Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

disease (OMIM 300009) (16, 268).

Glaucoma in Lowe syndrome results from a primary filtration-angle anomaly, likely with additional abnormalities secondary to removal of concurrent congenital cataracts. In a small retrospective gonioscopic study of eyes in patients with Lowe syndrome, anterior insertion of the iris, narrowing of the ciliary body band, and decreased visibility of the scleral spur were observed. Goniotomy surgery was uniformly unsuccessful in controlling the glaucoma, perhaps because of the superimposed adverse effects of cataract surgery on the filtration-angle structures. Nonangle surgical interventions are needed to control most cases, although selected milder cases of glaucoma have been managed medically (269) (Fig. 14.19).

Michel Syndrome

Michel syndrome is characterized by congenital anomalies of the anterior ocular segment, eyelids, and skeletal system and has an apparent autosomal recessive pattern of transmission (270, 271). This condition can be caused by mutations in the FGF3 gene, locus 11q13 (OMIM 610706) (16). Tekin (272) proposed that this syndrome be called deafness with labyrinthine aplasia, microtia, and microdontia (LAMM). Ocular findings include corneal opacities, conjunctival telangiectasia, and iridocorneal adhesions with blepharoptosis, blepharophimosis, and telecanthus; systemic findings include oromandibular anomalies, short stature, clinodactyly, subnormal intelligence, and hearing loss. Glaucoma may occur in eyes with extensive anterior segment anomalies (270).

Figure 14.19 A 13-year-old boy with Lowe syndrome and glaucoma controlled with medication use. He has aphakia in both eyes after removal of congenital cataracts, and has small stature, developmental delay, and esotropia.

Mucopolysaccharidoses

The MPS constitute a group of inherited disorders caused by deficiency of specific lysosomal enzymes

needed for the degradation of glycosaminoglycans, or mucopolysaccharides. The accumulation of partially degraded glycosaminoglycans causes interference with cell, tissue, and organ function. Deficiency of alpha-L-iduronidase (from mutations in the IDUA gene, locus 4p16.3) can result in a wide range of phenotypic involvement with three major recognized clinical entities: Hurler (MPS IH; OMIM 607014), Scheie (MPS IS; OMIM 607016), and Hurler-Scheie (MPS IH/S) syndromes. The Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression (16).

The prototype, Hurler syndrome, is an autosomal recessive disease with central nervous system, skeletal, and visceral abnormalities. The typical ocular finding is corneal clouding. Glaucoma has also been reported in Hurler syndrome and was thought to result from mucopolysaccharide-containing cells in the aqueous outflow system (273). In a 3-year-old child with Hurler syndrome and open-angle glaucoma, the IOP returned to normal after bone marrow transplantation (274). Medications and angle surgery are reasonable options to treat this glaucoma (Freedman SF, unpublished data).

Angle-closure glaucoma has occurred in Hurler-Scheie syndrome, responding initially to peripheral iridectomy and medications, but ultimately requiring clear lens extraction and then glaucoma drainagedevice implantation; the mechanism of angle closure remains elusive (Freedman SF, unpublished data). Patients with mucopolysaccharidosis type VI, the Maroteaux-Lamy syndrome, may have acute or chronic angleclosure glaucoma, which appears to be associated more with

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increased thickness of the peripheral cornea than with pupillary block (264, 275). This autosomal recessive disorder results from deficiency of the enzyme N-acetylgalactosamine-4-sulfatase, due to mutations in the gene ARSB (arylsulfatase B, locus 5q11-q13, OMIM 253200) (16).

Glaucoma (apparently with open angles) was also described in two siblings with mucopolysaccharidosis type IV, the Morquio syndrome (276). Two types of MPS IV are now recognized: (a) Morquio syndrome A, resulting from mutations in the gene encoding the enzyme galactosamine-6-sulfate sulfatase (GALNS; OMIM 612222; locus 16p24.3, OMIM 612222) and (b) Morquio syndrome B (OMIM 253010), a genetically distinct disorder with overlapping clinical features caused by mutation in the beta-galactosidase gene (GLB1; OMIM 611458) (16).

Nail-Patella Syndrome

The nail-patella syndrome, which includes dysplasia of the nails and absent or hypoplastic patella as cardinal features, has been associated with open-angle glaucoma. Two groups have reported cosegregation of primary open-angle glaucoma and nail-patella syndrome as the result of a pleiotropic effect of the gene causing nail-patella syndrome (LMX1B, gene map locus 9q34.1, OMIM 161200) (16, 277, 278).

