasses may further compromise the reduced visual acuity of some patients. Abnormal decussation of temporal optic nerve fibers in the optic chiasm is present in most, if not all,

forms of albinism.62 Visual acuity in patients with albinism usually clusters around 20/100 to 20/200, although acuities as good as 20/40 have been observed in some patients with tyrosinase-positive oculocutaneous albinism. The association of oculocutaneous albinism and anterior chamber cleavage malformations may not be coincidental292 (and personal observations).

Children with albinism should be carefully refracted and any error of refraction fully corrected to prevent anisometropic amblyopia. Strabismus is corrected surgically, although patients never achieve binocular vision. Referrals for special education and low-vision aids may be necessary, although most children attend regular school. Monocular telescopes may be prescribed at 5 or 6 years of age. Albino children, as are all children with low vision, are allowed to hold their reading material as close to their eyes as they wish; they should be seated in the front row in class.

Ochronosis

Ochronosis refers to the deposition of golden-yellowish- brownish pigment in the skin and eyes of patients with alkaptonuria. This autosomal recessive disorder affects 1 of 250,000 newborns and results from a deficiency of the enzyme homogentisic acid oxidase or homogenitsate 1,2-dioxygenase, whose gene maps to 3q21–q24.69 The disease is most common in Slovakia and in the Dominican Republic. Homogentisic acid is an intermediate in the degradation pathway of tyrosine and phenylalanine. When it accumulates in the disease, it is excreted unchanged in the urine. It is then transformed into the ochronotic pigment benzoquinone acetic acid and its polymers in cartilage and connective tissue through the action of homogentisic acid polyphenol oxidase. In the urine homogentisic acid is oxidized to melanin-like products, especially in an alkaline pH, resulting in the dark urine of patients with alkaptonuria and the black diapers of babies with the disorder. The diagnosis of alcaptonuria relies on the demonstration of homogentisic acid in the urine because it is absent in normal individuals.151

Exogenous ochronosis may develop in persons who use carbolic acid (phenol) dressings chronically for the treatment of ulcers. Less commonly it may be seen in black women who use hydroquinone bleaching creams and in patients who have taken large doses of some antimalarial agents.51