Ординатура / Офтальмология / Английские материалы / The Pediatric Glaucomas_Mandal, Netland_2006

capsulopupillary vessels are the lateral portion of the vascular tunic of the lens.

Each of these portions of the vascular tunic of the lens (anterior pupillary membrane, lateral capsulopupillary vessels and the posterior hyaloid system) atrophies in later embryonic development, leaving the lens avascular in postnatal life. Failure of the anterior portion to atrophy produces a persistent pupillary membrane. If the posterior hyaloid system does not involute, persistent hyperplastic primary vitreous may result.57

In aniridia, although other abnormalities of neural crest cells are possible, several mechanisms involving the capsulopupillary vessels have been suggested,57 including absence of the superficial stromal directional membrane, primary failure of optic cup growth, and persistence of capsulopupillary vessels. If the pupillary membrane fails to form primarily, the optic cup will lack a directional membrane, and only a rudimentary iris will develop. Also, as the optic cup grows axially, it carries with it a layer of mesoderm that will become the deep stromal layer of the iris. A primary failure of the optic cup to grow in may result in a rudimentary iris. In addition, persistence of the capsulopupillary vessels extending from the iris to the lens may block the optic cup as it grows axially between the iris stroma and the lens.

Developmental genetics

Experimental models for the anterior chamber angle have been developed that demonstrate organization of cellular and extracellular matrix components with a developmental sequence comparable to humans.58 Analysis of human fetal eyes has shown that uveal trabecular endothelial cells can be identified in early (12 to 22 weeks) development, and increases of extracellular matrix and intertrabecular spaces can be quantitated.41,59 At the same time, understanding of the molecular genetics of primary congenital glaucoma has improved, suggesting several genes that may play a role in the development of the anterior chamber.

The majority of patients with primary congenital glaucoma

demonstrate mutations in the cytochrome P4501B1 gene (CYP1B1). This gene is expressed in tissues in the anterior

chamber angle of the eye, suggesting a role in anterior chamber angle development.60,61 Anterior segment dysgenesis may occur in patients with mutations of chromosome 6 (6p25), implicating the forkhead transcription-factor gene (FOXC1) in development of the anterior chamber angle.62–66 The specific morphogens involved in the development of the human anterior chamber angle are not known at this time. In an experimental glaucoma model, anterior segment anomalies resembling those in human developmental glaucoma may be modified by tyrosinase, suggesting a role for this pathway in the development of the anterior chamber angle.67

Conclusion

The current knowledge about the development of the structures of the anterior segment has provided a theoretical basis for the developmental abnormality in congenital glaucoma

and other anterior segment anomalies. Evidence is mounting that neural crest cells make a prominent contribution to the embryonic derivation of these structures, and this realization may help provide a better explanation for the pathogenesis of the developmental glaucomas. Relatively little is known at present about the factors that induce the embryonic neural crest cells to differentiate into the structures of the anterior segment in the normal eye, and even less is understood about the causes of abnormalities that result in ocular neurocristopathies.

References

1.Duke-Elder S. System of ophthalmology, Vol III. CV Mosby: St. Louis; 1964.

2.Mann I. The development of the human eye. Cambridge University Press: Cambridge; 1928.

3.Mann I. The development of the human eye, 3rd edn. Cambridge University Press: Cambridge; 1964.

4.Streeter GL. Developmental horizons in human embryos. Contrib Embryol 1951; 34:165–196.

5.Kupfer C, Kaiser-Kupfer MI. New hypothesis of developmental anomalies of the anterior chamber associated with glaucoma. Trans Ophthalmol Soc UK 1978; 98: 213–215.

6.Bahn CF, Falls HF, Varley GA et al. Classification of corneal endothelial disorders based on neural crest origin. Ophthalmology 1984; 91:558–563.

7.Tripathi BJ, Tripathi RC. Embryology of the anterior segment of the human eye. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:3–38.

8.Johnston MC, Noden DM, Hazelton RD, et al. Origins of avian ocular and periocular tissues. Exp Eye Res 1979; 29:27–43.

9.Le Douarin N. Migration and differentiation of neural crest cells. In: Moscona AA, Monroy A, eds. Current topics in developmental biology, Vol 16. Hunt RK, ed. Neural development, Part II. Academic Press: New York; 1980.

10.Le Lievre C, Le Douarin N. Mesenchymal derivatives in the neural crest: analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol 1975; 34:125–154.

11.Noden DM. An analysis of migratory behavior of avian cephalic neural crest cells. Dev Biol 1975; 42:106–130.

12.Noden DM. The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Dev Biol 1978; 67:296–312.

13.Noden DM. Periocular mesenchyme: neural crest and mesodermal interactions. In: Jakobiec FA, ed. Ocular anatomy, embryology, and teratology. Harper & Row: Hagerstown, MD; 1982.

14.O’Rahilly R. The prenatal development of the human eye. Exp Eye Res 1975; 21:93–112.

15.Ozanics V, Jakobiec FA. Prenatal development of the eye and its adnexa. In: Jakobiec FA, ed. Ocular anatomy, embryology, and teratology. Harper & Row: Hagerstown, MD; 1982.

16.Wulle KG. Electron microscopy of the fetal development of the corneal endothelium and Descemet’s membrane of the human eye. Invest Ophthalmol 1972; 11:897–904.

17.Hay ED. Development of the vertebrate cornea. Int Rev Cytol 1980; 63:263–322.

18.Barkan O. Pathogenesis of congenital glaucoma. Gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955; 40:1–11.

19.Allen L, Burian HM, Braley AE. A new concept of the development of the anterior chamber angle. Its relationship to developmental glaucoma and other structural anomalies. AMA Arch Ophthalmol 1955; 53:783–798.

20.Smelser GK, Ozanics V. The development of the trabecular meshwork in primate eyes. Am J Ophthalmol 1971; 71:366–385.

21.Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485.

22.Worst JGF. The pathogenesis of congenital glaucoma. An embryological and goniosurgical study. Charles C. Thomas: Springfield; 1966.

23Hansson HA, Jerndal T. Scanning electron microscopic studies on the development of the iridocorneal angle in human eyes. Invest Ophthalmol 1971; 10:252–265.