Oculodentodigital Dysplasia

The systemic features of oculodentodigital dysplasia are hypoplastic dental enamel, microdontia, bilateral syndactyly, and a characteristic thin nose. Multiple ocular anomalies have been described, including glaucoma. There are probably several mechanisms of glaucoma in this syndrome, with reported cases of mild developmental abnormalities of the anterior chamber angle, gonioscopic changes resembling infantile glaucoma, and one case of chronic angle-closure glaucoma associated with bilateral microcornea (189, 279, 280). This autosomal dominant disorder is caused by mutation in the connexin43 gene (CJA1, gene locus 6q21-q23.2, OMIM 164200) (16).

Prader-Willi Syndrome

Prader-Willi syndrome, characterized by muscular hypotonia, hypogonadism, obesity, and mental retardation, is frequently caused by an abnormality of chromosome 15. This syndrome may be a contiguous gene syndrome due to deletion of the paternal copies of the imprinted SNRPN gene (OMIM 182279), the necdin gene (OMIM 602117), and possible other genes in the region 15q11-q13 (OMIM 176270) (16). Ocular findings include oculocutaneous albinism and congenital ectropion uveae, which may be associated with open-angle glaucoma (281). One patient with Prader-Willi syndrome, congenital ectropion uvea, and glaucoma had factor XI deficiency and the suggestion of a primary hypothalamic

defect (282). Rubinstein-Taybi Syndrome

Individuals with Rubinstein-Taybi (broad thumb) syndrome have mental and motor retardation and typical congenital skeletal deformities with characteristically large, broad thumbs and first toes. Ocular findings include bushy brows, hypertelorism, epicanthus, antimongoloid slant of eyelids, and hyperopia. Infantile or juvenile glaucoma has also been observed in several patients (283, 284 and 285). This autosomal dominant disorder is caused by mutation in the gene encoding the transcriptional coactivator CREB-binding protein (gene locus 16p13.3, OMIM 180849) (16) (Fig. 14.20).

Figure 14.20 A 3-year-old girl with Rubinstein-Taybi (broad thumb) syndrome. She has 13.5-mm corneas and is followed up for suspected glaucoma, but IOPs and optic nerves have been normal thus far.

Stickler Syndrome and Similar Syndromes

Stickler syndrome, or hereditary progressive arthroophthalmopathy, is an autosomal dominant connective tissue dysplasia, characterized by ocular, orofacial, and generalized skeletal abnormalities (286). The Pierre Robin anomaly of mandibular hypoplasia, glossoptosis, and cleft palate may be seen in some patients. The most common ocular manifestations are high myopia, open-angle glaucoma, cataracts, vitreoretinal degeneration, and retinal detachment (287, 288). In one study of 39 patients from 12 families, 10% had ocular hypertension, which may be associated with numerous iris processes, suggestive of a developmental abnormality of the angle (288). Neovascular glaucoma has also been reported in association with Stickler syndrome (289). The open-angle glaucoma can usually be controlled medically, although miotics should be avoided if possible because of the potential for retinal detachment.

Three forms of Stickler syndrome have been recognized genetically and involve abnormalities in

collagen genes. The Stickler syndrome type I results from a mutation in the COL2A1 gene (OMIM 120140, locus 12q13.11-q13.2) and includes glaucoma among its ocular clinical features. The Stickler syndrome type II results from a mutation in the a1-polypeptide of collagen XI (COL11A1, OMIM

121280, locus 6p21.3) and includes reported glaucoma (16). The Stickler syndrome type III is caused by mutations in the collagen, type XI, alpha 2 gene (COL11A2, OMIM 120290, locus 1p21) and does not have reported ocular features (16). There is evidence for at least one more Stickler syndrome locus. Although the above-described forms of Stickler syndrome have an autosomal dominant inheritance P.240

pattern, an autosomal recessive form of this syndrome can be attributed to mutations in the COL9A1 gene (OMIM 120210.0002).

Figure 14.21 A 4-month-old infant girl with bilateral glaucoma, and buphthalmic left eye. The eye was blind with corneal exposure and highly elevated IOP, and enucleation was elected.

Wagner syndrome can be caused by mutation in the gene encoding chondroitin sulfate proteoglycan-2 (CSPG2; OMIM 118661, 5q13-q14) (16), also called versican, a proteoglycan found in the vitreous. Wagner syndrome and Marshall syndrome (which can result from mutations in the COL11A1 gene [OMIM 120280], as can Stickler type II) show some clinical overlap with one another and with Stickler syndrome, but they may be distinct disorders (290), and all can be associated with glaucoma (Figs. 14.21 and 14.22).

Weissengacher-Zweymuller syndrome (OMIM 277610), also called Pierre Robin syndrome with fetal chondrodysplasia, links to gene map locus 6p21.3 and is caused by a mutation in the COL11A2 gene (as in Stickler syndrome type III). Congenital glaucoma has been reported in a baby with this disorder (291).

