Vicki M. Chen, MD and David S. Walton, MD
In this section, primary childhood glaucoma associated with systemic or ocular abnormalities will be described. See Table 70-1 for a complete listing of these types of childhood glaucoma.
PRIMARY GLAUCOMAS ASSOCIATED WITH SYSTEMIC DISEASES
Primary infantile glaucoma is associated with an astounding number of diverse systemic conditions (see Table 70-1). While glaucoma associated with nevus flammeus is relatively common, each of the other listed causes is quite uncommon. Some conditions are nonhereditary (eg, rubella syndrome, fetal alcohol syndrome), while others clearly are hereditary (eg, Lowe syndrome, hepatocerebral renal syndrome, neurofibromatosis).
Congenital Rubella Syndrome
The well-known diverse ocular complications of the maternal rubella syndrome may occur in up to 50% of neonates born to mothers infected during the first trimester.1,2 Ophthalmic findings include pigmentary retinopathy (25% to 40%), cataracts (14% to 30%), microphthalmia (10%), optic nerve atrophy (10%), and keratitis or corneal haze (8%).1,3–6 Infantile glaucoma is probably the least common of these secondary ocular anomalies, occurring in an estimated 5% to 10% of affected children.3,6
Congenital rubella infantile glaucoma is often detected in infancy secondary to corneal opacification and is usually bilateral (Figures 70-1A and B).7 It must be differentiated from permanent rubella leukomas and transient corneal opacification seen in some infants. In addition to corneal haze and enlargement, these children often possess diaphanous hypoplastic irides, along with other aforementioned ocular findings (Figure 70-1C). Glaucoma may also present later in life, particularly in microphthalmic patients; therefore, continued vigilance is necessary.6 Gonioscopy of children with rubella glaucoma reveals abnormalities similar to that seen in hereditary infantile glaucoma, with an anterior iris insertion, pigmentary changes, and increased opacification of the inner tissue of the filtration angle, making visualization of the scleral spur and ciliary body very difficult.3
Treatment of this glaucoma by goniosurgery is often successful at all ages, providing an additional similarity to hereditary infantile glaucoma.
Nevus Flammeus of the Eyelids With Glaucoma
Nevus flammeus of the face is a well-known component of Sturge-Weber syndrome, Klippel-Trenaunay-Weber syndrome, and cutis marmorata telangiectasia congenita (see Chapter 50). In Sturge-Weber syndrome, glaucoma is associated with a facial nevus flammeus and a leptomeningeal vascular defect. Usually, a side of the face is affected (68% to 78%),8,9 but bilateral involvement also occurs (Figure 70-2A). When the facial nevus is bilateral, glaucoma also is often bilateral. With intracranial involvement, seizures, hemiparesis, and hemianopsia may occur. Children without intracranial involvement, observed to have nevus flammeus not involving the upper eyelid, seem to be at no risk for glaucoma.10,11 On examination, it is appropriate to remember the neural crest origin of components of the vascular system, meninges, pigmentation tissues, trabecular meshwork (TM), iris, and other tissues.
I. Primary (developmental) glaucomas
A. Primary congenital glaucoma (PCG)
1. Newborn PCG
2. Infantile PCG
3. Late-recognized PCG
B. Juvenile open-angle glaucoma (JOAG)
C. Primary angle-closure glaucoma (PACG)
D. Primary glaucomas associated with systemic diseases
1. Sturge-Weber syndrome
2. Neurofibromatosis type 1
3. Stickler syndrome
4. Oculocerebrorenal syndrome (Lowe)
5. Rieger syndrome
6. SHORT syndrome
7. Hepatocerebrorenal syndrome (Zellweger)
8. Marfan syndrome
9. Rubinstein-Taybi syndrome
10. Infantile glaucoma with retardation and paralysis
11. Oculodentodigital dysplasia
12. Glaucoma with microcornea and absent sinuses
14. Trisomy 13
15. Caudal regression syndrome
16. Trisomy 21 (Down syndrome)
17. Cutis marmorata telangiectatica congenita
18. Walker-Warburg syndrome
19. Kniest syndrome (skeletal dysplasia)
20. Michels syndrome
21. Nonprogressive hemiatrophy
22. PHACE syndrome
23. Soto syndrome
24. Linear scleroderma
25. GAPO syndrome
26. Roberts’ pseudothalidomide syndrome
27. Wolf-Hirschhorn (4p-) syndrome
28. Robinow syndrome
29. Nail-Patella syndrome
30. Proteus syndrome
31. Fetal hydantoin syndrome
32. Cranio-cerebello-cardiac (3C) syndrome
33. Brachmann-de Lange syndrome
34. Rothmund-Thomson syndrome
35. 9p deletion syndrome
36. Phakomatosis pigmentovascularis (PPV)
37. Nevoid basal cell carcinoma syndrome (Gorlin syndrome)
