3. Glaucoma

Including: Peters' anomaly.

MIM

601771 (CYP1B1)

Clinical features

Primary infantile glaucoma is not associated with extraocular

manifestations or other ocular abnormalities. It is thought to be due

to abnormal development of the drainage angle of the anterior

chamber. Symptoms are of corneal enlargement or clouding,

excessive tearing, photophobia or general malaise. The condition is

usually bilateral although asymmetry is common.

Congenital glaucoma with corneal enlargement.

Congenital glaucoma with splits in Descemet membrane.

Age of onset

Onset is at birth or soon afterwards. Over 80% are symptomatic by

3 months of age.

Epidemiology

Incidence of 1:10,000

Inheritance

Autosomal recessive

58

Primary congenital glaucoma

Chromosomal location

MIM

Locus

Gene

Chromosome

231300

GLC3A

CYP1B1

2p22–p21

600975

GLC3B

-

1p36.2–p36.1

-

GLC3C*

-

Unknown

Gene

Cytochrome P450B1 (CYP1B1)

Mutational spectrum

A large number of mutations has been described including protein

truncating mutations, as well as missense mutations, of the

conserved domains of the protein. Studies of an inbred population in

Saudi Arabia, where primary infantile glaucoma is common, suggest

that mutations in CYP1B1 show reduced penetrance and expressivity.

A defect in CYP1B1 has been demonstrated in a single patient with

bilateral congenital glaucoma and bilateral Peters’ anomaly. The

individual carried two CYP1B1 mutations (compound heterozygote),

one nonsense (protein truncating) and the other was likely to abolish

translation. This finding underlies the phenotypic heterogeneity of

individuals carrying mutations in this gene.

Effect of mutation

CYP1B1 is a member of the cytochrome P450 multigene

superfamily, whose role is the physiological inactivation of both

endogenous and exogenous substrates. CYP1B1 is the first of these

enzymes identified to be involved in a developmental process and its

role in ocular development remains unclear.

Both protein truncation mutations and missense mutations in the

heme-binding region have been described; it is thought that both

may result in reduced heme binding, which is critical for the

functioning of cytochrome P450 molecules.

Glaucoma

59

Diagnosis

Clinical. Mutation testing is available on a research basis only.

Younger siblings of children with primary congenital glaucoma

should be examined soon after birth for evidence of glaucoma.

60

Primary congenital glaucoma

MIM

137750; 601652 (myocilin)

Clinical features

Early onset POAG. Individuals do not develop buphthalmos and

have normal anterior segment examination. Intraocular pressure

may be high—often over 50 mmHg. Patients are often myopic and

invariably require filtration surgery.

Grossly cupped disc in POAG.

Age of onset

JOAG typically affects children in their teenage years. Mean age at

diagnosis in one study was 18 years, although onset from the age of

3 years is described.

Inheritance

Autosomal dominant with high penetrance (80–100% by age

20 years).

One family with autosomal recessive JOAG has been described

(see below).

Chromosomal location

1q24.3–q25.2

Some families with juvenile POAG do not map to this region.

Glaucoma

61

Gene

Myocilin (MYOC); alternative name: trabecular meshwork-induced

glucocorticoid response protein gene (TIGR).

Mutational spectrum

JOAG – autosomal dominant

MYOC is a widely expressed gene that encodes a 504-amino acid

protein. The gene contains three exons. Exon 3 encodes a conserved

C-terminal homologous to frog olfactomedin, an extracellular matrix

glycoprotein of the olfactory epithelium.

Mutations have been described in a number of families with

JOAG–these are generally missense mutations within the conserved

exon 3 domain.

JOAG – autosomal recessive

Recessive families with JOAG associated with homozygous protein-

terminating MYOC mutations have been reported. These are

associated with loss of function of MYOC.

Adult-onset POAG

The impact of MYOC mutation on more common forms of adult-

onset POAG has been extensively investigated. One study examined

1700 individuals from five populations and found MYOC mutations

in 3–4% of adult POAG individuals. One mutation, Gln368Ter, is

common and accounts for ~1.5% of all POAG.

Effect of mutation

Myocilin was originally shown to be upregulated by the

administration of corticosteroids to the trabecular meshwork.

Its function is not known.

Mutations in juvenile forms of POAG may act in a dominant negative

fashion. In one extensive Canadian kindred, several individuals who

were homozygous for a highly penetrant dominant mutation did not

develop glaucoma; it is presumed that the mutant protein is functional

and, when homozygous, does not have a dominant negative effect.