Figure 14.22 Same child as in Figure 14.21, now 3 years of age, after enucleation of the left eye with prosthesis fitting. The right eye has medically controlled glaucoma but has a large, clear cornea, with very high myopia. Note the trachestomy due to coexisting Pierre Robin syndrome.

Waardenburg Syndrome

Waardenburg syndrome is an autosomal dominant disorder characterized by lateral displacement of the medial canthi; hyperplasia of the medial brows; a prominent, broad root of the nose; sectorial or complete iris heterochromia; congenital deafness; and a white forelock (292, 293). It is thought to represent a defect of neural crest-derived tissues and is caused by a mutation in the PAX3 gene (gene map locus 2q35, OMIM 193500) (16). Open-angle glaucoma is an uncommon finding, although it was present in one of Waardenburg's original cases, and it may be caused by a developmental abnormality of neural crest-derived tissues in the angle (293).

Walker-Warburg Syndrome

The Walker-Warburg syndrome, also known as the HARD±E syndrome, maps to gene locus 9q34.1 (OMIM 236670) (16). It is a congenital syndrome characterized by hydrocephalus (H), agyria (A), retinal dysplasia (RD), with or without encephalocele (±E), and it is usually fatal in the first year of life. Multiple eye abnormalities have been reported, including congenital glaucoma (294).

Cockayne Syndrome

Cockayne syndrome is an autosomal recessive disorder that is characterized by dwarfism and birdlike facies. Ocular manifestations include “salt and pep per” retinopathy, cataracts, corneal ulcers or opacities, nystagmus, hypoplastic irides, and irregular pupils. Although glaucoma has not been an associated condition, histopathologic examination of one case revealed a high insertion of the anterior uvea into the posterior aspect of the trabecular meshwork (295), similar to that seen in congenital glaucoma and the Axenfeld-Rieger syndrome.

SECONDARY CHILDHOOD GLAUCOMAS

Pediatric glaucoma may occur secondary to a wide variety of ophthalmic conditions (see Table 13.1). While secondary glaucoma is a consequence of another eye disease rather than a primary disorder of the aqueous humor filtration mechanism, the true mechanism of glaucoma in some conditions may be both primary and secondary. The distinction between primary glaucoma and secondary glaucoma has been largely abandoned in considering adult glaucomas, but continues to prove useful in the general classification of childhood glaucomas.

Trauma

Trauma-associated glaucoma in the pediatric population usually relates to an acute or secondary anterior chamber hemorrhage (hyphema). Rather than occurring acutely, the elevation of IOP elevation more commonly begins several days after acute blunt trauma, accompanied by a large initial hyphema or rebleeding. Clinical treatment of hyphema with moderately

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frequent administration of topical steroid, use of cycloplegics, and bedrest may decrease the risk of rebleeding. Children with sickle-cell hemoglobinopathies are especially susceptible to optic nerve damage with moderate IOP elevation, and should be followed up, as should all patients with hyphema, with serial examination and IOP measurement. Children presenting with elevated IOP in the setting of a hyphema can usually be managed with medications, and with gentle anterior chamber irrigation in refractory cases, because IOP often normalizes after the hyphema resolves, even in cases with angle recession. Patients showing angle recession on gonioscopic examination should be followed up long term, because the onset of chronic glaucoma may be delayed by years to decades (see Chapter 25). Intraocular Neoplasm

Neoplasms infrequently produce childhood glaucoma (see also Chapter 21). Advanced retinoblastoma is the most common cause of such glaucoma, usually due to neovascular glaucoma and angle dysfunction or closure rather than tumor cells in the anterior chamber (296). Medulloepithelioma, a neoplasm of the ciliary epithelium, can also induce secondary neovascular glaucoma (297).

Juvenile xanthogranuloma, a rare systemic disorder sometimes associated with histiocytic infiltration of the iris, can present with glaucoma due to spontaneous hyphema or the accumulation of histiocytes blocking the trabecular meshwork. Although conservative treatment with glaucoma medications, along with use of topical and systemic steroids, usually suffices, refractory cases may require surgical intervention, made challenging by the tendency for continued iris bleeding whenever the IOP is lowered (298).

