CHAPTER

Primary congenital
glaucoma

Fang Ko, Maria Papadopoulos, Peng T. Khaw1

9
National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye
Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
1
Corresponding author: e-mail address: p.khaw@ucl.ac.uk

Abstract
Primary congenital glaucoma (PCG) is the most common nonsyndromic glaucoma in infancy,
which can lead to blindness, or a lifetime of vision when diagnosed and treated properly.
PCG is more common in populations with a higher prevalence of consanguinity and is as-
sociated with CYP1B1 gene mutations which show variable expressivity and phenotypes.
The immature angle appearance of PCG likely results from arrested development of tissues
of neural crest origin in the third trimester, with the severity of abnormality varying according
to the stage at which arrested development occurred.
Classic symptoms at presentation include tearing, photophobia, blepharospasm, eye rub-
bing, and irritability. Examination may reveal elevated intraocular pressure, corneal edema,
increased corneal diameter, Haab striae, or enlarged axial length.
Angle surgery remains the first line treatment for PCG with a recent advance being circum-
ferential trabeculotomy with the potential to incise the whole angle during one operation as
oppose to an incremental approach and the associated multiple anesthetics. Once angle surgery
fails, either trabeculectomy or glaucoma drainage device surgery may be appropriate.

Keywords
Pediatric congenital glaucoma, Genetics, Goniotomy, Trabeculotomy, Trabeculectomy

Primary congenital glaucoma (PCG) is a rare but important disease, which can lead
to blindness, or alternatively a lifetime of vision with early diagnosis and successful
control of intraocular pressure (IOP). It is the most common nonsyndromic glaucoma
in infancy, with variable incidence depending on consanguinity. It probably results
from arrested development of tissues derived from neural crest cells, leading to ab-
normal drainage angle anatomy and decreased trabecular meshwork outflow. PCG is
classified according to age of onset, as either neonatal from 0 to 1 month, infantile
from 2 to 24 months, or late-onset or late-recognized from 3 to 4 years (Beck et al.,
2013). It may also be classified as spontaneously arrested, if there are findings of

Progress in Brain Research, Volume 221, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.06.005

© 2015 Elsevier B.V. All rights reserved.
177
178 CHAPTER 9 Primary congenital glaucoma

nonprogressive buphthalmos, Haab striae, and normal IOP. Surgical intervention

with angle procedures may lead to long-term IOP control.

1 EPIDEMIOLOGY
PCG can be sporadic or inherited in an autosomal recessive pattern. Its incidence
varies depending on the population and frequency of consanguinity. In Western
countries, PCG occurs in 1 of 10,000–20,000 live births (McGinnity et al., 1987;
Papadopoulos et al., 2007; Taylor et al., 1999). In the Middle East, incidence ranges
from 1:2500 to 8200 (Elder, 1993; Jaafar, 1988) but the highest incidence is in
Slovakian Gypsies at 1:11,250 (Gencik, 1989). Family history is reported in
10–40%, with penetrance varying from 40–100% (Khan, 2011a,b; Sarfarazi and
Stoilov, 2000).

2 GENETICS
The disease is typically bilateral in 70% of cases, but may be asymmetric. Sporadic
cases have higher male prevalence, and familial cases have more equal sex distribu-
tion (McGinnity et al., 1987; Sarfarazi and Stoilov, 2000; Suri et al., 2009; Turacli
et al., 1992; Walton et al., 2013). The CYP1B1 gene at the GLC3A locus, which en-
codes cytochrome P450 1B1, has been associated with PCG (Abu-Amero and
Edward, 2004; Stoilov et al., 1997). Pathogenic variants include p.Gly61Glu and
p.Glu229Lys on exon 2, with the former being typically homozygous and the latter
heterozygous; as well as p.Arg469Trp on exon 3, which tends to be heterozygous
(Badeeb et al., 2014). p.Gly61Glu and p.Arg469Trp have been associated with more
severe cases (Badeeb et al., 2014). Some have analyzed unilateral cases of PCG, and
have not found a link with CYP1B1, suggesting possible different etiology (Khan
et al., 2012). Mice deficient in CYP1B1 develop structural abnormalities in the iri-
docorneal angle, with decreased amount of collagen and increased endothelial cells
in the trabecular meshwork (Teixeira et al., 2015). Other loci, GLC3B and GLC3C
have also been linked to PCG; however, the genes at these loci are unknown at the
time of writing of this chapter. Latent transforming growth factor beta (LTBP2),
located adjacent to GLC3C, has been found in those with “PCG” (Ali et al.,
2009; Lim et al., 2013; Narooie-Nejad et al., 2009; Sarfarazi et al., 2003), although
secondary causes such as lens dislocation, in our experience, may play a part in the
pathogenesis (Khan, 2011a,b). LTBP2 is expressed in the trabecular meshwork, cil-
iary body, and ciliary processes (Ali et al., 2009). Others have suggested mitochon-
dria dysfunction may be related to PCG, although more research is needed to make
any clinical correlation (Kumar et al., 2013; Tanwar et al., 2010).
CYP1B1 mutations are associated with variable expressivity and penetrance
(Bejjani et al., 2000; Suri et al., 2009). Neonatal presentations of PCG are more likely
to have CYP1B1 mutations, but the same mutations can be associated with less severe
 3 Pathogenesis 179

