5. Vitreoretinal disorders

MIM

133780

Clinical features

The abnormalities of exudative vitreoretinopathy result from

abnormal peripheral vascularization and may progress with time.

In many of the families described penetrance is high but there is

significant variability of phenotype. The abnormalities may be

present from birth and may mimic ROP.

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Familial exudative vitreoretinopathy

Organized membranes cause vitreoretinal traction and may lead to

dragging of the disc and vessels or to macular displacement. There

are often scattered vitreous opacities. Traction may lead to localized

retinal detachment associated with suband intraretinal exudation

as well as peripheral retinal neovascularization. In some patients

there may be congenital retinal folds, which may represent one

manifestation of the disorder. Diagnosis in those mildly affected may

be difficult and may require fluorescein angiography for identification

of peripheral vascular abnormalities.

The ocular phenotype of the X-linked form, EVR2, is identical to

that of autosomal dominant exudative vitreoretinopathy, EVR1

(see Norrie disease). There are no extraocular manifestations.

Age of onset

Congenital/childhood

Inheritance

Autosomal dominant (EVR1); X-linked (EVR2). Recessive

inheritance has been suggested in some families.

Chromosomal location

11p13–q23 (EVR1). A second autosomal dominant locus maps to

chromosome 11p12–p13.

Gene

Not known

Effect of mutation

Not known

Diagnosis

As gene expression can be very variable, diagnosis in those mildly

affected may be difficult; fluorescein angiography may be required

for identification of peripheral vascular abnormalities.

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Blistering skin rash.

Late pigmented skin rash. Pigment is

linear, following developmental lines of

cell migration (Blaschko's lines).

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Dystrophic nails.

Chromosomal location

Xq28

Gene

NFκB essential modulator (NEMO)

Mutational spectrum

About 80% of new mutations are the result of an intragenic

recombination, which leads to deletion of exons 4–10 of NEMO. In

addition, missense mutations, frameshift mutations and nonsense

mutations have been described. There is no genotype-phenotype

correlation.

Effect of mutation

NEMO is essential for the activation of NFkB, a transcription factor

that is activated by cytokines. NFkB activation has been implicated

in inflammatory processes such as autoimmunity, asthma,

glomerulonephritis, inhibition of apoptosis and inappropriate

immune cell development. Thus NEMO is essential in the

modulation of immune, inflammatory and apoptotic responses.

Defective NFkB activation has been demonstrated in IP2 patients.

In the dermis it is hypothesized to cause defective cell growth and

apoptosis, which is thought to be the primary cause of the skin rash.

Diagnosis

Clinical. IP2 is usually diagnosed by the characteristic rash; girls

should have regular ophthalmic assessment in early life. Genetic

testing is available on a research basis only.

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Incontinentia pigmenti type II

Mutational spectrum

COL18A1 is a large 43-exon gene. Splice-site and frameshift

mutations that result in premature protein truncation have been

demonstrated.

Effect of mutation

It is not known why defects in collagen XVIII give rise to ocular and

brain abnormalities. Collagen XVIII is a widely expressed heparan

sulfate proteoglycan of the extracellular matrix. One short form is

found in brain and retina and is localized to vascular and epithelial

basement membranes suggesting a role in vascular development.

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Knobloch syndrome

Including: X-linked familial exudative vitreoretinopathy (EVR2).

MIM

310600; 305390 (EVR2)

Clinical features

Norrie disease is a cause of X-linked congenital blindness that very

rarely has manifestations in carrier females.

Ocular

Boys are generally born with severe congenital visual disability. The

most common finding is a retrolental yellowish, vascularized mass.

This represents an abnormally vascularized, congenitally detached

retina, which is drawn up and attached to the posterior lenticular

surface. This congenital detachment, which may be present as

leukokoria, leads to secondary cataract and ultimately phthisis bulbi.

In some patients with EVR2, visual disability is less marked and some

residual vision is retained. EVR2 is characterized by abnormalities of

peripheral retinal vascularization (see exudative vitreoretinopathy

section). Individuals with this milder ocular phenotype do not have

associated hearing problems or intellectual disability.

