Introduction

In the realm of genetic anomalies, few conditions are as visually striking as Fraser syndrome. Imagine a world where eyelids, normally sentinels of sight, are fused shut, a veil drawn over the windows to the soul. This is the reality for those born with cryptophthalmos, a hallmark of Fraser syndrome. But the story doesn't end there. Beneath the closed lids, a symphony of other anomalies unfolds, a tragic ballet of genetic missteps. From the absence of kidneys to the webbed fingers and toes, Fraser syndrome is a complex tapestry woven with threads of both beauty and hardship.

Defining the syndrome

Fraser syndrome is a rare genetic disorder that affects various parts of the body. People with this condition may have fused eyelids, webbed fingers and toes, and problems with their genitals, urinary tract, and respiratory system. They may also have other issues like a cleft lip or palate, skeletal abnormalities, and intellectual disability. While some cases can be fatal, others allow individuals to live into childhood or adulthood. Fraser syndrome is caused by changes in three genes and is inherited in an autosomal recessive pattern. It is diagnosed based on symptoms and can be confirmed through genetic testing.¹

Symptoms

Fraser syndrome is a rare genetic disorder characterised by a constellation of physical abnormalities affecting multiple body systems. The condition typically manifests with a distinctive set of features, primarily impacting the eyes, skin, and digits.²

One of the most prominent symptoms of Fraser syndrome is cryptophthalmos, a condition where the eyelids fail to develop properly, resulting in the skin covering the eyes completely or partially. This can lead to vision impairment or blindness. In some cases, the eyes themselves may be malformed or absent.²

Facial anomalies are common in individuals with Fraser syndrome. These may include a broad nose with a flattened bridge, widely spaced eyes, and a small mouth. The ears might be positioned lower than usual and appear malformed.

Skin abnormalities are another hallmark of the syndrome. Affected individuals often have areas of webbed or fused skin, particularly between the fingers and toes (syndactyly). This fusion can vary in severity and may involve both soft tissues and bones.

Respiratory issues are frequently observed in Fraser syndrome. Some infants may be born with a narrowed or blocked larynx, which can cause breathing difficulties. In severe cases, this may lead to respiratory distress or failure.²

Urogenital abnormalities are also prevalent. These can range from minor malformations to more severe issues such as absent or malformed kidneys, undescended testes in males, or structural abnormalities of the uterus in females.

Individuals with Fraser syndrome may exhibit musculoskeletal irregularities. These can include shortened limbs, curved spine (scoliosis), or chest wall deformities. Some may have extra fingers or toes (polydactyly) or missing digits (oligodactyly).

Cognitive development can be affected in some cases, with intellectual disability observed in a subset of individuals. However, the degree of cognitive impairment can vary widely among those with the syndrome.

Hair growth abnormalities are sometimes present, manifesting as sparse or absent eyebrows and eyelashes. Some individuals may also have patchy scalp hair or areas of excessive hair growth on the body.²

Gastrointestinal issues can occur, including anal atresia (absence of an anal opening) or other structural abnormalities of the digestive tract. These may lead to feeding difficulties or require surgical intervention.

It's important to note that the presentation and severity of symptoms can vary significantly among individuals with Fraser syndrome. Some may have a milder form with fewer affected body systems, while others may experience more severe manifestations across multiple organ systems. The diverse nature of the syndrome underscores the importance of individualised medical care and support for those affected by this rare genetic disorder.

Causes

Fraser syndrome is a genetic disorder caused by mutations in the FRAS1, FREM2, or GRIP1 genes. The FRAS1 gene is the most commonly affected, accounting for over half of Fraser syndrome cases. The remaining genes are responsible for smaller percentages.

This disorder is inherited in an autosomal recessive pattern. Both parents must carry one copy of the mutated gene, even if they don't show any symptoms. When these parents have a child, there's a chance the child will inherit both mutated genes, leading to Fraser syndrome.¹

Diagnosis

Diagnosis and complementary examinations

Fraser syndrome (FS) is diagnosed based on specific clinical features. These features include fused eyelids, webbed fingers and toes, and abnormalities in the urinary, genital, and respiratory systems. Additional examinations, such as ultrasound and CT scans, may be used to assess organ malformations.³

Prenatal diagnosis

While many key features of FS are present in most cases, they can be difficult to detect during prenatal ultrasounds due to reduced amniotic fluid. Therefore, prenatal diagnosis often relies on identifying other less common but more easily detectable abnormalities.³

Molecular diagnosis

Genetic testing, specifically targeted sequencing of the FRAS1, FREM2, and GRIP1 genes, can be used to confirm the diagnosis of FS both before and after birth.³

Living with fraser syndrome

The life expectancy for individuals with Fraser syndrome varies widely, with some cases being severe and leading to early death, while others allow for relatively normal lives. The limited information available on rare diseases can make it challenging to cope with these conditions. People living with Fraser syndrome or other rare disorders may face difficulties in their daily lives, including financial strain, adjusting to specific activities, feelings of isolation, and the need for caregivers.⁴

Improving quality of life

There are many ways to enhance the quality of life for those living with Fraser syndrome long-term. Supportive care, such as personalised medical care plans, family and friend support, and connections with patient and caregiver organisations, can help manage symptoms and the condition. These organisations often provide financial assistance, disability support, and crisis helplines.⁴

Government provisions

The government offers various provisions and subsidies to support individuals living with rare disorders. These include affordable medications, access to innovative treatments, and telehealth services.

Cryptophthalmos and fraser syndrome

Cryptophthalmos, a condition characterised by fused eyelids, has been linked to other birth defects. While it was once referred to as "cryptophthalmos syndrome," the term "Fraser syndrome" has become more common due to cases without cryptophthalmos.

Our study examined seven cases of cryptophthalmos syndrome, including three siblings. All patients presented with fused eyelids and missing kidneys, along with other typical birth defects. A literature review found 124 cases, with 27 having isolated cryptophthalmos and 97 showing a pattern of multiple birth defects. We established criteria to classify 86 cases as cryptophthalmos syndrome, leaving 11 unclassified.

Cryptophthalmos appears to be inherited in an autosomal recessive pattern, meaning both parents must carry the mutated gene. Isolated cryptophthalmos or cryptophthalmos sequence was more common in sporadic cases, while familial cases often showed vertical transmission.

The cause of cryptophthalmos syndrome is unknown, but there are similarities to animal models with vitamin A deficiency and cell death issues. When diagnosing multiple birth defects, especially those involving missing kidneys, cryptophthalmos syndrome should be considered, even if the eyes are not fused.⁴

Conclusion

Fraser syndrome, a complex genetic disorder marked by a constellation of birth defects, presents a poignant challenge for both medical professionals and affected individuals. While significant strides have been made in understanding its genetic underpinnings and associated symptoms, the road ahead remains fraught with uncertainties.

The development of targeted therapies and genetic interventions offers hope for those living with Fraser syndrome. As our knowledge of the disorder deepens, it is conceivable that innovative treatments may emerge to mitigate its impact. However, the rarity of the condition poses unique challenges for clinical research and drug development.

Moreover, the emotional and psychological toll of Fraser syndrome cannot be underestimated. The condition often requires lifelong care and support, and individuals may face significant challenges in their daily lives. It is essential to foster a supportive environment for individuals with Fraser syndrome, providing access to specialized healthcare, educational resources, and social services.

In conclusion, Fraser syndrome remains a complex and multifaceted disorder. While progress has been made, much remains to be learned about its aetiology, pathogenesis, and effective management. By advancing research, promoting awareness, and providing comprehensive support, we can strive to improve the quality of life for individuals affected by this rare condition.