PCG or no glaucoma in childhood at all (Khan, 2011a,b). Some have suggested se-
verity of angle dysgenesis and subsequent severity of disease may correlate with
CYP1B1; however, studies of this type have been small (Hollander et al., 2006).
Greater attempts at genotype–phenotype correlations have been inconclusive as have
attempts at establishing a relationship between genotype and surgical outcomes
(Abu-Amero et al., 2011; Tanwar et al., 2009).
Genetic testing methods include sequence analysis, targeted mutation analysis,
and deletion/duplication analysis. Testing strategies may target CYP1B1; alterna-
tively, others advocate use of multigene panel that includes other genes of interest
in the differential diagnosis. In general, the probability of identifying pathogenic var-
iants during genetic testing increases in bilateral disease, severe disease, positive
family history, and parental consanguinity. CYP1B1 accounts for 20–90% of famil-
ial cases, and up to 27% of sporadic cases (Sarfarazi and Stoilov, 2000). The risk of
PCG in siblings and offspring in families without consanguinity is low (<5%), but
screening is prudent, especially in the first 6 months of life. However, risk is higher if
there is a history of consanguinity, making screening of siblings and offspring essen-
tial. If both disease-causing alleles in an affected family member have been identi-
fied, it is possible to perform carrier testing for at risk relatives and prenatal
diagnosis.

3 PATHOGENESIS
Structures which comprise the drainage angle are derived from neural crest and me-
soderm lineage. Trabecular meshwork formation occurs at 12–22 weeks of gestation,
with mesenchymal cells forming a wedge-shaped structure between the corneal
endothelium and the deeper stroma (McMenamin, 1991). Schlemm canal becomes
visible at 16 weeks of gestation, formed from a venous plexus anterior to the trabec-
ular anlage, and becomes clearly defined with intercanal links by 36 weeks (Ramirez
et al., 2004). Development continues after birth and resembles the adult structure by
8 years (Ramirez et al., 2004).
The immature angle appearance of PCG probably results from arrested develop-
ment of tissues of neural crest origin in the third trimester, with the severity of ab-
normality varying according to the stage at which arrested development occurred.
Historically, it was thought that a membrane served as an impenetrable obstruction
to outflow, due to the shiny appearance of the angle and subsequent falling back of
the peripheral iris during goniotomy, as if there was tractional tissue which was re-
lieved by incision (Barkan, 1955). However, histopathologic studies have not been
able to identify any such membrane. Rather, the site of outflow obstruction is thought
to be trabecular rather than pretrabecular, due to thickened trabecular beams prevent-
ing normal posterior migration of the ciliary body and iris, with resulting traction
further compacting the already thickened trabecular beams and obstructing outflow
(Anderson, 1981). This may explain the observation that children with PCG typically
have an appearance of a high iris insertion.
180 CHAPTER 9 Primary congenital glaucoma