24.Van Buskirk EM. Clinical implication of iridocorneal angle development. Ophthalmology 1981; 88:361–367.

25.Tawara A, Inomata H. Developmental immaturity of the trabecular meshwork in congenital glaucoma. Am J Ophthalmol 1981; 92:508–525.

26.Maul E, Strozzi L, Munoz C, et al. The outflow pathway in congenital glaucoma. Am J Ophthalmol 1980; 89:667–673.

27.Shields MB. Axenfeld–Rieger syndrome. A theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983; 81:736–784.

28.Maumenee AE. The pathogenesis of congenital glaucoma. A new theory. Trans Am Ophthalmol Soc 1958; 56:507–570.

29.Maumenee AE. The pathogenesis of congenital glaucoma; a new theory. Am J Ophthalmol 1959; 47:827–858.

30.Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Trans Am Ophthalmol Soc 1962; 60:140–146.

31.Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176.

32.Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157.

33.Worst JGF. Congenital glaucoma. Remarks on the aspect of chamber angle, ontogenic and pathogenic background, and mode of action of goniotomy. Invest Ophthalmol 1968; 7:127–134.

34.Sampaolesi R, Argento C. Scanning electron microscopy of the trabecular meshwork in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 1977; 16:302–314.

35.Rodrigues MM, Spaeth GL, Weinreb S. Juvenile glaucoma associated with goniodysgenesis. Am J Ophthalmol 1976; 81:786–796.

36.Tawara A, Inomata H. Developmental immaturity of the trabcular meshwork in juvenile glaucoma. Am J Ophthalmol 1984; 98:82–97.

37.Kupfer C, Ross K. The development of outflow facility in human eyes. Invest Ophthalmol 1971; 10:513–517.

38.Kupfer C, Kaiser-Kupfer MI. Observations on the development of the anterior chamber angle with reference of the pathogenesis of congenital glaucomas. Am J Ophthalmol 1979; 88:424–426.

39.DeLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19.

40.Beauchamp GR, Lubeck D, Knepper PA. Glycoconjugates, cellular differentiation, and congenital glaucoma. J Pediatr Ophthalmol Strabismus 1985; 22:149–155.

41.McMenamin PG. A quantitative study of the prenatal development of the aqueous outflow system in the human eye. Exp Eye Res 1991; 53:507–517.

42.Tawara A, Inomata H. Distribution and characterization of sulfated proteoglycans in the trabecular tissue of goniodysgenetic glaucoma. Am J Ophthalmol 1994; 117:741–755.

43.Cook CS. Experimental models of anterior segment dysgenesis. Ophthalmic Paediatr Genet 1989; 10:33–46.

44.Shields MB. A common pathway for developmental glaucomas. Trans Am Ophthalmol Soc 1987; 85:222–237.

45.Edward WC, Torczynski E. Neural crest cell behaviour and facial anomalies. Pers Ophthalmol 1981; 5:47.

46.Kenyon KR. Mesenchymal dysgenesis in Peter’s anomaly, sclerocornea and congenital endothelial dystrophy. Exp Eye Res 1975; 21:125–142.

47.Schottenstein EM. Peters anomaly. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:887–897.

48.Waring GO, Rodrigues MM, Leibson PR. Anterior chamber cleavage syndrome: a stepladder classification. Surv Ophthalmol 1975; 20:3.

49.Cibis GW, Tripathi RC, Tripathi BJ. Glaucoma in Sturge-Weber syndrome. Ophthalmology 1984; 91:1061.

50.Tripathi RC, Tripathi BJ, Cibis GW. Sturge-Weber syndrome. In: Gold DH, Weinglist TA, eds. The eye in systemic disease. Lippincott: Philadelphia; 1987.

51.Weiss JS, Ritch R. Glaucoma in the phakomatoses. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:899–924.

52.Collins ET, Batten RD. Neurofibroma of the eyeball and its appendages. Trans Ophthalmol Soc UK 1905; 25:248.

53.Hoyt CM, Billson F. Buphthalmos in neurofibromatosis: is it an expression of giantism? J Ped Ophthalmol 1977; 14:228–234.

54.Leib WA, Wirth WA, Geeraets WJ. Hydrophthalmos and neurofibromatosis. Confin Neurol 1958; 19:239.

55.Wheeler JM. Plexiform neurofibromatosis involving the choroid, ciliary body and other structures. Am J Ophthalmol 1937; 20:368.

56.Wiener A. A case of neurofibromatosis with buphthalmos. Arch Ophthalmol 1925; 54:481.

57.Laibson PR, Waring GO. Disease of the cornea. In: Harely RD, ed. Paediatric ophthalmology. WB Saunders: Philadelphia; 1975.

58.Smith RS, Zabaleta A, Savinova OV, John SW. The mouse anterior chamber angle and trabecular meshwork develop without cell death. BMC Dev Biol 2001; 1:3.

59.McMenamin PG. Human fetal iridocorneal angle: a light and scanning electron microscopic study. Br J Ophthalmol 1989; 73:871–879.

60.Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye 2000; 14(Pt 3B):422–428.

61.Stoilov I, Jansson I, Sarfarazi M, Schenkman JB. Roles of cytochrome p450 in development. Drug Metabol Drug Interact 2001; 18:33–55.

62.Jordan T, Ebenezer N, Manners R, McGill J, Bhattacharya S. Familial glaucoma iridogoniodysplasia maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly. Am J Hum Genet 1997; 61:882–888.

63.Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/wingedhelix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998; 63:1316–1328.

64.Smith RS, Zabaleta A, Kume T, et al. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet 2000; 9:1021–1032.

65.Nishimura DY, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001; 68:364–372.

66.Lehmann OJ, Ebenezer ND, Ekong R, et al. Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions. Invest Ophthalmol Vis Sci 2002; 43:1843–1849.

67.Libby RT, Smith RS, Savinova OV, et al. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 2003; 299:1578–1581.

Introduction

Incidence

Heredity

Genetic studies

Genetic counseling

The majority of patients (about 60%) are diagnosed by age 6 months, and 80% are diagnosed within the first year of life. A slight predominance of males is common (about 65%), and involvement is usually bilateral (about 70%). Figure 4.1 shows the demographic data for a group of Indian patients with primary congenital glaucoma. Except for the high rate of consanguinity, the demographic data is typical of primary congenital glaucoma.

