Introduction

Imagine being told that your child has a rare condition named after the shape of a cat’s eye. This is Cat Eye Syndrome (CES), also known as Schmid-Fraccaro syndrome, a genetic disorder occurring in approximately 1 in 50,000 to 100,000 people.¹ The name of this disorder sounds whimsical, but behind it lies a complex genetic story. The diagnosis comes as a surprise for most families, often followed by questions about what it means for their child’s future. What caused this condition? What does it mean for the child’s health and development? Most importantly, why does it even occur?

At the heart of CES is something you cannot see with the naked eye: a tiny piece of extra genetic material from chromosome 22.¹ This small but significant change in our DNA is known as partial tetrasomy of 22p-22q11.21, which plays a crucial role in how the condition develops.² The symptoms can vary based on how much extra material is present, as well as the location of the partial tetrasomy. Some individuals may face more difficulties than others.² Understanding the essence of this chromosomal change can help us better grasp CES and remind us how intricate human development truly is.¹ 

Chromosome 22

Inside every cell in our body is a set of instructions made of DNA, which are packed into tightly coiled structures called chromosomes.³ Most people have 23 pairs of chromosomes, inheriting one copy from their mother and father.³ Chromosome 22 is the second smallest chromosome, containing over 500 genes that play a crucial role in the development of the eyes, ears, heart, kidneys, and digestive system (especially during early pregnancy).² The genes in chromosome 22 also play a key role in immune function and brain development. Hence, alterations to chromosome 22 can make individuals susceptible to genomic disorders that lead to intellectual disabilities and congenital malformations.⁴ 

Genetic alterations within the 22p-22q11.21 region of chromosome 22 are linked to CES and other rare genetic disorders such as DiGeorge syndrome.¹ A partial tetrasomy of chromosome 22 causes the body to be overwhelmed by the presence of additional DNA.¹ Given the importance of chromosome 22, even a small chromosomal change can lead to noticeable differences in how the body is built.² 

How partial tetrasomy of chromosome 22 occurs

CES displays its effects during the earliest stages of fetal development. In 90% of CES cases, there are two extra abnormal pieces of chromosome 22, which do not come from either parent.² Most CES cases occur by chance in early development with no prior family history (de novo formation).²  Parental transmission is uncommon, accounting for only 5 to 10 per cent of CES cases. However, when this occurs, it typically involves a parent who carries an extra circular or rod-shaped small supernumerary marker chromosome (sSMC).² This spontaneous mutation is called a partial tetrasomy of chromosome 22, when there are four copies of the same genes instead of the usual two, which disrupts the fundamental cell layers that give rise to all the tissues and organs during the initial phase of the baby’s development.² It can confuse the developmental pathway, especially during the formation of vital organs.² Depending on how much extra genetic material there is, and whether every cell in the body carries this extra piece (20% of CES patients demonstrate mosaicism), the symptoms of the individual may be milder depending on the location and how many of the cells are affected, which makes this syndrome unique.² 

This multisystem chromosomal disorder may come as a shock to the CES baby’s parents, but it is important to know that this change is not caused by anything the parents did or did not do. It is a naturally occurring genetic accident, and one that we are only just beginning to understand through ongoing research and improved testing.² 

Dosage-sensitive genes

Scientists have identified some genes within the duplicated 22p-22q11.21 region that are especially sensitive to having their dosage increased, which contributes to the onset of CES.² One important dosage-sensitive gene is CECR1 (ADA2), but when there are too many copies, it may lead to problems with how blood vessels form and how the immune system works, which could explain some of the heart and immune-related issues seen in CES individuals.⁵ Another gene, CECR2, helps control how DNA is packaged and used during development.¹ It plays a crucial role in tissue formation that comes from neural crest cells that are responsible for building parts of the face, ears, heart and nervous system.¹ So when it becomes overactive, it interferes with how these structures form, contributing to the facial asymmetry and organ differences that can be commonly seen in CES.¹ Additionally, SLC7A4 is a gene that helps to transport amino acids in and out of cells, which researchers have linked to kidney and digestive system formation that can be affected in this condition.² Finally, if the dosage of gene TXNRD2 is altered, it can disturb the balance of harmful and protective molecules inside our cells, which ultimately affects how cells function and their ability to protect cells from damage, particularly during early development.² 

While no single gene causes all the symptoms of CES, these dosage-sensitive genes together may explain why the condition can affect many different parts of the body. Research proceeds to uncover how each of these candidate genes plays their role in shaping the distinctive features and discover additional genes (ATP6V1E1, BCL2L13, etc) related to CES.¹ 

Symptoms of cat eye syndrome

Some people with Cat Eye Syndrome do not experience major complications. However, others may undergo serious health challenges that require medical support. Generally, Cat Eye Syndrome is distinguished by three distinct physical signs:

• Iris coloboma – The most distinctive eye feature is called iris coloboma, where the coloured part of the eye has a keyhole.⁴ This makes the iris resemble a ‘cat eye’, a symptom present in approximately half of affected CES individuals⁴
• Preauricular tags or pits – Many patients (81%) also have preauricular tags or pits, which are small skin tags or holes found near the ears that are usually harmless.⁵ More serious symptoms linked to genetic material include anal atresia, where the opening of the bottom is absent or blocked at birth that necessitates surgery shortly after birth²
• Congenital heart disease – Some children can also be born with congenital heart diseases, such as atrial septal defects that may call for surgical correction. Patients can also experience problems with how the kidneys are shaped or work that require lifelong treatment.⁵ Additionally, some may experience vision impairment, hearing loss due to ear deformity, learning difficulties, growth restrictions or delays in reaching developmental milestones like walking and talking¹

Two people with the same diagnosis may look and develop very differently. Therefore, these signs can help doctors identify the condition and diagnose other possible health concerns that may be linked to CES.² Nonetheless, many people with CES go on to live fulfilling lives when they receive the right care and support tailored to their needs.² 

Summary

CES is a rare genetic disorder caused by partial tetrasomy 22, which is when there is an unusual copy of the critical section 22p-22q11.21 in chromosome 22. This small but notable change can significantly change how the body is formed and functions from as early as the first stages of development in the womb. Individuals with CES experience their symptoms differently depending on how much extra genetic material is present, with some individuals facing more severe challenges than others, affecting multiple organ systems and even compromising neurodevelopment, which can become taxing for daily life. Some of the most recognisable features include an iris coloboma, preauricular tags, anal atresia, and organ abnormalities. Within chromosome 22, several dosage-sensitive genes have been linked to CES. Changes in dosage with such genes all impact a vital system in the body, which explains the diverse symptoms seen in CES. Although the condition may be overwhelming, tailored multidisciplinary medical care can greatly improve the outcomes of quality of life, along with research continuing to uncover more about the role of partial tetrasomy of chromosome 22 and CES.