4 PRESENTATION
Early detection and treatment of PCG can improve visual outcome. Most children
present at less than 6 months of age with classic symptoms at presentation of tearing,
photophobia, blepharospasm, eye rubbing, and irritability. Parents or primary care
physicians may notice corneal clouding or unusually large appearance of eyes
(buphthalmos). Examination may reveal corneal edema, increased corneal diameter,
breaks in Descemet membrane (Haab striae), or enlarged axial length. Table 1 lists
expected values of corneal diameter and axial length measurements. Mild corneal
clouding in newborns and premature infants need not induce alarm, as this can be
normal, but would be expected to resolve as the cornea thins from 960 mm at birth
to 520 mm at 6 months (Saw et al., 2004). The corneal diameter in this case would be
normal. IOP is typically high. Gonioscopy reveals abnormal angle anatomy, with
high iris insertion which may have a scalloped appearance (Fig. 1) and circumferen-
tial hyperemic iris vessels in the peripheral iris. The characteristic angle findings can
be seen in eyes with normal IOP in infants with asymmetric disease. Fundus exam-
ination may reveal optic disk excavation above what is expected for the child’s age.

Table 1 Normal Corneal Diameter and Axial Length in Children and Adults.
Corneal diameter (mm) Axial length (mm)

At birth 9.5–10.5 16–18

1 year 11–12 20–21
6 years 12 23
Adult 12 22–24

Adapted from Basic and Clinical Science Course, American Academy of Ophthalmology 2010–2011.

FIGURE 1
PCG angle anatomy showing high iris insertion and peripheral scalloped appearance.
 6 Management 181

5 DIFFERENTIAL DIAGNOSIS
PCG should be distinguished from other anterior segment disorders and syndromes
which may be associated with glaucoma such as aniridia, Peters anomaly, Axenfeld-
Rieger syndrome, microphthalmos, Sturge–Weber, Neurofibromatosis type 1, Lowe
syndrome, and others. It is important to examine the iris, lens, and cornea for asso-
ciated findings. Facial features such as choroidal hemangioma may be evident. If a
systemic syndrome is suspected, then consultation with pediatrician for systemic
evaluation is important.
Congenital hereditary endothelial dystrophy (CHED) may cause corneal opaci-
fication and measured IOP may be falsely elevated due to corneal edema making the
differentiation from glaucoma difficult. However, corneal diameter and axial length
are typically normal and there is no excavation of the optic disk (if visible). Genetic
testing may be helpful in confirming the diagnosis of CHED but a negative result
does not rule out the condition (Khan et al., 2010). It remains controversial as to
whether CHED and glaucoma can coexist (Khan et al., 2010; Khan, 2011b;
Ramamurthy et al., 2007).
Metabolic disorders, such as mucopolysaccharidoses (MPS) and cystinosis can
also be associated with corneal clouding mimicking glaucoma. The corneal haze
is usually bilateral, and of late infantile or early childhood onset, rather than congen-
ital. The classic dysmorphic features can be helpful in identifying a young child with
MPS. Transient or permanent corneal clouding with or without elevated IOP can re-
sult from intrauterine infection with rubella virus but the diagnosis is usually obvious
due to associated systemic signs.

6 MANAGEMENT
Visual prognosis depends on severity of disease at diagnosis and the response to in-
tervention with successful control of IOP on follow-up. Typically, those with earlier
onset of clinical manifestation (i.e., less than 1 month of age) have worse disease that
responds poorly to angle surgery (Zagora et al., 2015). There is a trend to proceed
rapidly to more effective surgery such as tube drainage surgery in these children.
Comprehensive examination is necessary but may be difficult in the office. As a
result, examination under anesthesia (EUA) is often needed, especially if there is a
high index of suspicion for glaucoma to confirm the diagnosis and document baseline
findings. However, the decision to proceed with an EUA is not a trivial one in light of
the increasing evidence that multiple exposures to general anesthetics may adversely
affect the developing brain (DiMaggio et al., 2011; McCann and Soriano, 2009; Sun,
2010; Sun et al., 2012). An EUA should be considered when its findings will assist in
making the diagnosis or provide important follow-up data that may influence
decision-making. PCG is a condition usually requiring surgery so parents must be
advised of the possible need for surgery following the EUA. All inhalation anes-
thetics decrease the IOP in an unpredictable fashion; thus some advocate
182 CHAPTER 9 Primary congenital glaucoma

