Introduction

Fryns Syndrome is a rare congenital disease first described in the late 1970s, where there are many abnormalities present at birth.¹ Fryns syndrome is a genetic disorder that leads to diaphragmatic defects such as the underdevelopment of lungs,¹ diaphragmatic hernia, eventration (abdominal organs protruding the abdominal wall), hypoplasia (underdeveloped organs) and agenesia (underdeveloped growth during embryonic growth.² Fryns syndrome is also accompanied by underdeveloped digits, facial feature abnormalities and abnormalities in organ systems around the body.¹

It is crucial to understand the importance of the etiology of Fryns syndrome to improve diagnostic approaches. Understanding what causes Fryns syndrome and the risk factors associated with the condition can improve diagnosing and prevent health professionals from misdiagnosing it with other congenital diseases that have similar symptoms. Improved diagnosis can also improve early detection, which can help prepare families and health professionals to understand the complications of Fryns syndrome. Understanding the genetic causes and risks of Fryns syndrome is important, especially in genetic counseling. If the inheritance pattern and genetic causes are understood, it can help with family planning and can also prevent families from having another baby with the condition. 

Overview of Fryns syndrome

Fryns Syndrome was first described in sisters by J.P. Fryns in 1979³ and there have been 50 patients recorded in medical literature¹. The clinical presentations of Fryns syndrome can include:

Diaphragmatic defects² such as:

• diaphragmatic hernia¹

Abnormal facial defects such as:²

• Coarse facials like prominent brows, thick lips and mouth and wide nose
• Low set and irregular ears
• Wide mouth and cleft lips
• Small jaw

Short, underdeveloped fingers and toes, for example, the nails may be too small² or fingers too small.⁴ Cloudy corneas² and abnormally small eyes¹,

Malformations in organs such as:²

• Brain
• cardiovascular system
• gastrointestinal system
• Kidney cysts
• and genitals

Excessive amniotic fluid

Congenital diaphragmatic hernia is the most common symptom associated with Fryns syndrome, present in more than 90% of cases,¹ and this has consequences in the development of other organs.¹ It can cause the small intestines, stomach and liver to move upwards into the chest cavity, which can also cause the lung and respiratory system to be underdeveloped, hence causing major complications after birth.¹

Facial features are another common clinical presentation of Fryns syndrome where most patients have abnormal facial features like wide-spaced eyes with a cloudy cornea, a wide flat nose and a wide mouth.² Cleft palate and cleft lips are common in 25% to 50% of patients.¹

Fryns syndrome also has organ malformation and this can cause abnormalities in the body.¹ For example, neurological abnormalities are common when there is brain malformation, and this can lead to patients experiencing seizures.¹ Heart malformation is also a common symptom found in Fryns syndrome, with 40% of patients having a ventricular septal defect where there is an opening in the heart.¹

Unfortunately, patients with Fryns syndrome surviving past neonatal is rare, and children who are able to survive past this stage have developmental delay.¹ The prognosis of Fryns syndrome is poor, with most cases stillborn or passing away during the early neonatal stage.³ Hence, survival is rare. There is a variety in the development delay among affected individuals, with some patients experiencing severe intellectual disability whilst others have mild learning disability.1 However, data in postnatal growth and development is limited to conclude anything. 

Genetic causes of Fryns syndrome

The specific gene that is responsible for Fryns syndrome is not known.¹ It is thought that deletions within chromosome 15 and chromosome 8 could be related to causing Fryns syndrome.⁴ Variation within the PIGN has been identified in some patients. Genetic variations in the glycosylphosphatidylinositol- anchor biosynthesis pathway (PIGV) and (PIGA)⁴ have also been identified in patients that show the same symptoms as Fryns syndrome. The pathway is important in normal development as it is involved in cell signalling, cell growth and cell development and disruption in this pathway can have a cascading effect that can lead to developmental abnormalities and prevent normal physiological function.

Fryns syndrome is inherited as an autosomal recessive disease.¹ This means that for someone to have Fryns syndrome, they will need to inherit two copies of the mutated gene, one from each parent. There is the same risk of developing Fryns syndrome for both male and female.¹ Parents who are consanguineous (close relatives) have a higher chance of carrying the same mutated gene,¹ and this will increase the chance of their children inheriting both of the affected genes, leading to Fryns syndrome.

Molecular mechanisms

Genetic variation in the glycosylphosphatidylinositol (GPI)- anchor biosynthesis pathway is thought to be the cause of Fryns syndrome. GPI is a post-translational modification that happens in eukaryotic cells, and its functions are important for biological functions thatincludes:⁵

• Cell signalling
• Cell adhesion
• Protein transport
• Immune response

 Cell growth and development. 

