Introduction

Fraser syndrome is a rare genetic disorder characterised by malformations in eyelids, fingers, toes, genitals, and urinary organs. First described in 1962, Fraser syndrome is classified based on the severity of symptoms: complete, incomplete, and abortive, from most to least severe. This disease is inherited in an autosomal recessive pattern, meaning one must inherit two defective copies of the affected gene in order to develop the disease, one from each parent.

The complexity of Fraser syndrome, given the involvement of multiple organ systems, presents challenges in both diagnosis and treatment. Diagnosis and management of this disease warrants coordinated efforts of a diverse team of physicians. Such a multidisciplinary approach ensures that patients receive comprehensive care and improved patient outcomes, ultimately increasing the quality of life for both the patient and their loved ones. This article explores a number of aspects of this disease – from its causes to the treatment methods and the key specialists involved. 

Causes of fraser syndrome

Since its discovery, Fraser syndrome has been found to be associated with mutations in FRAS1 (Fraser extracellular matrix complex protein 1), FREM2 (FRAS1-related extracellular matrix 2), and GRIP1 (glutamate receptor-interacting protein 1) genes. These genes are all associated with the development of embryonic structures, maintaining and regulating interactions between cell membranes and the epidermal layer of the skin.

Mutations in these genes interfere with these interactions, disrupting the normal tissue and organ formation, ultimately resulting in the diverse symptoms observed in this disease. The autosomal recessive inheritance pattern of Fraser syndrome means that both parents must carry one copy of the mutated gene each, with a 25% chance of passing the disease on to their children. This is similarly reflected in the reported 25% recurrence risk of Fraser syndrome among siblings.

Clinical features of fraser syndrome

Fraser syndrome might present differently in each affected person, with some people having more severe symptoms than others.

Major features include:

• Cryptophthalmos: fused eyelids
• Syndactyly: fused/webbed fingers or toes
• Abnormal genitalia
• Sibling with Fraser syndrome/cryptophthalmos

Minor features include:

• Congenital (present from birth) malformations of ears, nose and/or larynx
• Cleft lip, with or without a palate (the roof of the mouth)
• Skeletal defects
• Intellectual disability
• Umbilical hernia: Typically after birth, muscles close around the opening where the umbilical cord protrudes from. Sometimes, they don’t meet properly and leave a gap, causing an umbilical hernia.¹¹ This presents as a lump near or around the belly button 
• Renal agenesis: the absence of one or both kidneys in babies

Treatment and management of Fraser syndrome

Multidisciplinary management team

The characteristic involvement of multiple organ systems in Fraser syndrome means that a multidisciplinary approach involving a wide range of specialised healthcare professionals is a key part of an adequate diagnosis and proper disease management.

Physicians required to manage this disease may include: 

• Ophthalmologist: eye care specialist
• Orthopaedic surgeon: specialises in conditions involving muscles, bones, ligaments, joints, and tendons
• Plastic surgeon
• Gynecologist: specialises in the female reproductive system
• Otolaryngologist: specialises in conditions involving the head and neck
• Maxillofacial surgeon: specialises in conditions involving the face, mouth, jaw, and neck
• Paediatrician
• Dentist
• Speech therapist
• Physical therapist
• General Surgeon 
• Internal medicine doctor: specialises in conditions involving the internal organ systems
• Urologist: specialises in the urinary system
• Psychologist
• Psychiatrist

Treatment and management strategies

For now, there is still no cure for Fraser syndrome. Treatment of the disease is mainly focused on alleviating symptoms and correcting malformations associated with Fraser syndrome.

Surgical interventions

Surgical intervention is often required to correct some of the physical features associated with Fraser syndrome. Depending on the severity of these malformations, the timing of these surgeries is a crucial part of improving the patient’s quality of life.

In the case of cryptophthalmos (fusing of the eyelids) and syndactyly (fused fingers/toes), surgical corrections are often scheduled in the early stages, targeted at restoring or preserving the normal function of the affected body part

Other features of Fraser syndrome that may require surgeries include cleft lip, skeletal defects, umbilical hernia, and renal agenesis. However, it is important to remember that this is completely dependent on the severity of the symptoms and the patient’s prognosis. 

Supportive management

Beyond surgical interventions, medical support plays an important role in managing Fraser syndrome, particularly its non-surgical aspects. This includes: 

• Providing respiratory support to those struggling with malformations in the larynx
• Feeding tubes or the help of feeding therapists to assist with feeding techniques or devices to maintain or improve nutritional intake
• Consistent monitoring of the kidney function for those struggling with renal agenesis
• Regular eye checkups and visual rehabilitation therapy to help with maximising vision
• Physical therapy to aid with mobility and muscle strength
• Speech and language therapy to aid those struggling with speech delays as a result of the cleft lip or any hearing impairments caused by malformations in the ear
• Given the psychological stress that may be caused by living with a chronic condition like Fraser syndrome, psychologists and psychiatrists could address any mental health concerns for both the patient and their loved ones
• Genetic counselling may help families navigate the disease, helping them understand the genetic aspects of Fraser syndrome  

Summary

Fraser syndrome is a rare and complex genetic disorder, with its negative impact on the body spanning multiple organ systems. Its complexity requires a comprehensive, multidisciplinary approach to not only diagnose but to treat and manage as well. From early diagnosis and treatment to lifelong support, the involvement of a diverse team of specialists is a key component to addressing Fraser syndrome and the challenges it presents, and every aspect of this care plays equally important roles in helping patients navigate this disease. 

Despite the absence of a cure, timely diagnosis and management, as well as psychological support from professionals and loved ones can greatly improve patients' well-being. Medicine is an advancing science, and continued research may find improved treatment options and better prognoses for those affected by Fraser syndrome.