10. Defects of ocular/adnexal development

MIM

231550; 605378 (Aladin)

Clinical features

AAAS is a variable condition in which patients may have some,

but not all, of the features.

Ocular features

Congenital alacrima is present in most patients and leads to

significant ocular discomfort. Autonomic disturbance may

lead to anisocoria. The pupil is hypersensitive to topical

parasympathomimetics. Optic atrophy is described in a small

number of patients.

Extraocular manifestations

Adrenal insufficiency is usually diagnosed in the first years of life.

Symptoms relating to recurrent hypoglycemia generally begin

between the ages of 1–8 years. This is often associated with

hyperpigmentation of the skin. Adrenal insufficiency responds to

steroid replacement. A number of patients also have evidence of

mineralocorticoid deficiency.

Achalasia of the esophageal cardia is present in the majority of

patients and is diagnosed between the ages of 2–20 years, often

before cortisol deficiency is noted. When diagnosed, the majority

of patients require surgical intervention.

Neurological manifestations are highly variable but include evidence

of upper and lower motor neuron dysfunction, ataxia, sensory

impairment, as well as autonomic dysfunction. There may be late-

onset progressive neurological symptoms including cerebellar ataxia

and mild dementia.

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Alacrima

Age of onset

While a diagnosis of AAAS is often delayed, features of the

condition are usually present in the first years of life.

Inheritance

Autosomal recessive

Chromosomal location

12q13

Gene

Achalasia-addisonianism-alacrima syndrome gene (AAAS)

Mutational spectrum

The majority of mutations described are frameshift and

truncating mutations that result in premature protein truncation.

However, a number of missense mutations have also been

described.

Effect of mutation

The AAAS gene encodes a 546 amino acid protein (Aladin), which

contains so-called WD-repeats. While it is expressed in all tissues,

there is high expression in the adrenal gland, gastrointestinal

structures, pituitary and cerebellum. WD-proteins form a

b-propeller structure which facilitates protein-protein interactions.

The exact function of the protein, or the identity of the proteins

with which it interacts, is unknown. However, the presence of a

peroxisomal targeting signal suggests a peroxisomal function.

Diagnosis

Diagnosis of AAAS may be delayed, and the ophthalmic features

are often valuable in facilitating this process. Mutation testing is

available on a research basis only.

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MIM

110100; 605597 (FOXL2)

Clinical features

Ocular

BPES is associated with abnormal development of the eyelid

structures.

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Blepharophimosis, ptosis and epicanthus inversus

Age of onset

Congenital

Inheritance

Autosomal dominant. There is a high number of sporadic cases.

Infertility is sex-limited (i.e. only in females) but may be passed

on by males.

Chromosomal location

3q23

Gene

Forkhead transcription factor (FOXL2)

Mutational spectrum

In patients with type I BPES, there are premature protein

termination mutations. These are likely to result in loss of

function of the FOXL2 transcription factor.

In patients with type II BPES, intragenic duplications result in

expansion of a 14-residue polyalanine amino acid domain. This

may result in reduction, rather than abolition of protein function.

Several patients with translocations through 3q23 have been

described. The translocations lie within several hundred kb of

FOXL2.

Effect of mutation

FOXL2 is a transcription factor whose expression is highly tissue-

specific. During development, expression is confined to the

periocular mesenchyme—the developing eyelid structures.

In the adult, expression is confined to the ovary.

Diagnosis

Distinction between types I and II is important in order to counsel

females regarding the possible risks of infertility, in particular

amongst those with de novo mutations and no family history.

The gene has only recently been described, therefore mutation

testing is only on a research basis.

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MIM

135700 (FEOM1); 602078 (FEOM2)

Clinical features

Affected individuals are born with non-progressive restriction of

ocular movement. The disorder is characterized by anchoring of

the eyes in downgaze with ptosis and a chin-up head-tilt. There

is restrictive ophthalmoplegia with the globes frozen, often in

extreme abduction, with little or no ability to adduct, elevate or

depress them. In addition to fibrosis of the extraocular muscles

and Tenon’s capsule, adhesions between muscles, Tenon’s and

the globe are seen. It is thought that CFEOM is caused by

abnormal development of oculomotor subnuclei resulting in

anomalous innervation of the extraocular musculature.

Age of onset

Congenital

Inheritance

Autosomal dominant (FEOM1); autosomal recessive (FEOM2).

