“CES is best thought of as a spectrum disorder, as no two individuals with CES will have the same abnormalities or abnormalities with the same severity.”

Brief Summary of Disease
Down syndrome, or trisomy 21, is a widely known example of what happens when there are more than two copies of a chromosome. But what happens when there are three, or even four copies of a chromosome, specifically, chromosome 22?

The result is Cat Eye Syndrome (CES), a rare chromosomal disorder affecting about 1 in 50 000 to 1 in 150 000 live births in the general population, males and females equally. ¹ CES stems from the partial presence of an extra third or fourth copy of chromosome 22, which arises spontaneously from an error during cell replication. ² CES is best thought of as a spectrum disorder, as no two individuals with CES will have the same abnormalities or abnormalities with the same severity. ² The phenotypic variability of CES thus makes it hard to define clinical criteria for diagnosing the disorder, and the only way of confirming a diagnosis is through standard chromosomal studies such as karyotyping. Furthermore, since each individual presents a different combination of abnormalities, a multidisciplinary approach must be taken to effectively manage CES symptoms. Therefore, it is important to recognize the phenotypic variability of CES, so that diagnostic tests can be used early to confirm CES in individuals and an early symptom management system can be coordinated.

Etiology and Pathology
Healthy individuals, with a normal chromosomal make-up, have two copies of chromosome 22. Both copies have a short arm, titled 22p, and a long arm, titled 22q. However, individuals with CES have an additional one or two small copies composed of the short arm and a segment of the long arm of chromosome 22. ¹ Individuals with CES will therefore have four copies of chromosome 22 (known as partial tetrasomy) or three copies (partial trisomy), instead of the normal two copies seen in the autosomal cells of the body. In most cases, the extra chromosome(s) arises spontaneously due to an error during the cell division process in a parent’s reproductive cells and is not influenced by any particular actions undertaken by the parents during pregnancy. ^1,2 This means that healthy parents, each with two normal copies of chromosome 22, can have a child with CES with partial tetrasomy or partial trisomy.

Figure 1. A karyotype of an individual with CES. This individual has partial trisomy of chromosome 22. — Figure 1. A karyotype of an individual with CES. This individual has partial trisomy of
chromosome 22.

Multiple copies of chromosome 22 cause a number of abnormalities in various parts of the body. Since the genetic error occurs prior to conception, the proper development of the fetus can be affected and symptoms can manifest as early as birth. Many symptoms result from the abnormal functioning of, improper development of, or absence of specific organs. If the initial symptoms are not managed properly as the individual with CES grows older, there may be complications. Although, oftentimes, babies with severe abnormalities as a result of CES do not survive infancy, infants who do survive and those with mild abnormalities do not have a shortened life expectancy. ²

Symptoms
CES has extreme phenotypic variability and the presentation of symptoms vary from mild to severe. ² It is impossible to predict what symptoms an individual will have based on their genetics. Therefore, some individuals with CES may not have any of the characteristic symptoms, and function largely unimpaired, while other individuals may have a wide combination of symptoms. ^2,4

The classic symptom of CES, from which the name “Cat Eye Syndrome” is derived, is ocular coloboma. Ocular coloboma, coloboma originating from the Greek word “curtailed”, is the partial absence of ocular tissue, in or around the eye, resulting from an unclosed fissure in the eye during early fetal development. ⁵ An iris coloboma can result in the unusual “keyhole” or “cat-like” appearance of the eye where the pupil seems larger and the iris (coloured part of the eye) does not fully connect. If only the iris is affected by the coloboma, then the individual will not experience an impairment of vision, despite the unusual appearance of the eye; however, if the coloboma impacts other layers of the eye, then it may result in vision impairment and/or blindness. ⁵ Interestingly, although the name CES comes from the observation of this symptom, only around half of individuals with CES actually have ocular coloboma. ²

Individuals with CES may also experience other eye abnormalities apart from ocular colomba, such as crossing of the eyes, effects on different layers of the eye apart from the iris, abnormal smallness of one eye, cataracts, or absence of tissue from portions of the eyelid. ^2,6 Whether there will be vision impairment or blindness depends on the combination of the eye abnormalities as well as the severity.

Another characteristic symptom of CES is anal abnormalities, ⁷ which are present in approximately ¾ of CES patients. ² Abnormalities can include anal stenosis, the anal opening being abnormally small or narrow, or anal atresia, the anal canal being absent. ^2,7 In males, an anal fistula, a tunnel from inside the anus to the skin, may form between the rectum (the end of the large intestine) and the bladder, the urethra, or the area behind the genitals. While in females, an anal fistula may form between the rectum and the bladder or the vagina. ⁷ These would cause the abnormal functioning of the organs involved.

“Ocular coloboma, anal abnormalities, and ear abnormalities are the three classic features associated with CES; however, there are a variety of other symptoms such as kidney and genital defects, intellectual disabilities, skeletal defects and abdominal defects.”

