Introduction to Fryns syndrome

What is it?

Fryns syndrome is a rare genetic disorder that was first reported in 1979 and, since then, only a few individuals have survived beyond the neonatal period. It can result in the newborn having many distinctive abnormalities such as deformities of limbs including hand and toes, cleft palate, and insufficient lung development. It has clinical criteria whereby the following suggests Fryns syndrome:¹

• Diaphragmatic defect
• Facial appearance - wide eyes, small jaw, wide mouth
• Distal digital hypoplasia - underdeveloped thumbs
• Pulmonary hypoplasia - underdeveloped lungs
• Family history with autosomal recessive inheritance 

The remainder of the article will explain in further detail the causes, how diagnoses are made and what help is in place. 

Genetic basis and inheritance pattern

It is an autosomal recessive disorder, meaning that both biological parents must carry the mutated gene. The exact gene has not been identified, further study is required to understand this. Through the examination of affected families, links and patterns have been identified, for example, the PIGN gene.² During conception, there is a 25% chance of getting Fryns syndrome for a sibling of an affected individual. This increases to a 50% chance when it is an asymptomatic carrier (an individual that has the mutated gene but shows no symptoms). If you are unaffected and not a carrier, there is only a 25% risk of your baby inheriting Fryns syndrome. 

Significance of early diagnosis

Catching an early diagnosis is extremely important for several reasons. One is that an early diagnosis can lead to improved perinatal care. This is crucial as it allows time to plan and prepare for the newborn's arrival. In addition, it will allow your healthcare team to create a better care plan. It can help your physician and nurses be more aware of what surgical intervention may be required and have a better understanding of what abnormalities there may be.³ 

This can be done through the use of an ultrasound which will be further discussed later on. If there are significant abnormalities, the best decision may be the termination of the pregnancy for some parents. Again, an early diagnosis gives time to decide on what the best course of action is and will allow further investigations to take place.

Furthermore, once an early diagnosis is made, the NHS has guidelines regarding neonatal care. This states that there are resources and networks in place to deliver specialist care for those who require it the most. This can lead to better patient experience and improved neonatal outcomes although this is very low in Fryns syndrome.

Prenatal diagnostic modalities 

Ultrasound examination 

An ultrasound is the main modality used to detect prenatal Fryns syndrome. It is a scan that uses high-frequency sound waves to create an image. These sound waves are detected by a probe which then forms an image of the inside of the body onto a monitor. They are useful in examining the relative health of your baby. 

For example, it can show:

• Baby’s heartbeat
• Size of the baby 
• Baby’s position in the womb 
• Whether you are having a single baby or more (twins/triplets/quadruplets) 
• Baby’s organ structure - heart/kidney/arms/legs
• Any abnormalities

Before an ultrasound, it is required to drink roughly around 500 ml of water an hour. This excess water will allow the sonographer (the person conducting the ultrasound) to have a much clearer image of your baby.  A gel is applied to your stomach, which helps the ultrasound waves to be picked. The waves create an image that is displayed on the computer. This appointment usually takes around 30 minutes. Next, we explainwhat happens if any abnormalities linked to Fryns syndrome are detected. 

Foetal magnetic resonance imaging

If something unusual is seen on the ultrasound, a magnetic resonance imaging scan (MRI) is done. This provides a more detailed image of your baby. It is used to confirm the diagnosis or to further investigate what was previously seen in the ultrasound. Concerning  Fryns syndrome, it can see specific abnormalities associated with the illness such as:

• The level of the diaphragmatic hernia 
• Any brain/spinal cord damage
• Limb defects 
• Any organ damage e.g. specific cardiac defects

Genetic testing

Genetic testing plays a pivotal role in the diagnosis of Fryns syndrome.² However, it has to be noted that no specific gene has been linked to the causing Fryns syndrome rather there is a strong association. Genetic tests are used more often to rule out other genetic disorders that have similar symptoms and characteristics.⁴ There are different types of genetic testing that can be done which are mentioned below.

A chromosomal microarray analysis can be used to identify missing or additional chromosomes that are linked to Fryns syndrome like the PIGN gene. Alternatively, you may undergo an exome/genome sequencing, which looks at many genes at once. This can highlight any mutations associated with Fryns syndrome or other disorders.⁵

Diagnostic challenges and limitations

Even with these advanced tests, a specific diagnosis isn't always possible. This is because Fryns syndrome can look very similar to other genetic conditions, making it hard to tell them apart. Additionally, the specific gene causing Fryns syndrome hasn't been identified yet, which means genetic tests can't directly detect it. Another challenge is that the symptoms of Fryns syndrome can look very different from one baby to another, making it harder for doctors to recognise it. In the UK, access to advanced genetic testing is improving through the NHS Genomic Medicine Service, but understanding the results for rare conditions like Fryns syndrome remains complex. Despite these challenges, early and accurate diagnosis is vital for providing the best care for affected babies and support for you and other family members.

Research and future directions

While our understanding of Fryns syndrome has improved since its initial description, many questions remain. Current research efforts are focused on:

• Identifying the specific gene(s) responsible for the syndrome
• Developing more accurate diagnostic tests
• Exploring potential prenatal interventions to improve outcomes
• Understanding the complex interactions between genetic and environmental factors that may influence the syndrome's expression

Summary

Fryns syndrome is a rare and complex genetic disorder that has significant challenges in prenatal diagnosis and management. Early detection using advanced imaging techniques and genetic testing can provide crucial information to healthcare providers and soon-to-be parents. While the diagnosis for affected individuals remains poor, ongoing research offers hope for improved understanding and potential therapeutic interventions in the future.

For families affected by Fryns syndrome, support groups and genetic counselling services can provide invaluable emotional support and practical guidance. As knowledge of genetics and prenatal diagnosis continues to expand, we may see improvements in both the accuracy of diagnosis and the options available for affected families.

It's crucial for anyone suspecting or diagnosed with Fryns syndrome to work closely with a team of specialists, including maternal-fetal medicine experts, geneticists, and neonatologists, to ensure the best possible care and support throughout the pregnancy and beyond.