immediately measuring IOP as soon as anesthesia is induced, whereas others may

remeasure IOP when most anesthetic has blown off and the child is just about to
wake. It is important to use the same technique each time. Ketamine is a good alter-
native as it does not lower the IOP and is thought to provide IOP measurements that
are similar to those taken in awake infants (Blumberg et al., 2007).
PCG is a surgical condition. Yet, there remains a role for topical and/or systemic
intraocular-lower medications, for temporizing prior to surgery, and to decrease cor-
neal edema an improve visualization of angle anatomy during surgery. Prostaglan-
dins, carbonic anhydrase inhibitors, and beta blockers are generally the preferred
medications. Brimonidine risks depression of the central nervous system and should
be avoided in children under 6 years of age.

6.1 SURGERY
Goniotomy and trabeculotomy are the primary procedures for eliminating obstruction
to aqueous outflow due to structural abnormalities in angle, thus restoring the pathway
for aqueous drainage. Maumenee found successful angle surgery depended on the
presence of Schlemm canal (1963). The exact mechanism of action for these proce-
dures is unknown, but tonographic studies do confirm increased outflow and improved
IOP (Kupfer and Ross, 1971; Shaffer, 1967). Goniotomy in children was described by
Otto Barkan in 1942. However, the procedure was limited by the requirement for a
clear cornea. Subsequently, use of a nylon filament to rupture the internal wall between
Schlemm canal and trabecular meshwork was described with variations using a rigid
trabeculotome probe (trabeculotomy). More recently, a 6/0 prolene suture and an illu-
minated microcatheter have been used to potentially incise the angle 360° (circumfer-
ential trabeculotomy) (Beck and Lynch, 1995; Sarkisian, 2010).
Trabeculotomy has the advantage of being possible with a hazy cornea. However,
it may be difficult to locate Schlemm canal, and creation of a false passage with a
probe either anteriorly or posteriorly is possible with the potential for suture misdi-
rection into the suprachoroidal space. Furthermore, trabeculotomy requires a con-
junctival incision with potential impact against success of future filtering or shunt
procedures if performed superiorly. A recent major advance in angle surgery has
been the use of an illuminated microcatheter which has the potential to incise the
angle 360° and more safely than a suture by allowing early identification of misdi-
rection (Girkin et al., 2012). The impact of scarring on future procedures can be min-
imized by using a temporal or inferotemporal approach. Alternatively, a conjunctival
sparing, ab interno circumferential trabeculotomy with an illuminated microcatheter
has recently been described (Grover et al., 2015).
Some have advocated combining angle surgery with filtering surgery, combined
trabeculotomy/trabeculectomy, with or without antiscarring agents especially in re-
gions with advanced disease on presentation and those thought to be at greater risk of
failure from angle surgery such as in the Middle East and India (Al-Hazmi et al.,
2005; Debnath et al., 1989; Elder, 1993; Mandal et al., 2007). However, its advan-
tages over either surgery alone remain controversial as there are no prospective stud-
ies comparing all three procedures.
 6 Management 183

Both goniotomy and trabeculotomy have similar high success rates of 70–90%
with multiple surgeries, and tend to be more favorable in those with onset of signs
of PCG between 3 and 12 months of age (Akimoto et al., 1994; Dietlein, 2000; Lister,
1966; Shafer, 1982). Conversely, worse prognosis has been noted among those who
have more aggressive disease due to severe angle immaturity, or among those with
longer duration of disease and enlargement of anterior segment structures leading to
structural damage to the angle. The success of circumferential (360°) trabeculotomy
in eyes with PCG varies from 77% to 92% after 1–4 years similar to success rates of
angle surgery after multiple operations (Beck and Lynch, 1995; Beck et al., 2011;
Girkin et al., 2012; Mendicino et al., 2000). However, despite its advantages, success
may not always be possible with a single incision as the suture or microcatheter may
not advance all the way around Schlemm canal (Beck and Lynch, 1995; Girkin et al.,
2012). To date, no prospective randomized controlled trials directly comparing
goniotomy and trabeculotomy have been published but are thought to be equally ef-
fective, and surgical choice largely remains with the surgeon, based on corneal clar-
ity, preference, and experience.
The long-term success rates of trabeculectomy surgery in children are lower com-
pared to adults (Gressel et al., 1984), due to a more aggressive healing response in
children. As a consequence, antiscarring agents are often necessary. Outcomes of tra-
beculectomy for PCG vary widely with overall success at 1 year ranges between 50%
and 87% (Al-Hazmi et al., 1998; Beauchamp and Parks, 1979; Burke and Bowell,
1989; Fulcher et al., 1996; Rodrigues et al., 2004; Sidoti et al., 2000). Infants less than
1 year of age tend to have poorer results with trabeculectomy (Al-Hazmi et al., 1998;
Freedman et al., 1999). Complication rates with MMC tend to be higher than without
it, especially those related to hypotony (Freedman et al., 1999; Sidoti et al., 2000;
Susanna et al., 1995). However, modifications to the surgical technique with emphasis
on posteriorly directed flow and changes to the intraoperative application of MMC can
potentially minimize early and late complications (Wells et al., 2003; Figs. 2 and 3).

