Table 19-4  Horizontal cup-to-disc ratios at birth to 3 years

Data from Hoskins et al.60

Table 19-5  Changes in the cup-to-disc ratio after control of intraocular pressure

Data from Hoskins et al.60

enlargement. With successful control of the IOP, the cup will either remain stable or its size will decrease.6,59,63 An increased cup size is

indicative of uncontrolled glaucoma, and the ophthalmologist must make careful drawings or take photographs with a hand-held camera for future comparison.With normalization of IOP, a reduction

in cup size is especially evident in infants less than 1 year of age (Table 19-5).5,64

Other than the reversibility of cupping, the alterations of the optic nerve in infantile glaucoma are comparable to the disc changes seen in adults.24 For example, vertical notching at the inferior and superior poles of the disc appears less often than concentric cupping, as do nerve fiber slit defects. These findings suggest that other than the elastic properties of the infant’s disc, the child’s optic nerve is subject to similar effects that cause disc cupping in adult glaucoma.

Cycloplegic refraction

After therapeutic normalization of IOP, cycloplegic refraction should be performed to correct significant differences in refractive errors between the two eyes.The importance of refractive surveillance of these eyes cannot be over stressed. Anisometropic and strabismic amblyopia, as well as myopic astigmatism, are prominent causes of visual loss among these children, especially in unilateral cases.Vigorous amblyopia management is as important as adequate glaucoma control by surgery or medication.

Systemic evaluation

A thorough systemic evaluation is also warranted in these children, both to check for any signs of syndromes that may be associated with glaucoma and to ensure the safety of general anesthesia. The coordination of the child’s assessment with a pediatrician or ­specialist in genetics is invaluable.

Primary congenital glaucoma

Incidence

Although primary congenital glaucoma is the most common glaucoma seen in infancy, it is still an uncommon disease. A general ophthalmologist is unlikely to see more than one new case in several years. Its incidence is approximately 1 in 10 000 live births, though there is tremendous geographic variability, with some reports of 1 case in 1250 Slovakian Gypsy offspring and 1 in 2500 Saudi children.1,65 The disease is bilateral in approximately 75% of cases. Males have a higher incidence of the disease, comprising approximately 65% of all cases. More than 80% of primary congenital glaucoma is evident before the first year of life; after age 3 years, classic signs, such as corneal or ocular enlargement, do not occur.

Genetics and heredity

Most cases of primary congenital glaucoma occur sporadically.66,67 In approximately 10% of cases, an autosomal recessive hereditary pattern is evident. In this situation, both parents usually are heterozygous carriers but do not have the disease. By simple Mendelian genetics, if these parents have four children, one child would be homozygous for primary congenital glaucoma and would manifest the disease, two children would be heterozygous carriers, and one child would be homozygous normal.The actual situation, however, is more complex. Most researchers find a variable penetrance of 40–80%, although penetrance in certain families has been as high as 90–100%. In families with low penetrance, the number of affected children will be less than the expected 25%.

Other researchers believe that primary congenital glaucoma can be inherited through a polygenetic pattern.67 This is based on the high percentage of males affected and a rate of involvement of siblings of 3–11% (i.e., the chance of a second child showing the disease) versus the expected 25% if the inheritance were purely recessive. In practical terms, if a second child in a family does manifest infantile glaucoma, the chance for a subsequent sibling with the disease approaches one of four.66 It is likely that more than one mode of inheritance exists.

The presence of an affected child should alert the clinician to examine other children in the family. Parents of affected children naturally are concerned about the possibility of other siblings being affected. Some have reported that there is a 4–5% likelihood of occurrence in siblings or offspring of a single affected child. Others have identified the significance of gender on the phenotype’s expression. Approximately 3% of siblings may be affected if the affected child is male, and close to 0% if the child is female.68

There are, however, families in whom glaucoma appears frequently, and with the advent of molecular genetics, the at-risk

members may one day routinely be identified.9 This area is among the fastest growing in modern medicine.9a,9b The Human

Genome Organization/Genome Database has allocated the following nomenclature for glaucoma genes: GLC is the general symbol for glaucoma; 1, 2, and 3, respectively, stand for open-angle, angleclosure,­ and congenital glaucoma; and A, B, C, and so forth refer to the sequential mapping of the first, second, and third genes in that subgroup. By longstanding convention, chromosomes are identified by Arabic numbers (e.g., 1, 2, 3); the long arm and short arm of the chromosome are designated by q and p, respectively; and further

localization by Arabic number appears thereafter. By 2008, scores of loci have been linked to glaucoma and genes identified.70,71

Elucidating the causal chain of events is an ongoing research endeavor. Once 1 of the 26 human chromosomes has been identified as the locus of the genetic defect, the human genome has some 100 000 human genes comprised of 3 billion base pairs. One solitary defective base pair can manifest as a disease; moreover, there is remarkable phenotypic heterogeneity and expression

of genetic alterations, as well as clinical overlap of different genetic mutations.9,9b,72 For example, it has been estimated that 3% of

adult primary open-angle glaucoma patients in the United States

manifest a mutation in the trabecular induction glucocorticoid regulator

(TIGR), or myocilin, gene.72–74 But there are at least three known kinds of mutation in this GLC1A gene, with variable expressions of glaucoma. The precise manner in which a defectively coded protein participates in the cascade of events that manifest as clinical glaucoma also remains to be elucidated.

Clinical implementation of such technical information is a complex task, embracing a wide range of ethical, legal, and social issues. A particularly helpful compilation, underwritten by the Human Genome Project, addresses such dilemmas as predictive testing for adult-onset disease and alternative models for genetic counseling; non-directiveness in genetic counseling; morally relevant features of defining genetic maladies and genetic testing; abortion and the new

genetics, and ethics of gene therapy.75 An example of but one ethical issue in genetic screening for familial glaucoma (and, in fact, all medical diseases) is the uncertainty that a positive screening result will actually clinically manifest, combined with the unknown risk of clinical disease manifesting despite a negative gene screen battery. Clinical wisdom simply dictates that patients and their families at risk continue to undergo regular clinical surveillance until the predictive reliability of human genetic screening is more established.

Pathophysiology

Anderson described the normal development of the infant angle using scanning electron microscopy, transmission electron miscroscopy, and phase contrast light microscopy.76 The anterior surface of the iris meets the corneal endothelium at 5 months of gestation to form the peripheral aspect of the anterior chamber. Slightly posterior to this junction are cells forming the developing trabecular meshwork. Ciliary muscle and ciliary processes overlap the trabecular meshwork, being separated by loose connective tissue. The trabecular meshwork later becomes exposed to the anterior chamber as the angle recess deepens and moves posteriorly (Fig. 19-18).

B

D E

F

1–4: Developmental mechanics The shifting relations between: A–B: the corneo-scleral system C–D–E–F: the uveal meshwork

5–6: Congenital glaucoma C–D–E–F: the persisting uveal meshwork