Aniridia

Aniridia is a congenital eye disorder characterized by the complete or partial absence of the iris, which often leads to progressive vision loss and other ocular complications. It typically affects both eyes and can occur as an isolated condition or as part of a broader genetic syndrome.

Overview

Aniridia is an eye disorder that is characterized by a complete or partial absence of the colored part of the eye (the iris). Aniridia is typically present from birth (congenital) and affects both eyes. The pupils may also be abnormal or misshapen.

Symptoms & Associated Eye Problems

People with aniridia can have other eye problems that may be congenital or develop later in life. These include:

• Clouding of the lenses of the eyes (cataracts)
• Involuntary eye movements (nystagmus)
• An increased sensitivity to light (photophobia)
• Underdevelopment of a specific region at the back of the eye (foveal hypoplasia), which can reduce the sharpness of vision (visual acuity)
• Problems with the cornea, the clear outer covering of the eye (aniridia-associated keratopathy)
• Increased pressure in the eye (glaucoma) developing from late childhood through early adulthood
• Underdeveloped structures that carry information from the eyes to the brain (optic nerve hypoplasia)

Many of these eye problems contribute to vision loss that worsens over time. The severity of symptoms is typically the same in both eyes.

In rare cases, individuals with aniridia have additional health problems, which can include behavioral issues, metabolic disorders, and problems detecting odors.

Syndromic and Non-Genetic Forms

Aniridia can affect the eyes alone (isolated) or it can occur with other features as part of a syndrome. It is a common feature of certain genetic conditions, including Gillespie syndrome and WAGR syndrome.

Injuries to the head or eyes can also cause aniridia. This type of aniridia is not genetic and can occur at any age.

Frequency

Aniridia occurs in 1 in 40,000 to 100,000 newborns worldwide.

Causes & Genetics

Genetic changes that cause disease are called pathogenic variants. Aniridia is primarily caused by variants in specific genes:

• PAX6 gene: This gene provides instructions for making a protein involved in the early development of the eyes, brain, spinal cord (central nervous system), and pancreas. The PAX6 protein is a transcription factor that binds to specific regions of DNA to regulate other genes. Pathogenic variants cause cells to produce a nonfunctional PAX6 protein, disrupting eye formation before birth.
• Other genes: In a small percentage of cases, pathogenic variants occur in other genes, such as ELP4 and TRIM44. These genes produce proteins that control the expression of the PAX6 gene, and variants in them lead to a similar reduction in PAX6 protein activity.
• Syndromic causes: When aniridia is part of a syndrome, it is caused by gene variants associated with that specific syndrome.

Inheritance Pattern

Aniridia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In approximately two-thirds of cases, a person with aniridia inherits the pathogenic variant from an affected parent. The remaining one-third of cases result from a new mutation in the gene that occurs during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These individuals typically have no history of the disorder in their family.

Other Names for This Condition

• Absent iris
• Congenital aniridia
• Irideremia

Congenital diaphragmatic hernia

Congenital diaphragmatic hernia is a developmental defect in the diaphragm that allows abdominal organs to migrate into the chest cavity, potentially crowding the heart and lungs. This condition can cause severe, life-threatening breathing difficulties at birth or present with milder symptoms later in life.

Overview & Types

Congenital diaphragmatic hernia is a defect in the diaphragm, the structure composed of muscle and other fibrous tissue that separates the organs in the abdomen from those in the chest. Abnormal development of the diaphragm before birth leads to defects ranging from a thinned area to its complete absence. This results in an abnormal opening (hernia) that allows the stomach and intestines to move into the chest cavity and crowd the heart and lungs.

Congenital diaphragmatic hernias are often classified by their position:

• Bochdalek hernia: A defect in the side or back of the diaphragm. This type accounts for between 80 and 90 percent of congenital diaphragmatic hernias.
• Morgnani hernia: A defect involving the front part of the diaphragm. This type accounts for approximately 2 percent of cases and is less likely to cause severe symptoms at birth.
• Other rare types: These include defects affecting the central region of the diaphragm, or cases where the diaphragm muscle is completely absent with only a thin membrane in its place.

Symptoms & Clinical Presentation

The crowding of organs in the chest cavity can lead to underdevelopment of the lungs (pulmonary hypoplasia), potentially resulting in life-threatening breathing difficulties that are apparent from birth.

Depending on the severity and timing, symptoms can present in different ways:

• At birth: Severe, immediate respiratory distress due to pulmonary hypoplasia.
• Later in life: In 5 to 10 percent of affected individuals, signs and symptoms appear later and may include breathing problems or abdominal pain from the protrusion of the intestine into the chest cavity.
• Asymptomatic: In about 1 percent of cases, the condition has no symptoms and is detected incidentally during medical imaging for other reasons.

Frequency

Congenital diaphragmatic hernia affects approximately 1 in 2,500 newborns.

Causes & Risk Factors

Congenital diaphragmatic hernia has many different causes and can present in isolated or syndromic forms:

• Syndromic (10 to 15 percent of cases): The condition occurs as a feature of a disorder affecting multiple body systems. Examples include Donnai-Barrow syndrome, Fryns syndrome, and Pallister-Killian mosaic syndrome. These can be caused by single-gene changes or chromosomal abnormalities.
• Non-syndromic with additional abnormalities (about 25 percent of cases): Affected individuals have abnormalities in other major body systems, such as the heart, brain, skeleton, intestines, genitals, kidneys, or eyes, resulting from a common developmental disruption.
• Isolated (50 to 60 percent of cases): Affected individuals have no other major malformations.

In more than 80 percent of individuals, there is no known genetic syndrome or chromosomal abnormality, and the cause remains unknown. Researchers are studying genes involved in diaphragm development, such as transcription factors and proteins involved in cell structure or cell migration in the embryo. Unidentified environmental factors influencing prenatal development may also increase risk.

Inheritance Pattern

Isolated congenital diaphragmatic hernia is rarely inherited, with almost all cases occurring in only one individual in a family. When the condition occurs as a feature of a genetic syndrome or chromosomal abnormality, it may cluster in families according to the inheritance pattern of that specific condition.

Other Names for This Condition

• Congenital diaphragmatic defect