Extraocular

In around one-third of patients there is associated hearing loss. This

may not be present early on and may be progressive. In addition,

one-third have some degree of developmental delay. In a small group

of patients, often those with severe visual disability and deafness,

the delay is severe and is associated with behavioral problems,

progressive microcephaly and minor facial dysmorphism. Some of

these severely affected patients have a small X chromosome deletion

that is presumed to encompass other genes.

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Young boys with Xp11.4 microdeletion encompassing NDP locus and neighboring

monoamine oxidase genes. Both are blind, microcephalic and severely delayed.

Age of onset

Congenital

Inheritance

X-linked recessive

Chromosomal location

Xp11.4

Gene

NDP

Mutational spectrum

A large number and wide variety of mutations have been described.

The gene is small and is composed of 3 exons encoding a protein of

133 amino acids. The coding sequence is found within the final two

exons. The majority of mutations are found in exon 3.

Whole gene deletions, in particular those that encompass the

neighboring monoamine oxidase genes, are associated with the

most severe phenotype. Among missense mutations there is little

obvious correlation between site of mutation and the severity of

ocular, auditory or CNS complications.

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Norrie disease

EVR2 is also caused by missense mutations within NDP. It is not

known why some mutations are less severe.

Effect of mutation

The exact function of the encoded protein remains uncertain. There

is some evidence to suggest that the protein, which shares structural

similarities with TGF-b, is important in developmental retinal

vasculogenesis, although its function in the ear and brain remains

uncertain. The similarity of ocular phenotype in patients with whole

gene deletions and missense mutations suggests that many act

through loss of function.

Diagnosis

Norrie disease is associated with severe, usually congenital, visual

disability which may be compounded by further sensory deficit. The

X-linked nature of the condition and the availability of genetic testing

make genetic counselling necessary in potential cases. Mutation

analysis is now widely available to complement clinical evaluation

and, as a result, carrier detection and prenatal diagnosis are both

possible.

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MIM

108300 (STL1); 604841 (STL2); 184840 (STL3)

Young child with Stickler syndrome. There is severe mid-facial flattening.

The patient is highly myopic and has significant sensorineural deafness.

Clinical features

Ocular

Most patients develop high-degree, early-onset myopia (congenital

myopia). Cortical, segmental, comma-shaped lens opacities are

common, congenital and non-progressive.

The vitreous gel is degenerate and becomes condensed leaving a

large volume of the cavity optically empty. The vitreous changes

have been classified into type I (vestigial vitreous occupying the

immediate retrolental space surrounded by a folded membrane) and

type II (a sparse vitreous consisting of bundles of beaded filaments).

Broadly speaking, patients with type I vitreous anomaly have type I

Stickler syndrome caused by mutations in COL2A1, while the type II

anomaly has been found in patients with COL11A1 mutations.

Abnormalities of vitreoretinal adhesion result in paravascular

pigmented lattice degeneration. Stickler syndrome is the most

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Stickler syndrome

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181

Orofacial

Stickler syndrome is associated with a distinctive pattern of orofacial

features and growth. At birth, around one-quarter of individuals have

evidence of clefting, ranging from a Pierre-Robin sequence to a bifid

uvula. Micrognathia may be severe at birth but becomes significantly

less marked during the first months after birth. There is marked

mid-face hypoplasia; at birth there is often almost no nasal bridge

(a problem with high myopia), anteverted nares and prominent eyes.

Mid-face flattening becomes less marked in the majority and may

become almost unnoticeable.

Hearing loss

Hearing difficulties in Stickler syndrome are caused by cleft/palatal

abnormalities causing serious otitis media, and conductive and

sensorineural hearing loss, which is seen in around 40% of patients.

Many have no symptoms but hearing loss can be severe and have

early-onset.

Arthropathy

In early life, patients may describe significant joint laxity. Later

this becomes less marked and with time degenerative arthropathy

develops, typically in the third to fourth decade, often leading to

hip and/or knee replacements in mid-life.

Age of onset

Myopia may be present from birth, although this is usually

progressive. Clefting and mid-face hypoplasia are usually congenital.

Hearing loss may be progressive and may develop at any stage.