38. Epidermal nevus syndrome (Solomon syndrome)
39. Androgen insensitivity, pyloric stenosis
40. Diabetes mellitus, polycystic kidneys, hepatic fibrosis, hypothyroidism
41. Diamond-Blackfan syndrome
E. Primary glaucomas with profound ocular anomalies
a. Congenital aniridic glaucoma
b. Acquired aniridic glaucoma
2. Congenital ocular melanosis
4. Congenital iris ectropion syndrome
5. Peters’ anomaly syndrome
6. Iridotrabecular dysgenesis (iris hypoplasia)
7. Posterior polymorphous dystrophy
8. Idiopathic or familial elevated venous pressure
9. Congenital anterior (corneal) staphyloma
10. Congenital microcoria
11. Congenital hereditary endothelial dystrophy
12. Axenfeld-Rieger anomaly
II. Secondary (acquired) glaucomas
A. Traumatic glaucoma
1. Acute glaucoma
b. Ghost cell glaucoma
2. Glaucoma related to angle recession
3. Arteriovenous fistula
B. Glaucoma with intraocular neoplasms
2. Juvenile xanthogranuloma (JXG)
4. Melanoma of ciliary body
6. Iris rhabdomyosarcoma
7. Aggressive iris nevi
9. Mucogenic glaucoma with iris stromal cyst
C. Glaucoma related to chronic uveitis
1. Open-angle glaucoma
2. Angle-blockage mechanisms
a. Synechial angle closure
b. Iris bombé with pupillary block
c. Trabecular meshwork endothelialization
D. Lens-related glaucoma
1. Subluxation-dislocation with pupillary block
a. Marfan syndrome
c. Weill-Marchesani syndrome
d. Axial-subluxation high myopia syndrome
e. Ectopia lentis et pupillae
2. Phacolytic glaucoma
E. Glaucoma following lensectomy for congenital cataracts
1. Pupillary-block glaucoma
2. Infantile aphakic open angle glaucoma
F. Glaucoma related to corticosteroids
G. Glaucoma secondary to rubeosis
2. Coats’ disease
4. Familial exudative vitreoretinopathy
5. Subacute/chronic retinal detachment
6. Retinopathy of prematurity (ROP)
H. Angle-closure glaucoma
1. Retinopathy of prematurity
5. Persistent hyperplastic primary vitreous
6. Congenital pupillary iris-lens membrane
7. Topiramate therapy
8. Central retinal vein occlusion
9. Ciliary body cysts
I. Malignant glaucoma
J. Glaucoma associated with increased venous pressure
1. Sturge-Weber syndrome
K. Intraocular infection-related glaucoma
1. Acute recurrent toxoplasmosis
2. Acute herpetic iritis
3. Maternal rubella infection
4. Endogenous endophthalmitis
L. Glaucoma secondary to unknown etiology
1. Iridocorneal endothelial syndrome (ICE)
GAPO = growth retardation, alopecia, pseudoanodontia (failture of tooth eruption), and progressive optic atrophy, PHACE = posterior fossa brain malformations, hemangiomas of the face (large or complex), arterial anomalies, cardiac anomalies, and eye abnormalities, SHORT = short suture, hyperextensibility of joints or hernia (inguinal) or both, ocular depression, Rieger anomaly, teething decay.
Reprinted with permission from Yeung H, Walton DS. Clinical classification of childhood glaucomas. Arch Ophthalmol. 2010;128(6):680-684.
The glaucoma complicating these vascular diseases is usually of early onset and may often be congenital. In the absence of early intra ocular pressure (IOP) measurements, enlargement of the cornea and globe indicates the presence of glaucoma during the first 2 to 3 years of life. Because of frequent unilateral involvement, the examiner should take advantage of the opportunity to com pare IOP in affected and unaffected eyes, as symmetry is often marked.12
Children seen with this type of glaucoma usually have moderately advanced glaucoma associated with decreased visual acuity, anisometropia, and disc abnormalities. The bulbar conjunctiva usually shows fine tortuous vessels. The episclera will show a more uniform grid of permanent vessels, abnormal by their number and size. The cornea is usually enlarged, but breaks in Descemet’s membrane (Haab’s striae) are infrequent. The anterior chamber is usu ally deep. The iris of the involved eye is often hyperpigmented compared to the contralateral normal eye. With bilateral occurrence, the presence of bilateral iridal melanosis is less obvious than the heterochromia seen in unilateral cases. The lenses are clear. The fundi often appear diffusely red, suggesting the presence of an associated capillary hemangioma. Vascular anomalies can be demonstrated on fluorescein angiography. Ultrasonography for choroidal thickness will show thickening of the choroid in the presence of a typical choroidal hemangioma in this condition. Blood vessel abnormalities of retinal vessels are not seen. If the IOP is excessive, glaucomatous cupping and atrophy develop, as in other glaucomas.
