Fryns Syndrome is an exceptionally rare and challenging genetic disorder that deeply affects individuals and their families. This article provides an in-depth exploration and management of the condition, detailing its characteristics, prevalence, and the critical role of multidisciplinary care. It also outlines genetic counselling and the recommended support for the families that can be undertaken during pregnancy. This article covers the complex symptoms associated with Fryns Syndrome, including congenital diaphragmatic hernia (CDH) and distinctive facial features. Learn about the importance of genetic testing for diagnosis and how a coordinated team of specialists can offer comprehensive treatment and management strategies. 

Introduction

Fryns Syndrome is a rare and severe genetic disorder first described in 1979. The syndrome is characterised by a range of congenital anomalies, which can vary significantly from one individual to another. Key features include diaphragmatic defects, pulmonary hypoplasia, distinctive facial appearance, and distal digital hypoplasia. Due to its severe impact on multiple organ systems, Fryns Syndrome necessitates a comprehensive, multidisciplinary approach to care. Understanding these characteristics underscores the importance of a team-based approach in improving patient outcomes and supporting affected families.

Characteristics of fryns syndrome

Diaphragmatic Defects: Over 90% of individuals with Fryns Syndrome present with congenital diaphragmatic hernia (CDH), typically a left-sided Bochdalek hernia. This defect causes abdominal organs to move into the chest cavity, leading to severe underdevelopment of the lungs (pulmonary hypoplasia) and significant respiratory distress.

Facial Dysmorphism: Individuals often exhibit widely spaced eyes, a broad and depressed nasal bridge, a long philtrum, low-set ears, a tented vermilion of the upper lip, a wide mouth, and a small jaw.

Skeletal Anomalies: Affected individuals frequently have short distal phalanges of fingers and toes, accompanied by small nails.

Pulmonary Hypoplasia: Severe lung underdevelopment is a major consequence of diaphragmatic defects, contributing to high mortality rates.

Associated Anomalies: Additional anomalies may include excess amniotic fluid (polyhydramnios), cloudy corneas, microphthalmia, orofacial clefting, renal dysplasia or cortical cysts, and malformations in the brain, cardiovascular system, gastrointestinal system, and genitalia.

Congenital diaphragmatic hernia (CDH)

CDH is a central feature of Fryns Syndrome and the primary cause of immediate health concerns. The diaphragm's failure results in fully separating the chest from the abdomen, compressing the lungs and causing pulmonary hypoplasia. CDH is predominantly left-sided in 80% of cases, though its severity can vary.¹

Prenatal Diagnosis: Ultrasound and fetal MRI can diagnose CDH and assess its severity. Some pregnancies may be managed with in-utero treatments, while others are monitored with regular growth scans. Postnatally, infants with CDH typically require surgery and intensive care to address respiratory difficulties and other complications.

Prevalence and genetic basis

Fryns Syndrome is extremely rare, with an estimated prevalence of about 7 cases per 100,000 live births based on early studies. Approximately 50 cases were documented between 1979 and 2017. The syndrome is often linked with CDH, affecting 1.3% to 10% of CDH cases. Certain populations, such as those from La Réunion and the Indian Ocean islands, may have a higher incidence due to genetic factors.²

Before diagnosing Fryns Syndrome, it's important to check for other possible chromosomal disorders using a test called chromosomal microarray analysis. Recently, researchers found two specific mutations in the PIGN gene in three fetuses with Fryns Syndrome. However, more studies are needed to confirm if these mutations are a cause of Fryns Syndrome.

