Overview 

Fraser Syndrome¹ is a rare genetic condition caused by genetic changes in the following genes: FRAS1², FREM2³ and GRIP1.⁴ Individuals with Fraser syndrome often present with various malformations such as; cutaneous syndactyly^1,5 (fused skin between the fingers and toes), cryptophthalmos^1,6 (fused eyelids), and genital and or urinary tract^1,7 issues. In severe cases of this condition individuals can present with respiratory and or renal malformations.^35,36,37 This article will provide a clear and comprehensive overview of ophthalmic issues associated with Fraser syndrome, along with their diagnoses and management strategies.

Ophthalmic abnormalities associated with Fraser Syndrome 

Fraser Syndrome can cause several problems that affect vision and other functions of the eyes, making it important to identify and understand these issues. The following section will review associated ophthalmic conditions.

Cryptophthalmos

93% of individuals diagnosed with Fraser Syndrome have Cryptophthalmos.⁸ This is where either one or more of the eyelids are not correctly formed. Cryptophthalmos can occur in one or both eyes and to varying degrees. In literature, there are three types of Cryptophthalmos:⁹

1. Complete cryptophthalmos

Complete Cryptophthalmos (typical) is the most severe form of the condition in which an eye or both eyes are covered entirely by skin. The skin of the forehead and the cheeks are fused together and are directly attached to the surface of the affected eye(s) leaving no space around the affected eye(s).⁹ In complete Cryptophthalmos, there are no eyebrows, eyelashes or tear ducts.¹⁰ Often, complete Cryptophthalmos can be linked to Microphthalmia.¹¹

2. Incomplete cryptophthalmos

Incomplete Cryptophthalmos (atypical) is where the eyelids are only partially developed, with small spaces at the sides. However, the parts of the eyelids that didn’t fully form remain fused to a small underdeveloped eye.⁹ The majority of the eye is covered by skin, and the opening where the eyelids meet is much shorter than normal, about one-third of the usual length.⁹

3. Abortive cryptophthalmos

Abortive Cryptophthalmos is where the upper eyelid and upper tear duct is missing, and the skin from the forehead covers some of the cornea¹³ (clear part of the eye). In Abortive Cryptophthalmos, the cornea that is covered often presents as corneal keratinisation (cloudy and rough cornea) and the uncovered cornea remains clear.¹⁴ However, the lower eyelid is usually present.¹² The usual space around the eye is missing, and the eyeball can range from small to normal in size.⁹

Anophthalmia

Anophthalmia^15,18 is defined as being born without ocular tissue in either one or both eyes. This is a frequent feature of Fraser syndrome.¹ 

Microphthalmia

Microphthalmia^{11, 15} is characterised when one or both eyes don’t fully develop, resulting in a smaller eye or eyes.⁴⁴ Microphthalmia is associated with other conditions such as coloboma⁴⁶ and cataract⁴⁵(cloudy lens).⁴⁴ 

Hypertelorism

Hypertelorism⁴⁸ is when the distance between the pupils is greater than normal, giving the appearance of widely spaced eyes.⁴⁷

Diagnostic approaches for ophthalmic abnormalities associated with Fraser Syndrome 

Accurate diagnosis of ophthalmic issues in Fraser Syndrome involves a range of specialised techniques. This section will explore relevant diagnostic approaches. 

Prenatal ultrasound

A prenatal ultrasound²¹ is a way for clinicians to check on the health of a baby in utero.³⁸ A prenatal ultrasound can detect Cryptophthalmos, Anophthalmia, and Microphthalmia in utero from eighteen weeks of gestation.¹⁹ The ultrasound will show no normal gap between the upper and lower eyelids and if the skin extends continuously from the forehead to the cheek. It may also reveal if one or both the eyes are malformed, and or if one eye is smaller compared to the other.