Introduction

In the pediatric age group, glaucoma is a heterogeneous group of disorders. Primary congenital glaucoma is rare, with an incidence of approximately 1 in 10 000 births in Europe and the United States. Nonetheless, although it is less common compared with primary open-angle glaucoma in adults, primary congenital glaucoma is the most common form of glaucoma in children. The majority of cases of primary congenital glaucoma occur sporadically. Most of these patients demonstrate a recessive pattern with incomplete or variable penetrance and possibly multifactorial inheritance, while some pedigrees suggest an autosomal dominant inheritance. Several genetic loci have been identified that may play a role in primary congenital glaucoma. Genetics of disorders associated with glaucoma in children have also been evaluated, including Axenfeld–Rieger anomaly and aniridia.

Incidence

Primary congenital glaucoma is a rare inherited eye disorder which accounts for 0.01–0.04% of total blindness. The disease is usually manifested at birth or early childhood (before 3 years of age). The incidence of primary congenital glaucoma varies from one population to another. In western developed countries, the incidence is approximately 1 in 10 000 births.1

The incidence of primary congenital glaucoma is increased when founder effect or a high rate of consanguinity is found in a population. The ‘founder effect’ is a gene mutation observed in high frequency in a specific population due to the presence of that gene mutation in a single ancestor or a small number of ancestors. The incidence is 1 in 1250 in the Slovakian Roms (Gypsies),2 1 in 2500 in the Middle East,3 and 1 in 3300 in Andhra Pradesh, India.4 In the Indian state of Andhra Pradesh, the disease accounts for 4.2% of all childhood blindness.4 The high incidence of the disease observed among the Roms may be due to a founder effect, whereas consanguinity may play an important role in the high incidence observed in the Middle East and India.5–8

Heredity

Most cases of primary congenital glaucoma occur sporadically. Patients with a familial pattern usually show a recessive inheritance with incomplete or variable penetrance and possibly multifactorial inheritance. Transmission of disease in successive generations was also reported in several pedigrees, suggesting an autosomal dominant inheritance pattern.9,10 Pseudodominant mode of inheritance may also occur in a few patients with primary congenital glaucoma. These families show parent–child transmission of the disease.5,6,8,11 The disease is familial in 10–40% of cases with variable penetrance (40–100%).1,6,12,13

Genetic studies

Loci of recessively inherited primary congenital glaucoma (gene symbol GLC3) have been identified by genetic linkage analysis (Table 4.1). To date, GLC3A has been mapped to

Involvement Bilateral

Heredity Sporadic

Figure 4.1 Demographic data for 129 patients with primary congenital glaucoma from L.V. Prasad Eye Institute in Hyderabad, India. There is a high incidence of consanguinity (47%) in this population. The majority of cases are bilateral (86%) with 14% unilateral, there is a slight majority of males (57%), and most (87%) are sporadic with 13% familial, all of which are typical of primary congenital glaucoma.

Table 4.1 Known genetic loci for primary congenital glaucoma

AR, autosomal recessive; MIM, Mendelian Inheritance in Man number.

chromosome 2 (2p21)14 and GLC3B to chromosome 1 (1p36).15 The majority of patients with congenital glaucoma map to GLC3A on chromosome 2 (2p21). Families linked to these loci display severe phenotypes with autosomal recessive inheritance pattern. Some types of juvenile onset glaucoma

that have an autosomal dominant inheritance pattern have been mapped to chromosome 1q23–q25 (TIGR/MYOC gene).

The positional candidate gene approach has shown that mutations in CYP1B1 gene (encoding the cytochrome P450

enzyme) in the GLC3A locus are associated with the primary congenital glaucoma phenotype.5 Mutated gene in GLC3B is yet to be identified. The predominant genetic cause of this disorder in the Middle East (Turkey and Saudi Arabia) is mutation in CYP1B1 gene. Several mutations from various ethnic backgrounds have been implicated in the pathogenesis

of this disorder. To date more than 50 mutations in the coding region of CYP1B1 gene have been identified.6–8,16–30 It

has been reported that 87% of familial and 27% of sporadic cases are due to mutations in this gene.10

Extensive allelic heterogeneity has been noticed in several populations except the Slovakian Roms. Molecular genetic studies in Slovakian Roms revealed that there is locus, allelic, and clinical homogeneity of primary congenital glaucoma in this population. This homogeneity observed was due to the founder effect of a single ancestral mutation E387K, which is found segregating with the disease phenotype in this community.7 Analysis of families from Turkey and Slovakia showed complete penetrance, whereas Saudi Arabian families showed reduced penetrance.10,31 Reduced penetrance was

attributed to the possible existence of a dominant modifier locus that is not genetically linked to CYP1B1.18

Only a small proportion of Japanese families (20%) showed mutations in CYP1B1, whereas majority of the families (85%)

in Middle East showed mutations in this gene.21 In several families, no mutations were found in the CYP1B1 coding

regions or a single heterozygous mutation was found. This could be due to mutations in the promoter or regulatory sequences of the gene, or could be linked to another locus for primary congenital glaucoma.10,32

Digenic inheritance is an inheritance mechanism resulting from the interaction of two non-homologous genes. Digenic inheritance in glaucoma has been shown recently in two

instances: in early-onset glaucoma in humans and also in the mouse. CYP1B1 and MYOC mutations were identified in

early-onset glaucoma in humans,33 whereas mutations in CYP1B1 and FOXC1 were detected in the mouse with early-

onset glaucoma.34 This suggests that mutations in genes other than CYP1B1 could cause primary congenital glaucoma.

Primary congenital glaucoma is caused by unknown developmental defects in the trabecular meshwork and anterior chamber angle of the eye.10 Because angle structures are mainly derived from the neural crest cells, it is possible that defects in genes expressed in neural crest cells could also contribute to primary congenital glaucoma.