Fryns Syndrome is inherited in an autosomal recessive manner, meaning a person must inherit two copies of the altered gene - one from each parent - to be affected. If both parents carry one copy of the altered gene, each pregnancy has a 25% chance of resulting in an affected child and a 50% chance of producing a carrier child. The likelihood is the same for every pregnancy and for both boys and girls. If the parents are closely related, there’s a higher chance they both carry the same gene mutation, which increases the risk of having a child with a recessive genetic disorder.³

Diagnosis

Diagnosing Fryns syndrome involves several steps. Doctors look for specific signs, such as a hole in the diaphragm (which affects breathing), underdeveloped lungs, unusual facial features, limb problems, and other birth defects through an ultrasound. They also consider family history similar to that of Fryns syndrome. Due to the complexity of this condition, it typically doesn’t show up in standard genetic tests, so healthcare practitioners utilise more detailed methods to analyse the genes or chromosomes to rule out other similar conditions. Sadly, Fryns syndrome has a poor prognosis, with many babies not surviving past the first few months, and those who do often face serious developmental and intellectual challenges. Genetic changes in the PIGN gene can also add to the difficulties, sometimes causing additional neurological problems.

Management and multidisciplinary care

Managing Fryns Syndrome requires a team of specialists due to its complex effects on the body. Infants with Fryns Syndrome often need immediate surgical treatment for congenital diaphragmatic hernia (CDH) and intensive neonatal care to address acute complications, breathing issues, and feeding problems. Pediatric surgeons and neonatologists are crucial in these early stages. For long-term care, survivors generally need ongoing support from cardiologists, pulmonologists, and neurologists. Early intervention therapies, including speech, occupational, and physical therapy, are key in addressing developmental delays. A multidisciplinary team—comprising geneticists, pediatric surgeons, cardiologists, neurologists, pulmonologists, and developmental therapists—works together to create and implement personalised care plans to monitor and support the child's health and development.⁴

Genetic testing for fryns syndrome

Genetic testing for Fryns Syndrome involves several approaches. Gene-targeted testing, including single-gene sequencing and multigene panels, focuses on identifying mutations in the PIGN gene. Comprehensive genomic testing, such as exome or genome sequencing, can reveal additional genetic factors. It is also important to consider other genetic conditions with similar features, like Cornelia de Lange Syndrome or Trisomy 18. Genetic counselling plays a crucial role in providing families with information about inheritance patterns and recurrence risks. The recurrence risk depends on the specific genetic or chromosomal cause, with a 25% risk if associated with a recessive genetic syndrome, necessitating individualised counselling from a clinical genetics team. Family support is essential for dealing with the challenges of Fryns Syndrome, and psychological and social support services, including palliative care teams, are available to assist with end-of-life decisions in severe cases.

Following a Fryns Syndrome diagnosis, several evaluations are recommended, including imaging for congenital diaphragmatic hernia (CDH), brain imaging and EEG for neurological issues, comprehensive eye exams for ocular anomalies, echocardiograms for cardiac concerns, and assessments for gastrointestinal and genitourinary issues. Developmental assessments are also important for evaluating motor skills, cognitive abilities, and speech/language development. For managing CDH, prenatal care may involve referral to fetal medicine for diagnosis confirmation and counselling, with severe cases potentially requiring fetal MRI and in utero treatment options. Postnatal care includes immediate surgical repair and NICU support, and genomic counselling is advised if there is a recurrence risk. Autopsy information can guide further testing if the baby does not survive.⁵ Careful monitoring during pregnancy is crucial, and prenatal interventions, such as fetoscopic endoluminal tracheal occlusion, might be considered, though their effectiveness is still under investigation. The prognosis for Fryns Syndrome varies, with survival beyond the neonatal period being rare and a better outlook for patients without diaphragmatic defects. Raising a child with Fryns Syndrome involves significant emotional and practical challenges, making ongoing psychological and social support vital, with palliative care teams available to help with end-of-life decisions when needed.

Conclusion

Fryns Syndrome presents a complex array of medical challenges impacting multiple organ systems. While there is no cure, a multidisciplinary approach to care can significantly enhance the quality of life for surviving children and provide crucial support to their families. Compassionate, team-based care combined with ongoing research offers hope for better outcomes and a more comprehensive understanding of this rare syndrome.