FIGURE 2
Moorfields Safer Surgery system: simple modifications to improve trabeculectomy in children.
184 CHAPTER 9 Primary congenital glaucoma

FIGURE 3
Bleb appearance before (left eye) and after (right eye) change to Moorfields Safer Surgery
technique.

Glaucoma drainage device (GDD) surgery is an alternative to trabeculectomy or may

be performed after failed angle surgery. However, complications such as tube malpo-
sition, tube erosion, and endophthalmitis are consistently reported with greater fre-
quency in the pediatric compared to adult population (Chen et al., 2014).
Angle surgery remains the first line treatment for PCG. If there is inadequate im-
provement of IOP with goniotomy or probe trabeculotomy, additional incision of the
angle can be performed. If additional surgery is needed, filtering procedures such as
trabeculectomy with antiscarring agents or GDD surgery may be considered. How-
ever, recent results suggest that trabeculectomy with MMC and Moorfields Safer
Surgery System can have good long term outcomes (Jayaram et al., 2015). There
is no strong consensus regarding which is preferred after failed angle surgery
(Papadopoulos et al., 2013).
Whatever surgery is chosen, the surgeon must keep in mind the issues specific to
the pediatric population. Because of elasticity of pediatric tissue, as well as potential
structural weakness in a buphthalmic eye, there is a tendency for wound leaks, which
can be prevented by making long tracks with tighter sutures than what would be
needed in an adult. The choice of using releasable versus fixed sutures must balance
the desire to adjust postoperative results with the risk of eye rubbing by the child.
Also, parents may have difficulty instilling eye drops, and will need instructions
on the best way to hold a child. For the clinician, establishing trust with the child
prior to surgery may aid in examination postoperatively.

7 KEY POINTS
• PCG is the most common nonsyndromic glaucoma in infancy, which can lead to
blindness, or a lifetime of vision when diagnosed and treated properly.
• PCG is more common in populations with a higher prevalence of consanguinity
and is associated with CYP1B1 gene mutations which show variable expressivity
and phenotypes.
 References 185

• The immature angle appearance of PCG likely results from arrested development of
tissues of neural crest origin in the third trimester, with the severity of abnormality
varying according to the stage at which arrested development occurred.
• Classic symptoms at presentation include tearing, photophobia, blepharospasm,
eye rubbing, and irritability. Examination may reveal elevated IOP, corneal
edema, increased corneal diameter, Haab striae, or enlarged axial length. Clinical
screening of current and future siblings is essential if there is parental
consanguinity.
• Angle surgery remains the first line treatment for PCG with a recent advance
being circumferential trabeculotomy with the potential to incise the whole angle
during one operation as oppose to an incremental approach and the associated
multiple anesthetics. Once angle surgery fails, either trabeculectomy or GDD
surgery may be appropriate.

ACKNOWLEDGMENTS
The authors acknowledge the support of the Medical Research Council, Moorfields Special
Trustees/Moorfields Eye Charity, the Helen Hamlyn Trust in memory of Paul Hamlyn and
Fight for Sight (UK); Ron and Liora Moskovitz, John Nolan, Richard Desmond Foundation;
and the Michael and Ilse Katz Foundation. This research has received a portion of its funding
from the Department of Health’s National Institute for Health Research Biomedical Research
Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. The views
expressed in this publication are those of the authors and not necessarily those of the Depart-
ment of Health.

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