Inheritance

Autosomal dominant

Chromosomal location

MIM

Locus

Gene

Chromosome

120140

STL1

COL2A1

12q13.11–q13.2

120280

STL2

COL11A1

1p21

120290

STL3

COL11A2

6p21.3

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Stickler syndrome

Mutational spectrum

COL2A1 (type II collagen, a-1)

COL2A1 mutations cause a range of skeletal dysplasias and account

for over 50% of Stickler syndrome cases. STL1 generally results

from premature polypeptide termination. Kneist dysplasia, in which

affected individuals have a more severe skeletal phenotype but a

similar ocular phenotype, is usually caused by small in-frame

COL2A1 deletions. A small number of individuals with ocular-only

Stickler syndrome carry a mutation within the alternatively spliced

exon 2 which is only expressed in ocular tissues.

COL11A1 (type XI collagen, a-1)

The majority of mutations result in alteration of RNA splicing of 54-bp

exons. These patients have the characteristic Marshall phenotype

with severe mid-face hypoplasia that does not diminish with age,

early-onset severe hearing loss and few retinal detachments. Other

mutations (e.g. missense) are more typical of Stickler syndrome.

COL11A2 (type XI collagen, a-2)

A small number of families with Stickler syndrome have COL11A2

defects. Ocular features are lacking. This is due to absence of the

a-2 chain of type XI collagen in the vitreous gel matrix.

Effect of mutation

The vitreous gel is comprised of water with a proteinaceous matrix,

which is mainly collagenous. Defects in COL2A1 and COL11A1

result in premature collapse of the vitreous gel, abnormal

vitreoretinal adhesion leading to lattice degeneration and RRD.

Collagen molecules form a rod-like trimeric helix. COL2A1 mutations

resulting in premature termination lead to defective trimer formation

and abnormal construction of the collagenous matrix. Type XI

collagen aggregates with type II in thin fibrils of hyaline cartilage and

vitreous gel; as a result, defects in these molecules give rise to a

similar phenotype.

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183

Diagnosis

Stickler syndrome is highly variable (the diagnosis may first be made

in a child with Pierre-Robin sequence/cleft palate). Such variability,

even within families, makes predictions of the presence or absence

of any one feature difficult, complicating the counselling of

prospective parents. Early ophthalmic assessment of affected

individuals is important to assess refraction and the necessity for

prophylaxis against retinal detachment. DNA diagnosis is possible

in a number of centers on a research basis only. However, since

prenatal diagnosis is not commonly requested, such analysis is

generally supplemental to clinical diagnosis.

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Stickler syndrome

MIM

312700

Clinical features

RS1 occurs exclusively in males. The condition usually becomes

apparent during the first decade. It is variable within and between

families and prognosis is therefore difficult to predict. Visual

deterioration generally occurs during early childhood and vision

attained by teenage years often remains constant during early and

middle adult life. Central visual loss due to presenile macular

degeneration is common.

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185

Hemorrhage, either into the retina or into the vitreous occurs in

around 25% of cases. Retinal detachment is less common but may

occur when a full thickness hole develops within the inner retinal

layers of a peripheral schisis.

ERG examination is a valuable diagnostic tool. Virtually all affected

males show selective loss of the dark-adapted B-wave.

Age of onset

While schisis may be present from birth, visual reduction is generally

noticed in the early school years.

Epidemiology

1:5000–25,000

Inheritance

X-linked recessive. There are no manifestations in females.

Chromosomal location

Xp22.2–p22.1

Gene

RS1

Mutational spectrum

A wide range of mutations has been demonstrated, including

protein truncating mutations (small deletions/insertions/splice-site

mutations) and missense mutations. Missense mutations are

clustered within the so-called discoidin domain.

Effect of mutation

The lack of any genotype-phenotype correlation suggests that

mutations act via loss of protein function. Retinoschisin is an

extracellular matrix protein secreted by the photoreceptor. It contains a

discoidin domain but is of unknown function. The protein is found in

its highest concentration in the inner retinal layers. Loss of the B wave

on ERG suggests that the protein may interact with Müller cells.

Diagnosis

Clinical examination. ERG is useful to confirm the diagnosis.

Mutations may be found by direct gene sequencing in over 90% of

cases. This is useful for carrier detection, which is not otherwise

possible.

186

X-linked retinoschisis