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Congenital fibrosis of extraocular muscles

Chromosomal location

12p11.2–q11.2 (FEOM1); 11q13.2 (FEOM2).

Gene

Drosophila aristaless homeobox gene homolog (ARIX); MIM

602753 (FEOM2).

Mutational spectrum

In autosomal recessive FEOM, both splice-site mutations and a

missense mutation of a conserved amino acid have been described.

Effect of mutation

Unknown

Diagnosis

It is likely that the splice mutations would result in the production

of an unstable transcript or truncated, non-functional proteins.

ARIX encodes a homeodomain-containing transcription factor

that is required for generation and preservation of adrenergic

neurons and brainstem motor neurons. It is thought to be

important for the development of the cranial nerve nuclei.

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Microphthalmia is not a single clinical entity. It may be

associated with a large number of single gene disorders as

well as developmental abnormalities of broad etiology, including

chromosomal abnormalities, maternal infection, maternal toxin

ingestion (e.g. anti-epileptic drugs or alcohol) and fetal

disruptions. Environmental influences have also been suggested.

MIM

142993 (CHX10)

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Isolated microphthalmos (nanophthalmos and anophthalmos)

Clinical features

Microphthalmia is defined as an axial length of <19.5 mm

at the age of 1 year, or 21.5 mm at the age of 10 years. The

condition may be unilateral or bilateral. There is some confusion

in the terminology as nanophthalmos (in which patients have a

short axial length, high hypermetropia and a high risk of angle-

closure glaucoma, but normal visual function) is probably an

identical entity. It is likely that anophthalmia is part of this

spectrum, and does not represent a separate condition.

Microphthalmia may be associated with reduced anterior and/or

posterior segment growth and may be seen with other ocular

abnormalities, including microcornea, anterior segment dysgenesis,

cataract, persistent hyperplastic vitreous and coloboma. (The

description of microphthalmic individuals within kindreds with

autosomal dominant congenital cataract reflects the importance

of the lens in inducing ocular, particularly anterior, segment

development.) There is no satisfactory clinical, molecular or

etiological subclassification of microphthalmia.

Age of onset

Congenital

Epidemiology

The incidence of microphthalmia is approximately 2:10,000.

This varies in different populations.

Inheritance

Autosomal dominant; autosomal recessive; X-linked. While

true X-linked isolated microphthalmia has not been described,

X-linked anophthalmia is recognized in males with developmental

delay (IQ <50), anophthalmia and a secondary underdevelopment of

the bony orbit.

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275

Chromosomal location

Disorder

Inheritance

Locus

Gene

Anophthalmos

XL

Xq27–q28

-

Nanophthalmos

AD

11p

-

Colobomatous microphthalmia

AD

15q12–q15

-

Microphthalmos

AR

14q32

-

Microphthalmos

AR

14q24

CHX10

Cataract and Microphthalmia

AR

22q11.2

CRYBB2

Microcornea/Cataract

AD

16q23.2

MAF

Microphthalmia/Cornea plana

AR

12q21.3–q22

KERA

Microphthalmia/Persistant

hyperplastic primary vitreous

AR

10q21

-

Cataract and Microphthalmia

AD

21q22.3

CRYAA

Gene

CEH10 homeodomain-containing homologue (CHX10)

Mutational spectrum

In two families, both consanguineous, homozygous missense

alterations of a highly conserved arginine residue (in the

DNA-recognition helix of the homeodomain of CHX10) were

described in individuals with microphthalmia. The parents were

normal.

Effect of mutation

CHX10 is expressed in the developing neuroretina and in the

inner nuclear layer of the mature retina (bipolar cells) and

is therefore crucial for normal retinal development and

maintenance. Mutation of the homeodomain of CHX10 disrupts

normal function of the protein by altering its DNA-binding

specificity. In the mouse, CHX10 defects also cause

microphthalmia, progressive destruction of the retina, and

absence of the optic nerve.

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Isolated microphthalmos (nanophthalmos and anophthalmos)

Diagnosis

Microphthalmos is often sporadic and may be unilateral.

Accurate definition of recurrence risks is extremely difficult

and often only empiric risks can be given. Assessing whether

microphthalmia is genuinely isolated and examining parents for

signs of mild optic nerve abnormality, retinal coloboma formation

and anterior segment dysgenesis are useful for helping to exclude

genetic forms.

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