Primary congenital glaucoma phenotypes have been associated with CYP1B1 mutations in Indian patients.8 Reddy

and coworkers screened 146 primary congenital glaucoma patients from 138 pedigrees and reported six distinct CYP1B1

mutations from 45 primary congenital glaucoma patients from India.25 These include four novel mutations (ins 376 A or Ter@223{frameshift}, P193L, E229K, and R390C) and two known mutations (G61E and R368H). Of the mutations identified, R368H was the predominant mutation causing primary congenital glaucoma in India. This allele was found in a very low proportion of patients from the Middle East and Brazil, but in India 16.2% of the patients screened had this mutation.25 This indicates that the mutation frequency varies depending on the geographical location as well as ethnic background.

Though a spectrum of CYP1B1 mutations from various ethnic backgrounds have been implicated in the pathogenesis of primary congenital glaucoma, very few studies have reported genotype–phenotype correlations. A severity index was developed for primary congenital glaucoma, and the severity of disease was correlated with the genotype.32 All patients with severe phenotypes showed poor prognoses (r = 0.976; P < 0.0001). Of the mutations studied, frameshift and R390C homozygous mutations were associated with very severe phenotypes and very poor prognoses. This approach may help guide therapy and counsel the afflicted family regarding the likelihood of progression of the disorder.

Genetic studies of Axenfeld–Rieger anomaly

Axenfeld–Rieger anomaly is a congenital maldevelopment of the anterior segment of the eye that may be associated with glaucoma.35 It is inherited as an autosomal dominant trait, and 50–75% of the patients develop glaucoma.36 The anomaly is actually a spectrum of developmental defects of the anterior chamber of the eye, with wide variability in expression. Ocular features of Axenfeld–Rieger anomaly include prominent anterior Schwalbe’s line, abnormal angle tissue, hypoplastic iris, polycoria, corectopia, and glaucoma.37 The gene for this disorder has been mapped to the chromosome 6p25 region.36 A few mutations in a forkhead/winged-

helix transcription factor gene FOXC1 (formerly known as FREAC3 and FKHL7) have been implicated in the pathogenesis of this disorder.38–41

Genetic studies of aniridia

Aniridia is a hereditary anomaly associated with varying degrees of absence of iris tissue, occurring in approximately 1.8 per 100,000 live births. The incidence of glaucoma in aniridia ranges from 6 to 75% in clinical studies.42 In the

majority (approximately 85%) of patients, aniridia is inherited as an isolated, autosomal dominant trait, with variable expressivity. In the isolated form, aniridia is not associated with other systemic manfestations. In isolated aniridia, two-thirds of the patients have an affected parent (familial), while the remaining one-third of cases are the result of new mutations (sporadic). Wilms’ tumor occurs more frequently in sporadic cases. Approximately 13% of patients have an autosomal dominant form of aniridia that is associated with Wilms’ tumor, genitourinary abnormalities, and mental retardation (WAGR syndrome). Two percent of patients affected with aniridia have an autosomal recessive form that is associated with cerebellar ataxia and mental retardation (Gillespie’s syndrome).

Aniridia is frequently the result of a deletion on chromosome 11. The genetic locus for aniridia has been established as the PAX6 gene, which is located on the eleventh chromosome, specifically on the 11p13 segment.43 Various PAX6 gene mutations have been described to account for aniridia.44–51 Molecular genetic techniques have been used to screen the PAX6 gene for mutations for prenatal diagnosis of aniridia.52 Fluorescence in situ hybridization (FISH) testing has been helpful in identifying patients at risk for Wilms’ tumor.53–55

Genetic counseling

Genetic counseling for glaucoma patients usually includes providing information about the risks of glaucoma in children and other close relatives.42 It is the physician’s responsibility to inform patients and their relatives of the risk of developing the disease and the implications of the disease for their health. Also, patients must be informed of the need for early, regular monitoring in potentially affected offspring. Rarely, glaucoma patients in their reproductive years may make reproductive decisions based on information from the physician. As the understanding of the genetic basis of childhood glaucomas improves, and DNA-based diagnostic tests become more widely available, genetic counseling for childhood glaucomas will become more effective.

Identification of genes and the spectrum of mutations causing primary congenital glaucoma will have both basic and clinical relevance. It may help in early treatment and diagnosis, in carrier detection and genetic counseling, in population screening and prenatal diagnosis, in establishing genotype–phenotype correlations and prognosis, in understanding pathogenesis, and in the development of better treatment strategies. Because of the potentially high life-long morbidity of childhood glaucomas,56 improved understanding of the genetics of these disorders would be expected to have an impact on the quality of life in patients with pediatric glaucomas.

References

1.Francois J. Congenital glaucoma and its inheritance. Ophthalmologica 1972; 181:61–73.

2.Genicek A, Genicekova A, Ferak V. Population genetical aspects of primary congenital glaucoma. I. Incidence, prevalence, gene frequency, and age of onset. Hum Genet 1982; 61:193–197.

3.Jaffar MS. Care of the infantile glaucoma patient. In: Reineck RD, ed. Ophthalmol Annual. Raven Press: New York; 1988:15.

4.Dandona L, Williams JD, Williams BC, Rao GN. Population-based assessment of childhood blindness in Southern India. Arch Ophthalmol 1998; 116:545–546.

5.Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet 1997; 6:641–647.

6.Bejjani BA, Lewis RA, Tomey KF, et al. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 1998; 62:325–333.

7.Plasilova M, Stoilov I, Sarfarazi M, et al. Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. J Med Genet 1999; 36:290–294.

8.Panicker SG, Reddy ABM, Mandal AK, et al. Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees. Invest Ophthalmol Vis Sci 2002; 43:1358–1366.

9.Duke-Elder S. Congenital deformities. In: Duke-Elder S, ed. System of Ophthalmology. Mosby: St. Louis; 1969:548–565.

10.Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye 2000; 14:422–428.

11.Stoilov I, Akarsu AN, Alozie I, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1. Am J Hum Genet 1998; 62:573–584.

12.Westerlund E. Clinical and genetic studies on the primary glaucoma diseases. NYT Norsdic Forlag, Arnold Busck: Copenhagen; 1947.

13.Gencik A. Epidemiology and genetics or primary congenital glaucoma in Slovakia: description of a form of primary congenital glaucoma in gypsies with autosomal recessive inheritance and complete penetrance. Dev Ophthalmol 1989; 16:75–115.