In 32 patients having nevus flammeus of the upper lid with glaucoma in whom we have performed gonioscopy, all have had open angles and have had little in the angle to suggest a vascular abnormality. In general, when the glaucomatous eyes were compared with the contralateral normal eyes, except for peculiarities of Schlemm’s canal, the principal recognizable abnormality was similar to that which we believe is characteristic of ordinary congenital open-angle glaucoma. The iris was commonly attached farther forward in glaucomatous eyes than in normal eyes, but never hiding the scleral spur, and the level of attachment of the iris was variable, causing the insertion of the iris to appear wavy as one scanned circumferentially.
When blood has refluxed into Schlemm’s canal during gonioscopy in some eyes having glaucoma with hemangioma, we have had the impression that the distribution in Schlemm’s canal has been abnormal and different from the ordinary congenital open-angle glaucoma (Figure 70-2B). In some eyes, no distinct line of blood, but only a diffuse reddish glow, was seen deep in the corneoscleral meshwork. In eyes in which the blood in Schlemm’s canal could be seen in more distinct lines, Schlemm’s canal appeared to wander at a varying distance anterior to the scleral spur or to be broken up into multiple channels.
Measurements of episcleral venous pressure vessels in hemangioma of the lid with glaucoma show 2 categories of patients. One type has inconspicuous vessels on the globe with normal pressure. The other type has elevated episcleral venous pressure and the vessels appear abnormally prominent. According to tonography, there is obstruction to aqueous outflow in both types.
A noteworthy peculiarity about the IOP in this condition is that, when the patient changes from sitting to recumbent position, the IOP undergoes a greater change than in other types of glaucoma or in normal eyes. When the patient lies down, the IOP in the eye affected by hemangioma may increase by several mm Hg. However, if the patient remains in the recumbent position, the IOP drops again in 15 to 30 minutes, approaching what it was in the sitting position. Presumably, the rise in IOP is due to a rapid distention of an intraocular hemangioma, probably in the choroid, after which the eye gradually returns to its steady state IOP as a result of slow expulsion of an equal and compensatory volume of aqueous humor. When the eye is in a steady state, tonography indicates abnormal resistance to aqueous outflow to be responsible for the glaucoma.
Glaucoma treatment should first be medical therapy, especially in young children who might be expected to have fewer good results with filtration surgery. Beta-blockers, miotics, and carbonic anhydrase inhibitors (CAIs) are frequently helpful. If medical control proves inadequate, then surgery must be attempted. Goniotomies performed during childhood in 6 patients by us have been uncomplicated, but even multiple goniotomies have proven unsuccessful in controlling this type of glaucoma. Filtration surgery, in light of the poor results that can be expected with a goniotomy procedure, must be considered in the presence of uncontrolled glaucoma in these patients, and filtration surgery is sometimes successful. Trabeculectomy with use of intraoperative mitomycin C is the treatment of choice. Reasonably tight closure of the scleral flap with or without releasable sutures is appropriate, given the risk for rapid operative or postoperative uveal effusions.13 Consideration should be given to performing sclerotomy over the ciliary body at the time of surgery to allow immediate and postoperative choroidal drainage. The trabeculectomy surgeon will be impressed with the dense grid of episcleral vessels present at the flap and sclerotomy site (Figure 70-2C). These can be managed well with an underwater diathermy tip. In 5 patients under the age of 9 years with glaucoma associated with a nevus flammeus and who required trabeculectomy surgery with adjunctive use of mitomycin C, successful control of the glaucoma was achieved without medication in each of these patients.14
Our experience with cycloablative procedures, usually cyclocryotherapy, in a few patients suggests that it can also be helpful and that it is not more problematic in this glaucoma than in other types of glaucoma.
