Introduction

Fryns syndrome, also known as congenital diaphragmatic hernia-abnormal face-distal limb anomalies syndrome (CDH), is a genetic disorder causing craniofacial dysmorphisms (diaphragmatic hernia, eventration, hypoplasia, or agenesis) at birth.¹ It is a complex syndrome as it affects the development of many body parts.² The severity of the condition varies from person to person, and hence makes it difficult to diagnose.³ There are no current treatment for this syndrome; however, supportive care can be offered to individuals suffering from this. This syndrome is still being researched due to its poor prognosis.¹

In this article, we will understand the pathophysiology of Fryns Syndrome: the causes and consequences of the Mechanisms and Developmental Abnormalities. Understanding the pathophysiology of Fryns syndrome is essential for a multidisciplinary team as they work towards better diagnostic and therapeutic approaches for this syndrome.¹  

History of Fryns Syndrome:

First identified by Belgian geneticist Jean-Pierre Fryns in 1979, who discovered this in two siblings who were presented with CDH.⁴ It was thought to be an inherited autosomal recessive condition (both parents of an affected individual carry one copy of the mutated gene), but the specific genes causing this have not yet been recognised.² In 1980, the characteristic pattern for patients was being recognised for this syndrome with similar features and increasing mortality rates over time.¹ In 1987, it was officially named “Fryns syndrome”, and research began in the 1990s.⁵

Prenatal methods in 2000 allowed for its detection and genome technologies (e.g. chromosomal microarray and Whole Genome Sequencing (WGS) were introduced were introduced to understand the genetic causes of this syndrome and raise its awareness.⁶ Research continues today to understand its molecular mechanisms.

How are molecular mechanisms affected?⁷

Disruptions in the molecular pathway include:

• Embryonic development disruptions in the WNT Signalling Pathway mainly affect cell differentiation, organogenesis, and tissue patterning
• Transforming growth factor-beta (TGF-β Pathway) abnormalities mainly affect the diaphragm and lung development

How does it affect development?^1,8

Until now, the gene responsible for causing this syndrome remains unknown, but research continues for possible gene loci responsible for this. Research has shown that this syndrome disrupts the signalling pathways and cellular functions, causing a diverse range of abnormalities. Below is a list of these:

Embryological Development

There are 5 developmental areas in the body affected because of Fryns syndrome. These include Embryological Development, Craniofacial Development, Diaphragmatic Formation, Pulmonary Development, Cardiac Development and Limb and Skeletal Anomalies

Craniofacial Development: As a result of deformed pharyngeal arches (the structures that form the bones, cartilage, and soft tissues of the face) give rise to craniofacial abnormalities (e.g. microphthalmia (small eyes) and cleft palate). The deformed cleft palate is a result of abnormal signalling in neural crest cells which cause dysmorphogenesis.

Diaphragmatic Formation is affected by characteristic CDH, which is a fatal symptom. It is caused due to the inefficient closing of the diaphragm during embryogenesis. This results in pulmonary hypoplasia, a condition where the abdominal organs herniate into the chest cavity. This further affects the molecular mechanism and signalling pathway of the cell contributing to proper diaphragm formation.

The diaphragm sits proximity to the lungs, and this results in affected pulmonary development of the lungs which contribute to a high mortality rate. This is because, the reduced space in the upper thoratic cavity because of herniation leads to significant respiratory insufficiency and difficulty in breathing at birth.

Cardiac development is affected at an early stage of heart development in the individual and causes many congenital heart defects (e.g. ventricular septal defects (VSDs) and atrial septal defects (ASDs)) as a result of deformed growth, migration and differentiation of cardiac progenitor cells.

Limb and Skeletal Anomalies (e.g brachydactyly (short fingers or toes), polydactyly (extra digits) and syndactyly (fused digits)) because of disruptions in the cellular pathways of limb bud formation and growth during embryogenesis. Skeletal anomalies (e.g rib and vertebral malformations) affect mesodermal development (The middle layer developed during gastrulation during early development of animal embryos).

Neurological abnormalities are caused by disrupted neural tube development and brain patterning, causing brain malformations and affected neurodevelopment, resulting in genesis of the corpus callosum, hydrocephalus and microcephaly. This leads to severe cognitive impairment and a delay in the development of the individual.

Gastrointestinal and renal abnormalities are common in Fryns syndrome, including issues such as intestinal malrotation and renal dysplasia or agenesis. These defects likely result from disruptions during the embryonic development of the gastrointestinal tract and urogenital system, both of which originate from the mesoderm.

In Fryns syndrome, although less common, other organ systems can also be significantly affected. Abnormalities in the liver, spleen, and genitalia have been observed in some cases, highlighting the syndrome’s broad impact on the body. These systemic effects, while not as frequent as diaphragmatic or craniofacial abnormalities, still play a crucial role in the overall severity of the condition. These additional complications underscore the widespread developmental disruptions caused by Fryns syndrome, making the condition more challenging to manage and contributing to its complex clinical presentation.

FAQ Section

Can Fryns syndrome be diagnosed before birth?

• Yes, using prenatal imaging, ultrasound, and genome sequencing
• Useful for detecting congenital diaphragmatic hernia (CDH) or other structural anomalies such as craniofacial dysmorphisms, limb malformations, or heart defects
• Various genetic testing techniques, including chromosomal microarray analysis or whole-exome sequencing (WGS)

What causes Fryns Syndrome?

Unknown reasons but a result of genetic mutations on specific loci, and is inherited.

Is there a cure for Fryns Syndrome?

No cure for Fryns syndrome, but support is available for the syndrome.

How does Fryns Syndrome affect life expectancy?

Infants do not survive past the neonatal period due to complications of the syndrome and difficulty breathingto breathe.

What are potential areas of future research?⁹

• Candidate genes (involved in diaphragm and lung development) are being researched alongside broader genomic gene analysis to understand mutations
• Mice are used as part of animal models to understand the developmental effects of Fryns syndrome, which could be useful in making therapeutic drugs to cure the syndrome

Summary

Fryns Syndrome, a complex genetic disorder, causes various developmental abnormalities mainly affecting fetal life. Its most common developmental effect is seen by congenital diaphragmatic hernia (CDH), which leads to pulmonary hypoplasia due to restricted lung development. It affects various craniofacial features, along with potential heart, kidney, and brain malformations, all pointing to widespread disruptions in organogenesis. Believed to follow an autosomal recessive inheritance pattern, Fryns Syndrome remains poorly understood at the genetic level and thus requires research. It is important to diagnose and treat this condition to help improve the quality of life for children.

Read On

If you enjoyed reading this article from Klarity, you will enjoy reading:

• What Is Fryns Syndrome?
• Gene Therapy: Hope for Rare Diseases
• Understanding Cri Du Chat Syndrome Symptoms In Infants
• PURA Syndrome And Seizures