Diagnosis

Clinical. Mutation testing in families with JOAG is available on a

research basis. Testing for MYOC mutations in adult POAG is not

currently undertaken due to the low frequency of mutations.

62

Juvenile primary open angle glaucoma

MIM

See below

Clinical features

POAG is a common, highly variable condition of complex etiology

that causes a characteristic optic neuropathy, progressive disc

cupping and arcuate field loss. It is likely to be caused by a number

of interacting factors, both genetic and environmental. Raised

intraocular pressure is a major risk factor but not an absolute

requirement for diagnosis. Family history is another major risk factor

which justifies the screening of first-degree relatives. 1 in 10 first

degree relatives of affected individuals are themselves affected.

Like many complex disorders (e.g. heart disease, schizophrenia or

obesity), our understanding of the pathogenesis of POAG is

surprisingly rudimentary. POAG has a number of uncommon

Mendelian subforms which are amenable to analysis using current

techniques. Our understanding of the more common forms of POAG

may be improved by characterizing the genes underlying these single

gene disorders.

In the table below, chromosomal locations are listed for different

forms of open angle glaucoma. Genes have been found to underlie

juvenile POAG and nail-patella syndrome at the GLC1A, GLC1E

and NPS loci, respectively. The others have been defined by linkage

analyses in single families or, in one case (GLC1B), by pooling

small families. These are statistical methodologies for localizing

putative chromosomal positions. Within single families it is generally

assumed that a single gene defect affects all members of a family;

this assumption renders these techniques prone to error as it is not

possible to differentiate clinically identical, genetically distinct

‘phenocopies’ affecting different individuals of a family. Final proof

of their true relevance will follow confirmation of linkage in other

families or discovery of a causative gene at a given location.

Glaucoma

63

Age of onset

Adulthood

Epidemiology

POAG is the second most common adult-onset cause of blindness in

the developed world. It affects around 2% of the adult population.

Inheritance

The mode of inheritance of the common forms of POAG is complex.

The Mendelian forms are autosomal dominant.

Chromosomal location

MIM

Locus

Gene

Chromosome

Method of localization

137750

GLC1A

MYOC

1q24.3–q25.2

Gene

137760

GLC1B

-

2cen–q13

Pooled families

601682

GLC1C

-

3q21–q24

Single family

602429

GLC1D

-

8q23

Single family

602432

GLC1E*

-

10p14–p15

Single family

603383

GLC1F

-

7q35–q36

Single family

161200

NPS (q.v.)

LMX1B

9q34.1

Gene

Genes

Myocilin (MYOC; see juvenile POAG) and LIM homeo box

transcription factor 1, beta (LMX1B; see nail-patella syndrome).

Mutational spectrum

Unknown

Effect of mutation

Unknown

Diagnosis

Genetic testing is not yet available for POAG.

64

Primary open angle glaucoma

MIM

106210

Clinical features

There is usually total absence of iris tissue. Partial or segmental

aniridia may manifest as ‘atypical colobomata’. There may be

segmental iris hypoplasia. There is often intrafamilial variability

in severity and complications.

The condition affects numerous ocular structures. Peripheral

corneal vascularization associated with stem cell failure leads to

a progressive keratitis and ocular surface abnormalities that may

be problematic in later life. Abnormal development of the anterior

segment/trabeculum/angle structures poses a significant life-time

risk of developmental glaucoma in 20–50% of cases. Cataract, in

particular anterior polar cataracts, may occur.

Glaucoma

65

In the posterior segment, foveal hypoplasia is a major contributor

to reduced vision. There may be associated optic nerve hypoplasia.

Posterior segment abnormalities commonly lead to the development

of nystagmus.

Age of onset

Congenital

Inheritance

Aniridia is usually autosomal dominant. Sporadic cases are well

documented and in these cases a deletion may encompass adjacent

loci including the WT1 gene, which underlies Wilms’ tumor.

Chromosomal location

11p13

Gene

Paired box gene 6 (PAX6)

Mutational spectrum

Around 140 mutations have now been described throughout

the gene (Human PAX6 Allelic variant database;

http://www.hgu.mrc.ac.uk/Softdata/PAX6/). Missense mutations

are under-represented.