Iridocorneal Goniodysgenesis With Glaucoma
Under iridocorneal goniodysgenesis, we include all congenital ocular abnormalities that tend to combine malformations of the cornea, iris, and filtration angle. The abnormality may be predominantly corneal (as in embryotoxon) or may involve both cornea and iris (Axenfeld’s anomaly and Peters’ anomaly). In Rieger’s anomaly, the angle is involved, as well as the cornea and iris, and glaucoma is more likely. This eye condition can be associated with systemic abnormalities, including abnormalities of the teeth (hypodontia, microdontia, oligodontia), mid-face (hypertelorism, maxillary hypoplasia), pituitary (empty sella syndrome, isolated growth hormone deficiency, parasellar arachnoid cyst), cardiovascular system (atrial septal defect), genitalia (hypospadia, anal stenosis), and excessive peri-umbilical skin (Rieger’s syndrome).15
Axenfeld-Rieger syndrome is frequently transmitted as a heterogeneous autosomal dominant disorder. Recent cytogenetic studies have found an array of genetic defects in families with Axenfeld-Rieger syndrome, including deletions of 4q25 (Rieger syndrome type 1, or RIEG1), 13q14 (Rieger syndrome type 2, or RIEG2), 6p25 (FOXC1), and possibly 16q24. The region coding for RIEG1, also known as PITX2, is a type of homeobox transcription gene with widespread multisystem involvement during embryologic development.15–17 The loss of this gene may help to explain the diversity of anomalies associated with Axenfeld-Rieger syndrome.
Whether or not glaucoma develops in an eye with typical iridocorneal goniodysgenesis depends upon the degree of obstruction of outflow of aqueous humor, either by iridocorneal tissue overlying the TM or apparently in certain cases by abnormalities in the outflow channels themselves (Figure 70-3). The conspicuous processes seen bridging the filtration angle face do not seem to contribute to the obstruction to outflow of aqueous humor. As expected, goniotomy surgery, which strips these processes, frequently does not treat the complicating glaucoma successfully.
For discussion, we have divided cases of iridocorneal dysgenesis into 3 groups, representing different degrees of severity. In actuality, these conditions in the various categories probably are related in some instances. For example, we know that separating cases according to whether or not the pupil is involved is artificial because, in 2 families, we have seen pairs of individuals (mother and son, a pair of sisters) with iridocorneal dysgenesis with glaucoma, but with the pupils normal in one and abnormal in the other member of each pair. The categories are for convenience in description.
EMBRYOTOXON WITHOUT ATTACHMENTS TO THE IRIS
Probably the mildest and most common abnormality one may consider under iridocorneal dysgenesis is simple embryotoxon, or marginal corneal dysplasia, occurring with out other evident abnormality. Embryotoxon is an abnor mal thickening of the peripheral rim of Descemet’s membrane (Schwalbe’s line). The thickening has a refractile glassy character. This thickening may be in the form of a uniform, circumferential, prominent ridge on the inner surface of the cornea, but more commonly, it varies in thick ness and sometimes is abnormally prominent in only one sector. It often varies in thickness so much that it has a beaded appearance.
One can often see embryotoxon very well with the slit-lamp biomicroscope through clear cornea adjacent to the limbus, but only by gonioscopy can one be sure whether there are associated structural abnormalities in the angle. Embryotoxon without other abnormality and without glaucoma is noted in adults as an incidental finding on routine examination and also in infants and children when slit-lamp or gonioscopic examination is performed.
We have seen no eye in which we could relate embryotoxon to glaucoma, unless in addition to the embryotoxon there were congenital attachments across the angle between iris and cornea, as we will describe next.
EMBRYOTOXON WITH CONGENITAL ATTACHMENTS BETWEEN PERIPHERAL IRIS AND CORNEA, BUT PUPIL NORMAL
In iridocorneal dysgenesis having these qualifications, the principal feature is congenital bridging of the angle be tween Schwalbe’s line and peripheral iris by strands of tissue. The stroma of the iris may be normal, atrophic, or split, and the lens may or may not be cataractous, but the pupil is normal. The strands bridging the angle can usually be seen conclusively only by gonioscopy. These strands are variable in character. In some eyes, they consist of refractile avascular material like ropes of Descemet’s membrane; in other eyes, they consist of avascular iris stroma, with or without pigmentation; and in still other eyes, of iris stroma together with iris blood vessels.
We have found congenital iridocorneal bridges of this sort with normal pupils in the following circumstances:
- In adult or children’s nonglaucomatous eyes
- In eyes having what seemed to be adult open-angle glaucoma
- In eyes having congenital or childhood glaucoma
These anomalies are also seen in arteriohepatic dysplasia (Alagille syndrome). In this syndrome, posterior embryotoxon is a near constant abnormality and is frequently associated with multiple bridging angle processes and less frequent corectopia. This syndrome is an autosomal dominant condition with congenital cholestasis, facial defects, cardiovascular anomalies, and skeletal defects. The anterior segment anomalies are accompanied by other ocular defects, including pigmentary retinopathy, but glaucoma does not seem to complicate this syndrome.
