Introduction

Fryns syndrome is a rare genetic condition characterised by multiple congenital changes, including diaphragmatic hernias, facial abnormalities, and developmental delays. One of the challenges in diagnosing Fryns syndrome is that the specific gene responsible for the condition has not yet been identified, making genetic testing for early detection difficult.

However, advances in antenatal screening and imaging techniques, such as detailed foetal ultrasounds and prenatal MRI, offer some promise for earlier detection. These imaging tools can help identify the physical abnormalities associated with Fryns syndrome. These abnormalities are diaphragmatic hernias, underdeveloped lungs, or facial malformations, which may prompt further investigation. In some cases, Chromosomal Microarray Analysis (CMA) or Whole Exome Sequencing (WES) may also detect broader chromosomal abnormalities indicative of a syndromic condition like Fryns.

While the lack of a known genetic marker limits direct testing, increased awareness of Fryns syndrome’s characteristic features during pregnancy and high-resolution imaging could enable earlier diagnosis and better preparation for postnatal care. Research into the genetic underpinnings of Fryns syndrome continues, and future discoveries may further enhance prenatal detection methods.

What is fryns syndrome?

Fryns syndrome is a relatively rare congenital condition that can result in many different types of physical malformations that affect multiple organ systems. Most markedly, a diaphragmatic hernia, a diaphragm gap that separates the chest cavity from the abdomen, is most associated with Fryns syndrome. This permits the abdominal organs to migrate into the chest, which can interfere with lung and sometimes heart development.^{1, 2} Heart defects as well as kidney cysts or dysplasia may also be seen, and digestive system issues may result in conjunction with the diaphragmatic hernia^{1, 2} 

Other associated features of Fryns include a wide nasal bridge, short underdeveloped fingers (distal digit hyperplasia), and a cleft palate where the bridge between the nose and the mouth isn’t entirely closed.¹ Pulmonary hypoplasia, underdeveloped and sometimes abnormally developed lungs, often results in Fryns as a complication of the diaphragmatic hernia. Additionally, polyhydramnios, which is an overproduction of amniotic fluid surrounding the foetus, can occur, although this may not be caused by the Fryns as many factors can affect this. 

Eye issues such as clouded corneas or eyes which are too small (microphthalmia) may also occur. This may or may not be seen in conjunction with potential brain issues that can result in Fryns, such as an issue with the connection between the two halves of the brain (corpus callosum), excessive amounts of fluid in the brain (hydrocephalus), or a Dandy-Walker malformation which increases pressure within the skull along with a congenital cerebrum issue. Genital organ malformations may also be present.

Diagnostic methods of fryns syndrome before birth

Magnetic resonance imaging (MRI)

MRIs taken of the foetus during development are called foetal MRIs. They can be used to get very detailed images of the developing child in utero. They use strong magnetic fields and radio waves to create detailed images of soft tissues in the child, such as facial features, the lungs, the brain and the diaphragm. Unlike ultrasounds, foetal MRIs don’t expose the child to ionising radiation, so there is a lower risk involved in terms of getting repeated scans.

As foetal MRIs provide a detailed image of the developing child, they are typically not carried out until the 18^th week of gestation, as the foetus’s organs may not have developed enough for abnormalities to be detected up to this point. This is useful as the information gathered may be used to terminate the pregnancy safely at this point, though this may not be necessary and can instead permit for a better treatment plan or intervention both during and after pregnancy. 

Optimal imaging of vital organs can also be carried out between 20 and 32 weeks after gestation, providing clear, detailed images of the various organs that may not be seen with traditional ultrasounds. MRI helps to visualise abnormal facial structures. 

MRIs can also be enhanced to view specific features, for example, through T2-weighted MRI sequences. Since it highlights fluid-filled structures, it is useful in visualising the lungs and diaphragmatic hernias. 

Additionally, diffusion-weighted imaging (DWI) can help detect subtle tissue development issues. This MRI technique measures water-molecule movement in different tissues and thus can help assess tissue integrity, especially when the water movement detected is abnormal in specific tissue types. In cases where Fryns syndrome is suspected, DWI can provide additional information about the structure and function of organs such as the lungs and brain.