A wide variety of ocular phenotypes are associated with PAX6

mutations; apart from ‘simple’ aniridia these include Peters’

anomaly, autosomal dominant keratitis, autosomal dominant

cataract and isolated foveal hypoplasia.

One compound heterozygote has been reported. The infant had

severe craniofacial and central nervous system defects and no eyes.

The head was small with large ears; the brain was small with

abnormal cerebral hemispheres and a partially absent corpus

callosum. The infant died after 8 days.

Effect of mutation

The majority of mutations lead to premature termination of the PAX6

protein and are thought to act by means of haploinsufficiency.

66

Aniridia

Diagnosis

In the absence of a family history, aniridia may be due to a deletion

of 11p13, which could include neighboring genes. Of these, WT1,

when absent, may predispose to Wilms’ tumors. One such

contiguous gene syndrome is the WAGR syndrome (Wilms’ tumor,

Aniridia, Genitourinary abnormalities and mental Retardation).

Among individuals with a presumed de novo mutation,

chromosomal analysis and FISH should be used to exclude

a WT1 deletion.

In classical cases, in particular those with a family history, the

diagnosis is often simple. However, variant cases with partial

aniridia or atypical colobomata (in particular those not affecting the

inferior iris) or with other forms of anterior segment dysgenesis may

be suspected in the presence of nystagmus and/or foveal hypoplasia,

which is almost invariant among individuals with PAX6 mutations.

Mutation testing is available through diagnostic laboratories.

However, in most cases this is not of major clinical significance.

Prenatal diagnosis has been undertaken.

Glaucoma

67

MIM

107250; 602669 (PITX3); 601094 (FOXE3)

Clinical features

As discussed under iridogoniodysgenesis (q.v.), isolated anterior

segment dysgenesis forms a heterogeneous group. ASMD is a

generic term describing the broad range of anterior dysgenesis

phenotypes. The term suggests a potential pathogenic mechanism

common to different forms of anterior segment dysgenesis. Axenfeld,

Rieger and Peters’ anomalies may occur in the same family—this

suggests that these clinical distinctions do not necessarily reflect

underlying differences in etiology.

Age of onset

A developmental disorder which is present at birth. Secondary

developmental glaucoma commonly develops during childhood.

Inheritance

Isolated anterior segment dysgenesis is often autosomal dominant.

However, affected sib-pairs and affected children within

consanguineous marriages suggest that autosomal recessive

forms exist.

Chromosomal location

10q25 (paired-like homeodomain transcription factor 3 [PITX3])

1p32 (forkhead box E3 [FOXE3])

Gene

PITX3; FOXE3. Other families with dominant forms of the disease

do not have defects in these genes. This suggests that other genes

cause a similar phenotype.

Mutational spectrum

PITX3: a single premature protein truncation mutation was observed

in one family with ASMD. There was a variable phenotype including

Peters’ and Axenfeld anomalies as well as cataract. The protein

truncation mutation removes a highly conserved C-terminal domain,

thought to be involved in protein-protein interaction. Similar,

presumed haploinsufficiency mutations in PITX2 (q.v. Rieger

68

Anterior segment mesenchymal dysgenesis

syndrome) have been described. PITX2 and PITX3 are highly

homologous homeodomain-containing proteins that are critical to

ocular development. One missense mutation was observed in a

family with bilateral congenital cataract.

FOXE3: A mutation has been defined in a single family with anterior

segment ocular dysgenesis and cataracts. A frameshift mutation

resulted in an abnormal terminal amino acid sequence with the

addition of 111 amino acids.

Effect of mutation

PITX3 is a developmental transcription factor expressed in the

developing lens placode and through all stages of lenticular

development. In addition, the gene is expressed in the midbrain,

tongue and mesenchymal structures around the sternum, vertebrae

and head muscles. A spontaneous mouse mutant aphakia, in which

mice have small eyes with no lens, has a deletion mutation of the

murine homolog, Pitx3.

FOXE3 is a transcription factor that is critical during lens

development. It is regulated by other modulators of ocular

development such as PAX6. During development, FOXE3 is

expressed in developing lens tissues from the start of lens placode

induction and becomes turned off after lens fiber cell differentiation.

Diagnosis

Clinical examination. Children who are at risk need regular follow-up

to monitor the potential development of glaucoma.