14.Sarfarazi M, Akarsu AN, Hossain A. Assignment of a locus (GLC3A) for primary congenital glaucoma (buphthalmos) to 2p21 and evidence for genetic heterogeneity. Genomics 1995; 30:171–177.

15.Akarsu AN, Turacli ME, Aktan SG, et al. A second locus (GLC3B) for primary congenital glaucoma (buphthalmos) maps to the 1p36 region. Hum Mol Genet 1996; 5:1199–1203.

16.Plasilova M, Ferakova E, Kadasi L, et al. Linkage of autosomal recessive primary congenital glaucoma to the GLC3A locus in Roms (Gypsies) from Slovakia. Hum Hered 1998; 48:30–33.

17.Kakiuchi-Matsumoto T, Isashiki Y, et al. A novel truncating mutation of cytochrome P4501B1 (CYP1B1) gene in primary infantile glaucoma. Am J Ophthalmol 1999; 128:370–372.

18.Bejjani BA, Stockton DW, Lewis RA, et al. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet 2000; 9:367–374.

19.Martin SN, Sutherland J, Levin AV, et al. Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness. J Med Genet 2000; 37:422–427.

20.Ohtake Y, Kubota R, Tanino T, Miyata H, Mashima Y. Novel compound heterozygous mutations in the cytochrome P450 1B1 (CYP1B1) in a Japanese patient with primary congenital glaucoma. Ophthal Genet 2000; 21:191–193.

21.Mashima Y, Susuki Y, Sergeev Y, et al. Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2001; 42:2211–2216.

22.Kakiuchi-Matsumoto T, Isashiki Y, Ohba N, et al. Cytochrome P4501B1 gene mutations in Japanese patients with primary congenital glaucoma. Am J Ophthalmol 2001; 131:345–350.

23.Michels-Rautenstrauss KG, Mardin CY, Zenker M, et al. Primary congenital glaucoma: three case reports on novel mutations and combinations of mutations in the GLC3A (CYP1B1) gene. J Glaucoma 2001; 10:354–357.

24.Stoilov IR, Costa VP, Vasconcellos JPC, et al. Molecular genetics of primary congenital glaucoma in Brazil. Invest Ophthalmol Vis Sci 2002; 43:1820–1827.

25.Reddy ABM, Panicker SG, Mandal AK, et al. Identification of R368H as a predominant CYP1B1 allele causing primary congenital glaucoma in Indian patients. Invest Ophthalmol Vis Sci 2003; 44:4200–4203.

26.Belmouden A, Melki R, Hamdani M, et al. A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco. Clin Genet 2002; 62:334–339.

27.Ohtake Y, Tanino T, Suzuki Y, et al. Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma. Br J Ophthalmol 2003; 87:302–304.

28.Soley GC, Bosse KA, Flikier D, et al. Primary congenital glaucoma. A novel

single-nucleotide deletion and varying phenotypic expression for the 1546–1555dup mutation in the GLC3A (CYP1B1) gene in 2 families of different ethnic origin. J Glaucoma 2003; 12:27–30.

29.Sitorus R, Ardjo SM, Lorenz B, Preising M. CYP1B1 gene analysis in primary congenital glaucoma in Indonesian and European patients. J Med Genet 2003; 40:e9.

30.Colomb E, Kaplan J, Garchon HJ. Novel cytochrome P450 1B1 (CYP1B1) mutations in patients with primary congenital glaucoma in France. Hum Mutat 2003; 22:496.

31.Sarfarazi M, Stoilov I, Schenkman JB. Genetics and biochemistry of primary congenital glaucoma. Ophthalmic Clin North Am 2003; 16:543–554.

32.Panicker SG, Mandal AK, Reddy ABM, et al. Correlations of genotype with phenotype in Indian patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2004; 45:1149–1156.

33.Vincent LA, Billingsley G, Buys Y, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 2002; 70:448–460.

34.Libby RT, Smith RS, Savinova OV, et al. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 2003; 299:578–581.

35.Shields MB, Buckely E, Klintworth GK, Thresher R. Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 1985; 29:387–409.

36.Gould DB, Mears AJ, Pearce WG, Walter MA. Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25. Am J Hum Genet 1997; 61:765–768.

37.Alward WLM. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 2000; 130:107–115.

38.Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/wingedhelix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998; 63:1316–1328.

39.Nishimura YD, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001; 68:364–372.

40.Panicker SG, Sampath S, Mandal AK, et al. Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly. Invest Ophthalmolol Vis Sci 2002; 43:1358–1366.

41.Komatireddy S, Chakrabarti S, Mandal AK, et al. Mutation spectrum of FOXC1 and clinical genetic heterogeneity of Axenfeld-Rieger anomaly in India. Mol Vis 2003; 9: 43–48.

42.Netland PA, Wiggs JL, Dreyer EB. Inheritance of glaucoma and genetic counseling of glaucoma patients. Int Ophthalmol Clin 1993; 33:101–120.

43.Mintz-Hittner HA. Aniridia. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas. Mosby: St. Louis; 1996:859–874.

44.Jordan T, Hanson I, Zaletayev D, et al. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet 1992; 1:328–332.

45.Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet 1992; 2:232–239.

46.Davis A, Cowell JK. Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet 1993; 2:2093–2097.

47.Axton R, Hanson I, Danes S, et al. The incidence of PAX6 mutation in patients with simple aniridia: an evaluation of mutation detection in 12 cases. J Med Genet 1997; 34:279–286.

48.Azuma N, Hotta Y, Tanaka H, Yamada M. Missense mutations in the PAX6 gene in aniridia. Invest Ophthalmol Vis Sci 1998; 39:2524–2528.

49.Lauderdale JD, Wilensky JS, Oliver ER, Walton DS, Glaser T. 3′ deletions cause aniridia by preventing PAX6 gene expression. Proc Natl Acad Sci USA 2000; 97:13755–13759.

50.Zumkeller W, Orth U, Gal A. Three novel PAX6 mutations in patients with aniridia. Mol Pathol 2003; 56:180–183.

51.Dharmaraj N, Reddy A, Kiran V, et al. PAX6 gene mutations and genotypephenotype correlations in sporadic cases of aniridia from India. Ophthalmic Genet 2003; 24:161–165.