However, the most common characteristic in CES patients, observed in over 80% of afflicted individuals, is skin tags and/or pits. ^2,8 Skin tags are small outgrowths of skin in front of the outer ears, while skin pits are slight depressions in the skin in front of the outer ear. ⁶ Additionally, some individuals may also have an absence of the external ear canal, which can cause mild hearing impairment. ⁸

Ocular coloboma, anal abnormalities, and ear abnormalities are the three classic features associated with CES; however, there are a variety of other symptoms such as kidney and genital defects, intellectual disabilities, skeletal defects and abdominal defects. ^2,6,9

**Table 1. Incidence of typical features of cat eye syndrome present in over 10% of affected individuals.**

Diagnosis
Diagnosis of CES is often based on the presence of characteristic signs and symptoms in an individual which then can be confirmed by genetic testing. ⁷ Sometimes, early diagnosis of CES can be suspected before birth using prenatal testing techniques such as ultrasound, chorionic villus sampling, or amniocentesis. Ultrasounds can reveal an image of a fetus with specific defects to suggest CES, while chromosomal studies can be performed on cells obtained from amniocentesis and chorionic villus sampling to reveal an extra chromosome 22. ⁶

After birth, CES may be diagnosed through clinical evaluation by looking for a combination of the common or classic abnormalities resulting from CES, and confirmed with chromosomal studies to identify the presence of partial trisomy of tetrasomy of chromosome 22. Standard genetic testing includes karyotyping, which is a test that provides a snapshot of an individual’s chromosomes. ^6,9

“CES is rarely passed down from an affected parent to their child as the chromosomal abnormality generally occurs randomly during the cell division process in reproductive cells.”

Is CES Hereditary?
CES is rarely passed down from an affected parent to their child as the chromosomal abnormality generally occurs randomly during the cell division process in reproductive cells. ¹ However, individuals with CES should consider genetic counseling as there is the risk that they may pass down the extra chromosome to a portion of their children. Since early detection is possible with prenatal testing, it is important to order genetic testing if CES is suspected in fetuses since early testing results in the early coordination of a symptom-management team and reduces the risk of future complications. ⁶

Symptom Management
CES often requires the coordinated effort of a medical team consisting of various medical professionals as the disease can impact many parts of the body. Disease management is specifically tailored towards the unique combination of symptoms each individual experiences. For example, individuals with ocular defects may require surgical repair or correction, ⁵ while those with congenital heart defects require treatment with certain medications or surgical intervention. ⁶ Some individuals with CES may exhibit extremely rare symptoms such as asplenia (the absence of normal spleen functioning). ⁹ For these individuals, early intervention is necessary to lower the risk of future complications. For example, it is critical to place CES patients with asplenia on long-term antibiotic use until age five to protect against fatal infections. ¹⁰ However, regardless of the symptom management plan, collaboration between different medical professionals is required to ensure that all symptoms of CES are managed effectively.

Ilziba Yusup

Relevant Resources
Cat Eye Syndrome International: An international reference point dedicated for all people affected with CES designed to encourage medical scientific research, raise awareness and give moral, legal, and economic support to CES families.¹¹

References
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2. Rosias PR, Sijstermans JM, Theunissen PM, et al. Phenotypic variability of the cat eye syndrome. Case report and review of the literature. Genet Couns. 2001;12(3):273-282.
3. Win TN, Roberts S, Laws D. Duane syndrome associated with the Cat Eye syndrome: a case report. Eye. 2007;21(2):289-291. doi:10.1038/sj.eye.6702538
4. Sharma D, Murki S, Pratap T, Vasikarla M. Cat eye syndrome. BMJ Case Rep. 2014;2014. doi:10.1136/bcr-2014-203923
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6. Cat Eye Syndrome. NORD (National Organization for Rare Disorders). Accessed September 26, 2020. https://rarediseases.org/rare-diseases/cat-eye-syndrome/
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8. Jedraszak G, Receveur A, Andrieux J, Mathieu-Dramard M, Copin H, Morin G. Severe psychomotor delay in a severe presentation of cat-eye syndrome. Case Rep Genet. 2015;2015:943905. doi:10.1155/2015/943905
9. Avior G, Derowe A, Fliss DM, Leicear-Trejo L, Braverman I. [Associated brachial cleft anomalies in the cat eye syndrome]. Harefuah. 2007;146(2):99-101, 166-167.
10. Chellapandian D, Schneider A. Anatomical Asplenia in Cat Eye Syndrome: An Expansion of the Disease Spectrum. Case Rep Pediatr. 2013;2013. doi:10.1155/2013/218124
11. CESI onlus - CAT EYE SYNDROME INTERNATIONAL onlus | Rare Disease International Association. Accessed September 26, 2020. https://cateyesyndrome.info/