Glaucoma

69

MIM

600510

1

2

Clinical features

Pigment dispersion syndrome is an early-onset form of open angle

glaucoma. There is pigment loss from the iris epithelium leading

to slit-shaped defects visible on transillumination (1). Pigment is

deposited throughout the anterior segment, onto the lens, lens

zonules, iris, trabecular meshwork (2) and corneal endothelium,

where it forms Krukenberg spindles (3). Pigment loss is thought to

occur from physical abrasion between the iris and the lens zonules.

Initially, increased pressure may result directly from pigment

accumulation (for example, there may be an increase in pressure

after exercise). Ultimately, this pigment is phagocytosed, leading

to trabecular meshwork damage.

70

Glaucoma-related pigment dispersion syndrome

The disorder is said to be more common in myopes and males,

although autosomal dominant inheritance has been demonstrated.

Pigment dispersion is a strong risk factor for glaucoma but does not

always lead to glaucomatous damage.

Age of onset

Usually affects individuals under the age of 40 years.

Inheritance

Autosomal dominant. The occurrence of many sporadic individuals

suggests that there may be reduced penetrance.

Chromosomal location

7q35–q36

Gene

The gene underlying GPDS has not been defined.

Effect of mutation

Unknown

Diagnosis

Clinical, including examination of first-degree relatives.

Gene identification may aid screening of family members.

Glaucoma

71

MIM

601631; 601090 (FOXC1)

Clinical features

Autosomal dominant IGDA is characterized by iris hypoplasia and

goniodysgenesis. The major risk is of childhood-onset developmental

glaucoma. The phenotype is highly variable and may include

Axenfeld anomaly, Rieger syndrome and iris hypoplasia. In general,

there are no extraocular manifestations.

Age of onset

This is a developmental disorder which is present at birth.

Developmental glaucoma is common during childhood.

Inheritance

Isolated anterior segment dysgenesis/iridogoniodysgenesis is often

autosomal dominant. However, affected sib-pairs and affected

children within consanguineous marriages suggest that autosomal

recessive forms exist.

Chromosomal location

6p25

Gene

Forkhead box C1 (FOXC1) (alternative names: FREAC3/FKHL7).

There are other known dominant families that are not caused by

defects in this locus; this suggests that other genes cause a similar

phenotype.

Mutational spectrum

Nonsense mutations that result in premature protein truncation and

missense mutations within the forkhead transcription domain have

been described. The range of phenotypes shows intrafamilial

variability. One family with Rieger syndrome with extraocular

manifestations has been shown to carry a FOXC1 mutation.

Affected patients with a duplication of 6p25 have been described.

This is not visible microscopically but results in the presence of

three functional copies of FOXC1. This suggests that increased, as

well as decreased, dosage of FOXC1 can cause anterior segment

abnormalities.

72

Iridogoniodysgenesis type I

Effect of mutation

FOXC1 is a transcription factor that regulates the expression of genes

critical to ocular anterior segment development. The mutations

currently described result in haploinsufficiency. Those within the

forkhead transcription domain abolish the ability of the protein to

bind to specific DNA sequences.

Diagnosis

Clinical examination. At-risk children need to be maintained under

regular follow-up as the risk of developmental glaucoma is high

(>50% in many proven dominant families). Genetic testing, while

possible, has few clinical benefits, although exclusion of a mutation

among the children of proven gene-carriers gives confidence that an

individual carries no risk of developmental glaucoma.

Glaucoma

73

MIM

161200; 602575 (LMX1B)

Clinical features

Ocular

Primary open angle glaucoma is common. Ophthalmic follow-up is

therefore suggested for all patients.

Extraocular

Hypoplasia or aplasia of the patellae is a cardinal feature, leading

to instability of the knee and recurrent patellar dislocation.

Generalized joint laxity is also described. On x-ray examination there

may be iliac horns on the pelvis. Patients may have reduced

extension and/or supination/pronation of the elbow due to radial

head dysplasia/dislocation.

The nails of the hand are dystrophic and small. They split easily and

have triangular lunules at the base.

Around a quarter of patients develop renal disease, which may

manifest at any age. About 5% may develop renal failure. Renal

symptoms include proteinuria, nephrotic syndrome and

glomerulonephritis. Thickening of the glomerular basement

membrane may be observed on renal biopsy.

Age of onset

Congenital

Epidemiology

2:100,000

Inheritance

Autosomal dominant

Chromosomal location

9q34.1

Gene

LIM homeobox transcription factor 1beta (LMX1B)

74

Nail-patella syndrome

Patellar aplasia.