52.Churchill AJ, Hanson IM, Markham AF. Prenatal diagnosis of aniridia. Ophthalmology 2000; 107:1153–1156.

53.Muto R, Yamamori S, Ohashi H, Osawa M. Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am J Med Genet 2002; 108:285–289.

54.Gronskov K, Olsen JH, Sand A, et al. Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet 2001; 109:11–18.

55.Crolla JA, Cawdery JE, Oley CA, et al. A FISH approach to defining the extent and possible significance of deletions at the WAGR locus. J Med Genet 1997; 34:207–212.

56.Craig JE, Mackey DA. Glaucoma genetics: where are we? Where will we go? Curr Opn Ophthalmol 1999; 10:126–134.

Introduction

Barkan’s membrane theory

Histopathological observations in primary congenital glaucoma

Histopathological observations in secondary glaucoma Causes of elevated intraocular pressure

Effects of elevated intraocular pressure in the infant eye Conclusion

Introduction

The initial theory for the pathogenesis of primary congenital glaucoma was Barkan’s membrane theory, which attributed resistance to aqueous flow to an imperforate membrane covering the angle structures. This membrane, however, has not been confirmed histopathologically. Known histopathological changes in primary congenital glaucoma include an anterior iris insertion, thickened trabecular beams, compressed trabecular sheets with loss of intertrabecular spaces, iris processes, and insertion of the fibers of the ciliary muscle into the trabecular meshwork. The main theory that accounts for these changes is a developmental arrest of the anterior chamber angle structures derived from neural crest cells during gestation. The degree of angle immaturity has been correlated with the age of presentation of glaucoma, with more severe angle immaturity or dysgenesis presenting in the perinatal period. Other mechanisms have been proposed for other congenital and secondary glaucomas.

Barkan’s membrane theory

The initial observations of Barkan1–7 suggested that in primary infantile glaucoma a thin, imperforate membrane covering the anterior chamber angle of the eyes prevents aqueous humor outflow, and leads to increased intraocular pressure. At the time of goniotomy, the theory asserts, this surface tissue is severed, the peripheral iris ‘falls’ posteriorly, and aqueous humor flow is established.8 This surface membrane, given the eponymic name Barkan’s membrane, was proposed as an endothelial surface that normally breaks apart, but which persists in congenital glaucoma. Indeed, Hansson and Jerndal9 demonstrated in scanning electron micrographs a continuous endothelial surface layer of trabecular meshwork that normally cavitates during the last weeks of fetal

development, but could conceivably remain imperforate in primary infantile glaucoma.

Several reasons have been proposed for the lack of histopathological confirmation of a persistent membrane in primary congenital glaucoma, including: inadequacy of the specimens examined,10,11 surgical manipulation of the infant eye before specimens are obtained for histopathological examination, the late stage of the disease (with secondary changes) that is typically available for microscopic study, and artifacts induced by the fixation process itself.9–11 However, even in suitable specimens, Anderson,10,12 Hansson,9 Maul and co-workers,11 and Maumenee13 could find no evidence of a membrane in any of the specimens they examined by light and electron microscopy. The most likely explanation for no histopathological confirmation of a persistent membrane is that a membrane has little or no role in the pathogenesis of primary congenital glaucoma.

Histopathological observations in primary congenital glaucoma

Based on the numerous examinations of the anterior chamber angle of eyes with primary congenital glaucoma, certain microscopic and ultrastructural observations have been confirmed in this disease (Table 5.1).8,10,11–22 These studies have shown an anterior iris insertion with thickened and compact trabecular beams and excessive extracellular matrix material. Proliferation of fibrous tissue has been described at the inner wall of Schlemm’s canal, with accumulation of collagen fibers and agglomerations of microfibrillar material.23 The microfibrillar material was found to form basement membrane-like structures and fingerprint-like patterns.23

Figure 5.1 shows the common microscopic findings in primary congenital glaucoma. An anterior insertion of the iris is a characteristic finding. The general appearance has been described as nondifferentiation of the trabecular meshwork and persistence of embryonic characteristics. The thickening of the uveal cords may prevent the posterior migration of the ciliary body and iris that normally occurs during the last weeks of gestation, thus causing incomplete differentiation of the angle.10,24,25 Observations strongly suggest developmental immaturity26 of the trabecular meshwork and Schlemm’s canal system, rendering it functionally incompetent.

Corneal findings by in vivo confocal microscopy have been described in patients with primary congenital glaucoma.27 There was a reduction of keratocyte density in the stroma,

C

AC

TM

I

Figure 5.1 Microscopic appearance of the anterior chamber angle in a patient with primary congenital glaucoma. There is an anterior insertion of the iris (I), which extends over the poorly developed trabecular meshwork (TM). Schlemm’s canal is present adjacent to the trabecular meshwork. The ciliary muscle and the rudimentary scleral spur insert into the trabecular meshwork. C = cornea, AC = anterior chamber. Periodic acidSchiff (PAS) stain, original magnification ×100. Original photograph provided courtesy of William R. Morris, MD.

and discontinuous hyperreflective structures overhanging the endothelial layer at the level of Descemet’s membrane. The endothelium showed severe polymegethism, pleomorphism, and a markedly decreased cell density, with focal cellular lesions.27

Histopathological observations in secondary glaucoma

Cases of secondary glaucoma associated with other neonatal or developmental anomalies include anterior chamber cleavage syndrome of Axenfeld and Rieger and Peters anomaly

(iridocorneotrabeculodysgenesis), encephalotrigeminal angiomatosis (Sturge–Weber syndrome), neurofibromatosis (Von Recklinghausen disease), maternal rubella syndrome, and retinopathy of prematurity. The pathogenesis in most of these disorders is different from that in primary infantile glaucoma, as evidenced by the poor response of these secondary glaucomas to classic infantile glaucoma surgery, such as goniotomy or trabeculotomy ab externo. The occasional association of trabecular dysgenesis with other anomalies may be explained by a common neural crest cell origin of the affected tissue.28