Inflammation and Steroid-Related Glaucoma

Pediatric glaucoma secondary to chronic inflammation often presents in association with chronic anterior uveitis (e.g., antinuclear antibody-associated idiopathic uveitis or arthritis) and less often with other inflammatory conditions (299) (see also Chapter 22). Uveitis-associated glaucoma occurs by various possible mechanisms in these children. IOP elevation may result acutely from trabeculitis, trabecular obstruction, iris bombé, and pupillary block, or chronically from peripheral anterior synechiae, trabecular scarring or dysfunction, and steroid-induced trabecular obstruction. The diagnosis of uveitis-related glaucoma is sometimes delayed in children, because the IOP rise is thought to be steroid induced, but inflammation-related aqueous outflow reduction masks the true glaucoma when inflammation increases from steroid reduction. Judicious use of systemic steroid-sparing therapy (best comanaged with pediatric rheumatologists) often proves vital to manage refractory uveitis cases (300). Managing glaucoma secondary to uveitis requires control of the underlying inflammation, followed

initially by medical management, provided the anterior chamber angle remains open. Angle surgery often controls the IOP when medication is insufficient, but success is reduced in those eyes with extensive peripheral anterior synechiae and after cataract removal (301, 302); glaucoma drainage-device surgery has also been successful in refractory cases (303), whereas trabeculectomy surgery has a high incidence of complications in this population (304). Cycloablation should be used with extreme caution in patients with uveitic glaucoma, because of the risk of phthisis.

Lens-Induced Glaucoma

Acute glaucoma with pupillary block and angle closure may develop in any child with ectopia lentis (from various causes, e.g., homocystinuria, Weill-Marchesani syndrome, Marfan syndrome), because of forward shifting of the lens into the pupillary aperture (see also Chapter 18). The angle-closure attack can sometimes be broken by nonsurgical means, including supine patient positioning, manual displacement of the lens posteriorly in the eye, medication with aqueous suppressants, mydriatics, and analgesics, and subsequent miotic use. Iridectomy helps prevent repeated IOP elevation but not anterior lens displacement, and lensectomy may ultimately be needed (but is more safely performed in eyes with controlled IOP) (305).

Aphakic (Pseudophakic) Glaucoma

Glaucoma often occurs after removal of congenital or developmental cataracts, with reported incidence ranging from 3% to 41%. This aphakic or pseudophakic glaucoma represents a serious cause of late visual loss in eyes after cataract removal. Aphakic or pseudophakic glaucoma is usually of the openangle type, asymptomatic, and delayed in onset for many years after cataract removal (median postsurgical onset, 5 years) (306, 307). Factors associated with an increased risk for glaucoma after cataract extraction include cataract removal in the first year of life, microphthalmia, and coexistence of persistent fetal vasculature. The pathogenesis of open-angle glaucoma after cataract removal remains elusive; proposed theories include both mechanical (trabecular collapse due to loss of zonular tension on the scleral spur) and chemical (postoperative inflammatory trabecular damage or vitreous-derived toxic factors), with no proof of either (308).

When angle-closure glaucoma occurs in an aphakic or pseudophakic eye, prompt peripheral iridectomy (and sometimes synechialysis or anterior vitrectomy, or both) is mandatory, and often curative. By contrast, medical therapy is the first-line treatment in aphakic or pseudophakic eyes with openangle glaucoma; the angle, albeit open, often has typical acquired angle abnormalities (309). When medical therapy has failed to control aphakic or pseudophakic glaucoma, angle surgery often has disappointing results, although 360-degree trabeculotomy sometimes temporizes in cases of early-onset glaucoma (Freedman SF, unpublished data). Trabeculectomy with antiproliferative agents should be used with extreme caution in aphakic or pseudophakic eyes because of the likelihood of bleb scarring and the high risk of endophthalmitis should postoperative bleb infection occur. Moderate success has been reported with glaucoma drainage-device surgery, and

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cycloablation in selected refractory cases (123, 129). Intraocular lens implantation, either primary or secondary, does not protect against glaucoma after cataract removal (310).

Miscellaneous Causes

Children may develop glaucoma in response to topical steroid use (see Chapter 23) and because of various other reported causes (Table 13.1). Although there is no consensus on the optimal strategy for managing secondary pediatric glaucoma, determining the cause in each case assists the clinician in planning reasonable treatment options.

KEY POINTS

Childhood glaucomas constitute a heterogenous group of serious conditions.

Current classification systems are varied, but all fall short of complete consistency and consensus.

Glaucoma disorders in children share clinical features often related to the age of onset and the magnitude of IOP elevation.

Many of the developmental glaucomas have coexisting ocular and systemic abnormalities. These disorders, most of which have a genetic basis, are typically bilateral and are usually diagnosed at birth or in early childhood.

Children may also develop glaucoma secondary to acquired outflow pathway defects, many of which are shared by adults (examples include uveitic and traumatic glaucoma). One notable exception is glaucoma occurring after surgical removal (in childhood) of congenital or developmental cataracts.

Although genetic advances may assist in our understanding of the complex interplay between genotype and phenotype in developmental glaucomas, much future work awaits before visual loss from childhood glaucoma will be adequately curtailed.

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