Disruptions to this pathway can cause cellular dysfunction due to impaired cell signalling. This GPI pathway is important in cell signalling,⁵ and disruption can cause cell miscommunication due to incorrect cellular signalling. Cell adhesion disruption would also mean that protein will not attach itself to the surface of the cell, and this could prevent the cell from being recognised and could trigger the immune system. More importantly, development and organogenesis (development of organs in an embryo) would be impacted, leading to development abnormalities which is a main symptom of Fryns syndrome. As discussed earlier, there are abnormalities and malformation in the organs of a Fryns syndrome patient,¹ and this could be caused by abnormal tissue structures caused by disruption in GPI-anchored pathways. Development is important for a healthy baby, but disruptions in developmental delays can lead to short fingers, diaphragmatic hernia, abnormal facial features and under-developed organs.

There is variety in symptoms and clinical features in Fryns syndrome patients, which can be due to specific gene mutations; however, as the specific gene is not fully known, more research is required to understand the genotype-phenotype correlations.

Risk factors associated with Fryns syndrome

Genetic risk factors

As discussed earlier, Fryns syndrome is inherited in an autosomal recessive pattern, and there is a chance that there is of 25% for developing Fryns syndrome if both of your parents are carriers.² A carrier means that an individual carries one copy of the affected mutated gene and if both parents are carriers with one affected gene, there is a chance that their child could inherit both of the faulty mutated gene. For Fryns syndrome to occur, the patient will need both copies of the gene, if they only have one copy, then they will also be a carrier like their parents. There is a higher risk of children developing fryns syndrome if parents are related.²

Environmental factors

It is unknown whether there are any potential environmental influences during pregnancy that can cause Fryns syndrome nor if there are any non-genetic causes for Fryns syndrome. There is very little research and data available for Fryns syndrome, and there are a lot of gaps in our knowledge about Fryns syndrome.

Diagnostic approaches

Diagnosing Fryns syndrome is observational and depends on its clinical presentations.¹ Doctors or health professionals look for the following:¹

1. Defects in the diaphragm
2. Abnormal facial features
3. Short fingers and toenails
4. Under-developed lungs
5. Cloudy corneas and organ malformations
6. Family history, i.e, any affected siblings or how closely related parents are

To get a Fryns syndrome diagnosis, 4/6 of the above clinical presentation will need to be met, but this could be difficult due to the high variability in symptoms of Fryns syndrome.¹ Genetic testing can be possible, like copy number variation analysis or comparative genomic hybridisation for the genes involved in the GPI-anchored synthesis pathway.⁴ Nearly all diagnoses are made after birth, but it is possible to diagnose Fryns syndrome if the ultrasound images results are abnormal.¹

Advances in research and future directions

There is no cure or treatment available for Fryns syndrome however, current research has been focused on treating diaphragmatic hernia.¹ The cause of Fryns syndrome is not known, and this is limiting the progress towards a cure. New emerging genetic technologies such as Next Generation Sequencing (NGS) can be used to identify the specific genetic cause. Genetic counselling is important to consider for parents who want a family, as Fryns syndrome is an inherited disease. Understanding the risk assessment and proper family planning can allow parents to have healthy children.

Summary

Fryns syndrome is a genetic disorder inherited at birth that leads to diaphragmatic defects, underdeveloped digits, facial features abnormalities and malformations in organ systems. Unfortunately, the prognosis of Fryns syndrome is poor, with most cases stillborn or passing away during the early neonatal stage,³ and survival is rare. 

The specific gene that is responsible for Fryns syndrome is not known.¹ It is thought that deletions within chromosome 15 and chromosome 8 could be related to causing Fryns syndrome.⁴ Genetic variations in the glycosylphosphatidylinositol- anchor biosynthesis pathway (PIGV) and (PIGA)⁴ have also been identified in patients who show the same symptoms as Fryns syndrome. 
Fryns syndrome is inherited as an autosomal recessive disease¹ and this means that there is a chance that there is 25% of developing fryns syndrome if both of your parents are carriers.² For Fryns syndrome to occur, the patient will need both copies of the gene, if they only have one copy, then they will also be a carrier like their parents. There is a higher risk of children developing Fryns syndrome if parents are related.² There is no cure or treatment available for Fryns syndrome but current research has been focused on treating diaphragmatic hernia.¹ The cause of Fryns syndrome is not known and this is limiting the progress in a cure for Fryns syndrome. Understanding the underlying cause of Fryns syndrome can increase the progress and research in this field where there is limited data and research.