Although Axenfeld–Rieger syndrome is characterized by a prominent, anteriorly displaced line of Schwalbe with attachment of tissue strands of peripheral iris, several reports have documented structural alterations in the trabecular meshwork and Schlemm’s canal29–31 similar to that seen in primary congenital glaucoma. Shields has postulated that the changes in the anterior segment of the eyes in patients with Axenfeld–Rieger syndrome result from an arrest in the development of the tissues derived from neural crest cells that occurs late in gestation.29,30

Peters anomaly is characterized by a spectrum of changes in the anterior segment structures. Only a few studies have been reported on the structure of the trabecular meshwork and Schlemm’s canal in patients with Peters anomaly. In one patient who had total peripheral anterior synechia, Schlemm’s canal and the trabecular meshwork could not be identified.32 Kupfer et al33 studied the trabeculectomy specimen from the eye of a 2-year-old child with Peters anomaly and reported that the trabecular beams showed thickening, with the presence of ‘curly’ collagen. The endothelial cells contained an abnormal amount of phagocytosed pigment granules. Again, the authors suggested that the structural alterations could have resulted from a failure of differentiation of neural crest-derived cells that were destined to form the trabecular and corneal endothelial cells.33,34

In some cases of Sturge–Weber syndrome, the anterior chamber angle is histologically identical to that in primary

infantile glaucoma. Phelps35 and Weiss36 have suggested that elevated episcleral venous pressure may be an additional problem in the etiology of the glaucoma in this condition. Trabeculectomy specimens from patients with Sturge–Weber syndrome revealed not only a compact trabecular meshwork with thickening and hyalinization of the trabeculae, but also the presence of amorphous material and abnormal collagen. The juxtacanalicular region showed an excess of extracellular elements (granuloamorphous material, basal lamina material, banded and non-banded structures), and degenerative changes were noted in the cellular component.37 These alterations in patients with Sturge–Weber syndrome suggested premature aging of the trabecular meshwork and Schlemm’s canal. The defect in the aqueous outflow pathway can arise early in the development of the anterior chamber, because some of these patients have glaucoma and even buphthalmos soon after birth.

In the maternal rubella syndrome, the anterior chamber angle resembles that in primary infantile glaucoma both clinically and histopathologically.12 Indeed, several cases of reported primary infantile glaucoma were actually cases of maternal rubella syndrome, which were either inapparent or subclinical.12 Retinopathy of prematurity has been associated with a shallow anterior chamber and angle-closure glaucoma.38 However, gonioscopic observation in infants with stage IV and V retinopathy of prematurity has identified structural abnormalities of the anterior chamber angle that may have developmental origin.39

Causes of elevated intraocular pressure

Clinical evidence supports the theory that the obstruction to aqueous flow with a resultant increase in intraocular pressure is located at the trabecular meshwork area. Incision into the trabecular meshwork by goniotomy or trabeculotomy relieves the obstruction and normalizes the intraocular pressure in the majority of cases.

The surgical incision may relieve the compaction of the trabecular sheets and allow the trabecular spaces to open. Surgical success with goniotomy is achieved by a superficial incision into the trabecular meshwork.40 The iris root drops backward as the blade incises the meshwork. It may be that the thickened cords of uveal meshwork hold the iris anteriorly. Superficial incision of the thickened uveal meshwork will allow the iris root to drop posteriorly with accompanying posterior rotation of the scleral spur. This might allow opening of the corneoscleral trabecular sheets with improved outflow of aqueous.

Schlemm’s canal has been found to be open both histologically and clinically, and does not appear to be the site of obstruction to aqueous flow.10,41 Tissue abnormalities adjacent to or involving the internal wall of Schlemm’s canal are a less likely source for the resistance to aqueous flow as it is unlikely that goniotomy incisions consistently cut this tissue. Incisions at various heights along the meshwork have all been found to relieve the resistance to outflow.42

Effects of elevated intraocular pressure in the infant eye

During the first 3 years of life, the extracellular fibers of the eye are softer and more elastic than in older individuals. Thus, elevation of the intraocular pressure causes rapid enlargement of the globe, which is especially apparent as a progressive corneal and limbal enlargement. The normal neonatal horizontal corneal diameter of 10.0 to 10.5 mm may be enlarged to as much as 16 to 18 mm.

As the cornea and limbus enlarge, Descemet’s membrane and the corneal endothelium are stretched. This can result in linear ruptures (Haab’s striae), which in turn can lead to corneal scarring if the problem is chronic. The thinned endothelium may also decompensate in adult life, despite a normal intraocular pressure, when aging changes are superimposed upon the initial endothelial damage.43 As the eye enlarges, the iris is stretched and the overlying stroma may appear thinned.

The scleral ring through which the optic nerve passes also enlarges with elevated intraocular pressure, which can lead to an enlargement of the optic cup even in the absence of loss of optic nerve fibers.44 The disc is cupped more quickly in the infant as compared to the adult eye, and reversal of the enlargement can also occur rapidly after normalization of the intraocular pressure. This is probably related to the increased elasticity of the connective tissues of the optic nerve head in the infant eye, which allows an elastic or compression response to fluctuation in intraocular pressure.45,46

Eyes with advanced disease are enlarged in all dimensions. The root of iris and trabecular meshwork are degenerated and thinned, and Schlemm’s canal may not be evident. The ciliary body is atrophic, as are the retina and choroid. The zonules may be degenerated and the lens displaced.43 The optic nerve may show complete cupping.

Conclusion

There are certain similarities in the morphologic features of the trabecular meshwork and Schlemm’s canal in most of the disorders associated with the developmental glaucoma. This disorder usually manifests itself as an anterior iris insertion with thickening of the trabecular beams caused by increased amounts of extracellular components, a consequent reduction of the intertrabecular spaces, and an attenuation of the endothelium. These findings have been described as nondifferentiation of the trabecular meshwork or as persistence of embryonic characteristics. Observations strongly suggest developmental immaturity of the trabecular meshwork and Schlemm’s canal system, which renders it functionally incompetent. The more extensive the immaturity, the earlier the glaucoma appears.

References

1.Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217.

2.Barkan O. Operation for congenital glaucoma. Am J Ophthalmol 1942; 25:525.

3.Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 1948; 32:701.

4.Barkan O. Techniques of goniotomy for congenital glaucoma. Arch Ophthalmol 1949; 41:65.