Nail dystrophy.

Mutational spectrum

A broad range of mutations have been described. Premature protein

termination mutations are common. Missense mutations, when

present, are often within important, conserved residues of both the

LIM and homeodomains.

Effect of mutation

Haploinsufficiency. There is no genotype-phenotype correlation.

Functional studies have shown that missense mutations disrupt

sequence-specific DNA binding.

Glaucoma

75

Diagnosis

Clinical. While DNA diagnosis is now possible this is largely of

academic interest. Prenatal diagnosis is rarely an issue as this can

only detect the presence of a mutation rather than predict its

severity. NPS is highly variable and ocular complications are rarely

present early in life: families should be aware of the risks and

ongoing screening made available to them.

76

Nail-patella syndrome

MIM

180500 (type I); 601499 (type II)

Clinical features

Ocular

Rieger syndrome is characterized by anterior segment dysgenesis

associated with goniodysgenesis, posterior embryotoxon and

anterior synechiae. Variable iris hypoplasia is often associated

with corectopia and/or polycoria. In Rieger syndrome, the ocular

manifestations are variable and may include iris hypoplasia,

Axenfeld anomaly or Peters’ anomaly, and anterior polar cataract.

Foveal hypoplasia is not seen and, in the absence of media opacity,

vision may be normal. However, the risk of developmental glaucoma

is extremely high (perhaps 75%).

Glaucoma

77

Dental hypoplasia/aplasia.

Redundant umbilical skin.

Age of onset

Congenital

Inheritance

Autosomal dominant

Chromosomal location

4p25 (type I); 13p13 (type II)

Gene

Paired-like homeodomain transcription factor 2 (PITX2).

Bicoid-related homeobox-containing gene (type I). The gene

for type II is unknown.

Mutational spectrum

Splice-site mutations, missense mutations (in particular within the

homeodomain) and nonsense mutations are all described. Many

patients (~50%) have no proven genetic abnormality.

Effect of mutation

It is likely that most mutations result in functional haploinsufficiency.

All families with PITX2 mutations have evidence of some systemic

abnormalities (in particular dental/umbilical abnormalities).

Diagnosis

Systemic features suggest the presence of a PITX2 mutation that

may be tested on a research basis. Visual impairment will be seen

in those with significant media opacities (e.g. Peters’ anomaly) or

resulting from the complications of developmental glaucoma. The

high risk of glaucoma requires life-long screening.

78

Rieger syndrome

MIM

180849; 600140 (CREBBP)

Clinical features

Rubinstein-Taybi syndrome is a rare cause of mental handicap

associated with characteristic facial dysmorphism, broad thumbs

and toes.

Ocular

The ocular manifestations of RSTS are under-recognized but wide-

ranging. There may be congenital or early-onset glaucoma due to

goniodysgenesis with high iris insertions. Congenital cataract of

variable severity is also described. Retinal dystrophy is a frequent

and important finding (>70%), which becomes more common with

age. Retinal examination and ERG investigation demonstrate cone

and cone-rod dystrophy.

Extraocular

Developmental delay is often severe with a mean IQ of around 50.

Children are generally shorter than average, with relative

microcephaly. Facial features are characteristic with down-slanting

palpebral fissures, long beaked nose and unusual thickened ears.

Thumbs and big toes are broad with spatulate distal phalanges.

Age of onset

Congenital

Inheritance

Most cases are sporadic

Chromosomal location

16p13.3

Gene

CREB-binding protein (CREBBP)

Glaucoma

79

(L) Characteristic facial features include a long beaked nose with prominent

columella. (R) Spadulate distal phalanx of the thumb in Rubinstein-Taybi syndrome.

Mutational spectrum

A microdeletion of 16p13.3 is estimated to cause around 10–15%

of RSTS. Mutations of CREBBP have been described; the majority

result in protein truncation.

Effect of mutation

It is likely that loss of function of one copy of CREBBP leads to

RSTS. CREBBP is a transcriptional co-activator that binds to the

transcription factor CREB. The exact functions of CREB (and hence

of CREBBP) are not fully understood.

Diagnosis

Children with RSTS have significant handicaps. Screening for ocular

abnormalities and recognizing multisensory handicap are important

in their long-term care. When suspected clinically, FISH analysis

may detect a 16p13.3 microdeletion. Mutation analysis is available

on a research basis only.

80

Rubinstein-Taybi syndrome