Since abnormal tissue development may restrict water movement, DWI can help highlight these areas, potentially offering earlier detection of subtle defects that may not be as visible using standard MRI sequences. This technique enhances diagnostic accuracy by providing detailed insights into the microstructure of developing fetal tissues.

Genetic testing

Chromosomal microarray analysis (CMA) and whole-exome sequencing are advanced genetic tests that can help identify chromosomal abnormalities potentially linked to Fryns syndrome. CMA works by scanning a person's entire genome for missing or extra pieces of DNA, known as copy number variations (CNVs). These CNVs can reveal broader chromosomal changes that might be associated with developmental and congenital abnormalities, even though Fryns syndrome itself doesn’t have a pinpointed genetic cause.

Whole-exome sequencing (WES), focuses on the protein-coding regions of the genome, which are the parts most likely to harbour disease-causing mutations. While Fryns syndrome does not have a definitive genetic marker, mutations in the phosphatidylinositol glycan anchor biosynthesis (PIGN) gene have been observed in some cases with Fryns-like features. This gene is involved in critical cellular processes, and its dysfunction may contribute to the array of symptoms seen in Fryns syndrome. WES can identify mutations in the PIGN gene or other genes that could suggest a similar syndrome, providing more insight into the underlying cause when traditional tests are inconclusive.

CMA and WES offer valuable tools for identifying genetic patterns that may suggest Fryns syndrome or closely related conditions, even without a specific, known genetic mutation responsible for the syndrome. Coupled with detailed imaging during pregnancy, this may help narrow down the diagnosis and aid in decisions about the future of the infant. 

Table 1: Genetic analysis of those with Fryns syndrome and 2 copies of altered PIGN genes. From (2). These specialised sequences can provide greater detail, potentially improving early diagnosis of foetal abnormalities.

Foetal ultrasound

2-dimensional and 3-dimensional sonographic scans with an ultrasound machine in the second or third trimester can be indicative of Fryns syndrome. In addition to a diaphragmatic hernia and lung abnormalities, abnormal kidneys, heart issues, brain issues, and digit malformations may also be viewed. Although ultrasounds won’t give specific information about the issue and thus cannot be a diagnostic technique for Fryns syndrome or another congenital condition, it can hint at an issue in certain areas of the foetus’s body. Bi-allelic confirmation of PIGN mutations, as well as a sibling already born with Fryns syndrome, along with ultrasound abnormalities indicative of Fryns syndrome, can normally be used to diagnose Fryns syndrome, but ultrasound information alone is not diagnostic.

Currently, there is no known cure for Fryns syndrome, and no gene has been identified to be responsible for the syndrome. Although PIGN mutations have been identified as indicators of Fryns syndrome, PIGN mutations are also present in many different congenital conditions, for example, epilepsy. Therefore, it can not be assumed that a child identified in utero with PIGN mutations will have Fryns syndrome.^{2, 3, 4}

Medical research is continuing to try and identify the exact cause of this condition. Some clinical trials are looking into treatment for foetal diaphragmatic hernias, such as those found in Fryns syndrome.¹ The option for foetal surgery of diaphragmatic hernias may also be possible while the child is still growing within the mother’s uterus if the case is severe and the healthcare specialists involved believe that it will alleviate suffering or improve the child’s quality of life.⁵ Anti-seizure medication is also given to children upon diagnosis to help prevent further brain damage, and depending on the specific symptoms present, other specialist doctors may be required.²

Summary

Fryns syndrome is a genetic condition of unknown origin which can often result in death soon after birth. Antenatal (pre-birth) diagnosis of the syndrome may help parents make informed decisions about the future of the child, including choosing treatment options which may improve the child’s quality of life. Although the genetic cause for the condition is unknown, sometimes PIGN mutations may increase the chances of a child having Fryns, though this alone is not diagnostic. Previous family history, physical malformations, and bi-allelic PIGN mutations can determine Fryns, but limited treatment options are available.