5.Barkan O. Surgery of congenital glaucoma. Review of 196 eyes operated by goniotomy. Am J Ophthalmol 1953; 36:1523–1534.

6.Barkan O. Pathogenesis of congenital glaucoma. Gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955; 40:1–11.

7.Barkan O. Goniotomy. Trans Am Acad Ophthalmol 1955; 59:322–332.

8.Worst JGF. Congenital glaucoma. Remarks on the aspect of chamber angle, ontogenic and pathogenic background, and mode of action of goniotomy. Invest Ophthalmol 1968; 7:127–134.

9.Hansson HA, Jerndal T. Scanning electron microscopic studies on the development of the iridocorneal angle in human eyes. Invest Ophthalmol 1971; 10:252–265.

10.Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–465.

11.Maul E, Strozzi L, Munoz C, Reys C. The outflow pathway in congenital glaucoma. Am J Ophthalmol 1980; 89:667–673.

12.Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157.

13.Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Trans Am Ophthalmol Soc 1958; 56:507–570.

14.Sampaolesi R, Argento C. Scanning electron microscopy of the trabecular meshwork in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 1977; 16:302–314.

15.Holmberg AS. Schlemm’s canal and the trabecular meshwork. An electron

microscopic study of the normal structures in man and monkey (Cereopithecus ethops). Doc Ophthalmol 1965; 19:339–373.

16.Barishak YR. The development of the angle of the anterior chamber in vertebrate eyes. Doc Ophthalmol 1978; 45:329–360.

17.Sampaolesi R, Zarate JO, Caruso R. Congenital glaucoma light and scanning electron microscopy of trabeculectomy specimens. In: Leydhecker W, Krieglstein GK, eds. International Glaucoma Symposium, Nara, Japan, 1978: Glaucoma Update. Springer Verlag: New York; 1979:39–51.

18.Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Trans Am Ophthalmol Soc 1962; 60:140–146.

19.Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176.

20.Shaffer RN. Pathogenesis of congenital glaucoma. Gonioscopic and microscopic anatomy. Trans Am Acad Ophthalmol Otolaryngol 1955; 59:297–308.

21.Ikui H, Iwaki S. Histological studies on the development of narrow angle glaucoma (Preliminary report). Acta Soc Ophthalamol Jpn 1959; 63:2412.

22.Crombie AL, Cullen JF. Hereditary glaucoma occurrence in five generations of an Edinburgh family. Br J Ophthalmol 1964; 48:143–147.

23.Bakunowicz-Lazarczyk A, Sulkowska M, Sulkowski S, Urban B. Ultrastructural changes in the trabecular meshwork of congenital glaucoma. J Submicrosc Cytol Pathol 2001; 33:17–22.

24.Speakman JS, Leeson TS. Pathological findings in a case of primary congenital glaucoma compared with normal infant eyes. Br J Ophthalmol 1964; 48:196–204.

25.Hoskins HD Jr, Hetherington J Jr, Shaffer RN, Welling AM. Development glaucomas: diagnosis and classification. In: Symposium on glaucoma. Trans New Orleans Acad Ophthalmol. St. Louis, 1981.

26.Tawara A, Inomata H. Developmental immaturity of the trabecular meshwork in congenital glaucoma. Am J Ophthalmol 1981; 92:508–525.

27.Mastropasqua L, Carpineto P, Ciancaglini M, Nubile M, Doronzo E. In vivo confocal microscopy in primary congenital glaucoma with megalocornea.

J Glaucoma 2002;11:83–89.

28.Kupfer C, Kaiser-Kupfer MI. Observations on the development of the anterior chamber angle with reference to the pathogenesis of congenital glaucomas. Am J Ophthalmol 1979; 88(3 Pt 1):424–426.

29.Shields MB. Axenfeld-Rieger syndrome: a theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983; 81:736–784.

30.Shields MB, Buckley E, Eleintworth G, Threshwer R. Axenfeld-Rieger syndrome: a spectrum of developmental disorders. Surv Ophthalmol 1985; 29:387–409.

31.Wolter JR, Somdall GS, Fraliek FB. Mesodermal dysgenesis of anterior eye with a partially separated posterior embryotoxon. J Pediatr Ophthalmol 1967; 4:41.

32.Scheie HG, Yanoff M. Peter’s anomaly and total posterior coloboma of retinal pigment epithelium and choroid. Arch Ophthalmol 1972; 87:525–530.

33.Kupfer C, Kuwabara T, Stark W. The histopathology of Peters anomaly. Am J Ophthalmol 1975; 80:653.

34.Kupfer C, Kaiser-Kupfer MI. New hypothesis of developmental anomalies of the anterior chamber associated with glaucoma. Trans Ophthalmol Soc UK 1978; 98:213.

35.Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Trans Ophthalmol Soc UK 1978; 98:213.

36.Weiss DI. Dual origin of glaucoma in encephalotrigeminal haemangiomatosis. Trans Ophthalmol Soc UK 1973; 93:477–493.

37.Cibis GW, Tripathi RC, Tripathi BJ. Glaucoma in Sturge-Weber syndrome. Ophthalmology 1984; 91:1061–1071.

38.Pollard ZF. Secondary angle-closure glaucoma in cicatricial retrolental fibroplasia. Am J Ophthalmol 1980; 89:651–653.

39.Hartnett ME, Gilbert MM, Richardson TM, et al. Anterior segment evaluation of infants with retinopathy of prematurity. Ophthalmology 1990; 97:122–130.

40.Shaffer RN, Weiss DI. Congenital and pediatric glaucomas. CV Mosby: St. Louis; 1970.

41.Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Am J Ophthalmol 1959; 47:827–858.

42.Hoskins HD Jr, Kass MA. Becker-Shaffer’s diagnosis and therapy of the glaucomas. CV Mosby: St. Louis; 1989.

43.Spencer WH. Ophthalmic pathology, an atlas and textbook. WB Saunders: Philadelphia; 1985.

44.Quigley H. Childhood glaucoma, results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–226.

45.Quigley HA. The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 1977; 84:358–370.

46.Wu SC, Huang SC, Kuo CL, Lin KK, Lin SM. Reversal of optic disc cupping after trabeculectomy in primary congenital glaucoma. Can J Ophthalmol 2002; 37:337–341.