Fetal MRI (magnetic resonance imaging)

A fetus³⁹ can require additional checks whilst developing. A fetal MRI is a way for clinicians to confirm possible abnormalities seen in a prenatal ultrasound.⁴⁰ 

Postanal examination 

Examining the eye

A clinical member of the ophthalmology team may use a slit-lamp or an ophthalmoscope, (like a lighted microscope) to examine the front part of the eye, including the eyelids, cornea, iris, and lens.^{26,27,28,29,30} For a more detailed exam, the clinician might use dilating drops to widen the pupil, allowing a clearer view of the optic nerve and retina.^31,32,33,34

Pediatric vision assessment 

Vision in very early childhood can be checked with visually evoked potential (VEP). A VEP test can see if any vision is present in cases where the eye is missing or very small.²¹ A pattern VEP helps measure how clearly a child can see and checks for optic nerve issues.^21,22 An electroretinogram looks for any problems with the retina.^23,24

Management and treatment options for ophthalmic abnormalities associated with Fraser Syndrome

Effectively managing and treating ophthalmic issues related to Fraser Syndrome requires a tailored approach to address the unique challenges each affected individual may face. This section will discuss these management and treatment options.

Ophthalmic lubricants 

Cryptophthalmos can cause damage to the surface of the eye due to exposure and a lack of eye protection.⁹ Using ophthalmic lubricants and artificial tears can help prevent dryness and reduce discomfort for an individual.¹⁶

Patching

Children with microphthalmia may still have some vision in the smaller eye. Wearing a patch over the eye with better vision for a few hours a day can help improve vision in the smaller eye by encouraging the brain to rely on the smaller eye with reduced vision.¹¹

Surgery

Surgical options for cryptophthalmos

The severity of cryptophthalmos (complete, incomplete, or abortive) determines the surgical approach.^9,17

1. Complete cryptophthalmos 

Surgery is mostly for cosmetic reasons since improving vision is rare. The procedure involves creating a space around the eye and reconstructing the eyelids, though normal eye function is hard to achieve.^9,17

2. Incomplete cryptophthalmos 

Surgery focuses on improving the appearance of the eye, but vision improvement is limited. The process includes creating a space around the eye and rebuilding the eyelid, with the timing and method of surgery being debated.^9,17

3. Abortive cryptophthalmos 

This form risks vision loss due to upper eyelid defects and limited eye movement. Surgery aims to reconstruct the eyelid and surrounding area to prevent further issues and enhance appearance.^9,17

Surgical options for anophthalmia and microphthalmia

Children with anophthalmia or microphthalmia might need surgery to enlarge their eye socket, fill it out, or help prosthetics or devices fit properly.²¹ 

Prosthetics 

When surgery is not an option or is unsuccessful, prosthetic eyelids can be a viable alternative. These prosthetics are designed to resemble natural eyelids, offering protection for the eye and improving an individual’s appearance.²⁵

Impact on quality of life 

Although there is no current cure for Fraser Syndrome, treatment is focused on managing the various malformations and symptoms associated with the disorder. The prognosis for eye-related issues in Fraser Syndrome depends heavily on the severity of the abnormalities.⁴² Unfortunately, in cases with severe ocular malformations, alongside other critical issues like respiratory tract malformations, the risk of early mortality remains high.³⁵

Complete cryptophthalmos can lead to glaucoma and a painful non-functional eye, and abortive cryptophthalmos can cause the cornea to become rough and cloudy, resulting in reduced vision.⁴² However, when there is no chance of restoring vision, treatment usually focuses on improving an individual’s appearance.⁴³ A team of specialists, including ophthalmologists, evaluates each patient and develops a personalised treatment plan. 

For families affected by Fraser Syndrome, genetic counselling is recommended to understand the inheritance patterns and risks for future pregnancies.⁴¹

Summary

Eye abnormalities associated with Fraser Syndrome can result in visual issues or blindness. Many of the ophthalmic abnormalities require surgery to improve appearance or restore some vision. Usually, treatment focuses on protecting the eyes, easing discomfort, and improving an individual’s quality of life. Early detection and specialised care are key in addressing the eye-related challenges of Fraser Syndrome.