Ever wondered what Fraser syndrome is? A family member might be diagnosed with it but you are still unsure of what it is? Have you heard of it before but were too lazy to search about it? You are at the RIGHT PLACE! In this article, we will explore the causes, symptoms, diagnosis and management of Fraser syndrome in a very simplistic and easy way to understand and navigate. 

Overview

In 1962, Canadian geneticist George R. Fraser made the first ever report about Fraser syndrome. It is an infrequent genetic disorder (autosomal recessive disease) with irregularities occurring in the limbs, genital, head, lungs and kidneys. In most cases, it is due to the mutation of the FRAS1 gene on chromosome 4q21.¹ This will later on lead to utmost physical and developmental challenges. Due to the rareness of the disease and with fewer than 100 cases reported, early and accurate diagnosis using ultrasonography and thorough clinical examination is essential.²

Causes of Fraser syndrome (FS)  

Fraser syndrome is caused by the mutations of the following genes according to the National organization of rare disorders: 

• FRAS1 gene mutation is the most common among the others because it represents roughly 50% of the reported cases. The FRAS1 gene is crucial in skin formation and the embryonic structure
• The FREM2 gene is associated with FRAS1 in the complex formation of the embryonic structure
• The GRIP1 gene encodes a protein that helps in the stability of the FRAS1 and FREM2 complex³

Genetic basis and inheritance 

According to the autosomal recessive inheritance pattern illustrated by Fraser syndrome, the affected person will inherit two copies of the mutated gene, one from each parent. Fraser syndrome is predominantly linked to the mutation of the FRAS1 gene, which is mostly associated with skin formation. 

Genetic counselling before pregnancy is essential because the parents of the affected child are known to be asymptomatic carriers, meaning they have one copy of the mutated gene. Therefore, if both parents have the affected gene there is a 25% chance of having an affected child.¹⁰

Signs and symptoms of Fraser syndrome 

The clinical presentations of Fraser syndrome can vary significantly from major to minor. Below are the most notable features of the syndrome: 

Major 

• Cryptophthalmos, the most common feature in Fraser syndrome, refers to the full or partial coverage of the eye and in some cases, it can lead to blindness
• Syndactyly, demonstrated by linked fingers or toes
• Renal agenesis is when one or both kidneys are absent
• Genital abnormalities
• Respiratory issues 

Minor 

• Otolaryngological anomalies (ear malformation or hearing loss) 
• Facial dysmorphism 
• Musculoskeletal anomalies (disruption of joints, bones and connective tissues)^4,9

Management and treatment of Fraser syndrome

There are no current treatments for Fraser syndrome,¹ but there are several ways to manage it which include: 

• Genetic counseling
• Involvement of specialists (ophthalmology, orthopaedic and urologist)
• Regular checkups for monitoring symptoms
• Psychological support for family members affected
• Surgery (to fix any malformation associated with the disorder)^5,6,7

Options to treat Fraser syndrome are very limited, regardless of the progress that has been made within the genetic field. The most recommended option would be surgical management, depending on the malformation present which could be Cryptophthalmos, Syndactyly, etc.²

Diagnosis of Fraser syndrome 

There are several methods and tools to diagnose Fraser syndrome which include: 

• Clinical examination (family history and physical examination)
• Molecular genetic testing (sequencing the genes) 
• Imaging (ultrasound and MRI or CT scan)
• Prenatal diagnosis (ultrasound markers and genetic testing)
• Differential diagnosis (comparing with other syndromes)²

Therefore, Fraser syndrome can be diagnosed on two different occasions which are, antenatally by using ultrasonography and postnatally with accurate and thorough examinations. According to a case study that was carried out in Cameroon, it suggests high emphasis on the importance of sufficient antenatal and postnatal follow-ups on pregnant women due to the poor-resource setting they are located at.² 

Challenges in the diagnosis of Fraser syndrome 

Due to the rarity of the syndrome, there are some challenges associated with it which include: 

Condition rarity 

There have only been a few hundred cases of Fraser syndrome reported worldwide, making it an exceptionally rare condition. Owing to the small number of cases of this illness, many medical practitioners might not be aware of it, which could delay the diagnosis process. Early recognition and diagnosis of the illness can be difficult because of professionals' lack of experience and awareness due to its rarity.⁴

Phenotypic variability 

The symptoms of Fraser syndrome can differ greatly from patient to patient; while some may exhibit conventional symptoms of cryptophthalmos or syndactyly, others may exhibit unusual symptoms that do not point to or suggest Fraser syndrome. Phenotypic variability confuses the diagnosis process of the syndrome and mistakes it with another syndrome.⁹

Limited Access to genetic testing 

Genetic testing has an essential role in the diagnosis procedure of Fraser syndrome in order to identify the mutated genes (FRAS1, FREM2 or GIRL1). Nonetheless, having access to this type of testing might be limited due to its cost and availability.²

FAQ’s

What are the criteria for Fraser syndrome?

Six major criteria include Cryptophthalmos, Syndactyly, Renal agenesis, Genital abnormalities, Otolaryngological anomalies, Respiratory issues, Facial dysmorphism, and Musculoskeletal anomalies.^4,9

What is the lifespan of someone with Fraser syndrome?

Life expectancy is >1 year¹¹

How common is Fraser syndrome?

• The occurrence of it is 0.04 per 10,000 live births and 1 per 10,000 stillbirths.¹

Can Fraser syndrome be detected before birth? 

Yes, prenatal diagnosis is possible¹² 

What are the treatments for Fraser syndrome? 

There is no current treatment for FS but there are ways to manage it which includes genetic counseling and surgical procedures.⁷

Summary 

Fraser syndrome is a rare and infrequent autosomal recessive genetic disorder that was first described by George R. Fraser in 1962. It is caused by the mutations of the FRAS1, FREM2 and GRIP1 genes, which play a very essential role in embryonic development. Mutations of those genes will lead to major symptoms like Cryptophthalmos (full or partial coverage of the eye), Syndactyly (joined fingers or toes), Renal agenesis (absence of one or both kidneys) and Genital abnormalities.⁸

Currently, there is no cure for Fraser syndrome, but there are various ways to manage it, which are predominantly: genetic counselling, surgical corrections of physical anomalies, and Regular checkups for monitoring symptoms like renal function and respiratory issues.⁴

Genetic testing is mostly utilised to identify the mutated gene. However, access to it is extremely restricted due to factors such as availability and cost. Prenatal diagnosis is also being used through ultrasound, specifically with families that have a previous history of Fraser syndrome.9
Advances in diagnosing Fraser syndrome have been significantly improved in recent years, by expanding the genetic data-base to accommodate as much information as possible about the syndrome in order to identify and discover new mutations which are linked to it.¹³