Anophthalmia/microphthalmia-esophageal atresia syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Anophthalmia/microphthalmia-esophageal atresia (AEG) syndrome is a rare disorder that is characterized by the abnormal development of the eyes and other parts of the body, including the tube that carries food from the mouth to the stomach (esophagus).

People who have AEG syndrome are usually born without one or both eyes (anophthalmia), although some individuals have underdeveloped and abnormally small eyes (microphthalmia). People who have anophthalmia have no vision in the affected eye, but people who have microphthalmia may or may not have significant vision loss.

Affected individuals who have some remaining eye tissue can have additional eye abnormalities. Some people may be missing pieces of tissue in the structures that form the eye (coloboma), or the nerves that carry signals between the eyes and the brain may be underdeveloped (optic nerve hypoplasia). The presence of other eye problems can worsen an affected person's vision.

Some people with AEG syndrome are born with a blocked esophagus (esophageal atresia), which is often accompanied by an abnormal connection between the windpipe (trachea) and the esophagus (tracheoesophageal fistula). Additional features of AEG syndrome can include brain abnormalities, slow growth, delayed development of motor skills (such as walking), and intellectual disabilities. Affected individuals may also have genital abnormalities, which can include undescended testes (cryptorchidism) and an unusually small penis.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the SOX2 gene cause AEG syndrome. This gene provides instructions for making a protein that regulates the activity of other genes, including those that are important for the normal development of the eyes.

The SOX2 protein plays a critical role in the formation of many different tissues and organs during embryonic development. Variants in the SOX2 gene can cause cells to produce a version of the SOX2 protein that does not function properly. As a result, the protein cannot regulate the activity of genes that are essential for the development of the eyes and other parts of the body. Abnormal development of these structures causes the signs and symptoms of AEG syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

AEG syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These affected individuals typically have no history of the disorder in their family.

In a small number of cases, people with AEG syndrome have inherited the altered gene from an unaffected parent who has a SOX2 variant only in their sperm or egg cells. This phenomenon is called germline mosaicism.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

AEG syndrome is estimated to affect 1 in 250,000 individuals.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Anophthalmia · Very frequent (99-80%)

Absence of the globe or eyeball.

Esophageal atresia · Very frequent (99-80%)

A developmental defect resulting in complete obliteration of the lumen of the esophagus such that the esophagus ends in a blind pouch rather than connecting to the stomach.

Microphthalmia · Very frequent (99-80%)

A developmental anomaly characterized by abnormal smallness of one or both eyes.

Tracheoesophageal fistula · Very frequent (99-80%)

An abnormal connection (fistula) between the esophagus and the trachea.

Agenesis of corpus callosum · Frequent (79-30%)

Absence of the corpus callosum as a result of the failure of the corpus callosum to develop, which can be the result of a failure in any one of the multiple steps of callosal development including cellular proliferation and migration, axonal growth or glial patterning at the midline.

Cryptorchidism · Frequent (79-30%)

Testis in inguinal canal. That is, absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.

Hearing impairment · Frequent (79-30%)

A decreased magnitude of the sensory perception of sound.

Visual loss · Frequent (79-30%)

Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).

Other findings in the same source

From: Orphanet

Additional reported features include 11 pairs of ribs (Occasional (29-5%)); Abnormal vertebral morphology (Occasional (29-5%)); Global developmental delay (Occasional (29-5%)); Growth delay (Occasional (29-5%)); Hemivertebrae (Occasional (29-5%)); Holoprosencephaly (Occasional (29-5%)); Hydrocephalus (Occasional (29-5%)); Hypospadias (Occasional (29-5%)); Intellectual disability (Occasional (29-5%)); Iris coloboma (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Anophthalmia/microphthalmia-esophageal atresia syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

Additional services that may be relevant, depending on the findings, include: Gastroenterology.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Anophthalmia/microphthalmia-esophageal atresia syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.