EMBRYOTOXON WITH CONGENITAL ATTACHMENTS BETWEEN PERIPHERAL IRIS AND CORNEA, PLUS ABNORMALITIES OF THE PUPIL
This combination of congenital abnormalities consists of a combination of posterior embryotoxon (posterior marginal dysplasia of the cornea), with attachments across the angle from iris to cornea and TM, often with hypoplasia of the stroma of the iris, which may give the iris a dark appearance, plus a considerable variety of possible abnormalities of the pupil, including eccentric pupil (corectopia), pinpoint pupil, slit-like pupil, ectropion of the pigment layer of the iris at the pupil (ectropion uveae), and multiple holes in the iris, inaccurately called polycoria. (Eyes with polycoria may show progressive changes in the iris that may behave like essential atrophy of the iris.) If the angle face can be seen through the processes, it is usually not possible to define the TM, scleral spur, and ciliary body band. In their places, a uniform plane of white tissue is typically seen. These malformations occasionally are associated with microphthalmia or cataract.
This most conspicuous form of iridocorneal goniodysgenesis that involves the pupil and iris as well as the angle often has a hereditary basis, with similar conditions occurring in relatives as seen in Rieger’s syndrome.18
Children with these associated defects of the pupil, iris, angle, and peripheral cornea are at significant risk (50%) for glaucoma, which may be present in infancy or be later acquired.15 Those patients with progressive anterior segment changes characterized by degeneration of the iris and associated blockage of the angle by peripheral iris tissue are especially at risk. These degenerative changes with development of glaucoma or worsening of glaucoma usually occur in the first 5 years of life.
When the anterior segment defects possess a dense central corneal opacification, the presence of Peters’ anomaly should be considered. In this condition, which is often bilateral and may be hereditary, a dense central leukoma is present with the attachment of iris processes at the periphery of the opacity. A cataract may be present. The angle is usually open but abnormal with scattered bridges of tissue from the iris root to the TM. These patients also are at risk for glaucoma. We have frequently seen moderate IOP elevations in infancy in this condition slowly improve over the first 5 years of life.
Treatment of children with glaucoma complicating iridocorneal goniodysgenesis should be initiated with medical therapy. Such treatment is more often helpful with cases of glaucoma that develop later in childhood. Beta-blockers and CAIs have been helpful. When the glaucoma is present from infancy, medical therapy generally is inadequate for satisfactory IOP control but may be useful before glaucoma surgery to decrease the IOP or as an adjunct to therapy after glaucoma surgery.
Goniosurgery should always be considered in these forms of trabecular dysgenesis, especially in infancy. Better control may be achieved with continued medical therapy for a period of time, but in our experience, definitive glaucoma control with goniosurgery is rarely achieved. Best results with goniosurgery can be expected in those eyes with less severe defects, such as those with iris processes alone, unassociated with iris abnormalities. Failure of goniosurgery to help with one eye may be useful information in deciding against goniosurgery for a fellow eye.
Trabeculectomy with adjunctive use of mitomycin C has been helpful in these patients and now represents the surgical treatment of choice.
The Oculocerebrorenal (Lowe) Syndrome
Lowe syndrome is a rare x-linked recessive disease characterized by mental retardation, hypotonia, systemic acidosis, rickets, and ocular defects, including glaucoma. The condition is caused by mutation of the OCRL-1 gene located at Xq26.1.19 The most constant defects are cataracts, which are characteristically bilateral, irregularly dense, thin, and are associated with extreme miosis (Figure 70-4). Glaucoma occurs less frequently than cataracts (47% to 64%). In a recent review of 7 patients with Lowe syndrome,19 5 patients (71%) were found to have glaucoma. Of those 10 eyes, 6 eyes presented with increased IOP prior to lensectomy. Gonioscopy revealed an open angle with normal gray TM without abnormal iris processes. The ciliary body bands were abnormally narrow and visibility of the scleral spur was variable and often limited.19
Treatment of glaucoma associated with Lowe syndrome is difficult. Goniotomy frequently fails to control IOP. It also has been associated with extensive postoperative bleeding. Medical therapy consisting of a beta-blocker and a CAI is appropriate as first-line treatment. There is an appropriate reluctance to recommend an oral CAI in the presence of a condition complicated already by systemic acidosis and rickets. Patients with Lowe syndrome will be on supplemental base therapy (eg, Bicitra/Polycitra, Baker Norton). The dose of this supplement usually can be increased to take into account the effect of the oral CAI to allow its use for this ocular indication. Consultation with the patient’s pediatrician is recommended.