Introduction

Fryns syndrome is a rare genetic disorder characterised by abnormalities in the diaphragm, such as diaphragmatic hernia, diaphragmatic eventration, underdeveloped diaphragm (hypoplasia), or even absence (agenesis). Individuals with Fryns syndrome typically have distinctive facial features that include:

• Coarse appearance
• Widely spaced eyes
• Broad and flat nasal bridge with a wide tip
• Elongated philtrum
• Low-set and unusual ears
• Tented upper lip
• Wide mouth
• Small jaw

Other common features include:

• Underdeveloped lungs
• Excess amniotic fluid
• Cloudy corneas or abnormally small eyes
• Cleft lip and/or palate
• Kidney abnormalities like renal dysplasia or cortical cysts
• Malformations of the brain, heart, digestive system, and genitalia

Survival beyond the newborn phase is uncommon. There is limited information on growth and psychomotor development after birth, but severe developmental delays and intellectual disabilities are frequently observed.^1,2

Although the precise genetic cause of Fryns syndrome has yet to be fully understood, it is thought to be inherited in an autosomal recessive pattern; this means that both parents carry the Fryns gene but do not develop the disease. The diagnosis of Fryns syndrome is primarily clinical, based on the presence of characteristic physical findings and anomalies, and sometimes confirmed with genetic testing and imaging studies.³

Gastrointestinal abnormalities in fryns syndrome

Gastrointestinal (GI) abnormalities are among the most common and significant features of Fryns syndrome. They can lead to substantial morbidity and are often a major factor in the poor prognosis or outcome associated with the syndrome. The digestive system issues commonly seen in Fryns syndrome are diverse and can involve various parts of the GI tract, from the mouth to the anus. This section will discuss the primary GI abnormalities observed in Fryns syndrome, including diaphragmatic hernia, gastrointestinal malrotation, omphalocele, and other digestive system anomalies.¹

Congenital diaphragmatic hernia

One of the hallmark features of Fryns syndrome is a congenital diaphragmatic hernia (CDH), which is characterised by an abnormal opening in the diaphragm, the muscle that separates the chest cavity from the abdominal cavity. This defect allows abdominal organs, such as the stomach, intestines, and liver, to herniate into the chest cavity, impeding normal lung development and function. CDH is present in approximately 60-70% of individuals with Fryns syndrome, making it a critical feature for diagnosis.

The diaphragmatic hernia in Fryns syndrome usually occurs at the back and side of the body and is often referred to as a Bochdalek hernia. This type of hernia typically occurs on the left side of the diaphragm, though it can occasionally be bilateral. The presence of a diaphragmatic hernia leads to pulmonary hypoplasia (underdevelopment of the lungs) and respiratory distress at birth, which are significant contributors to the high mortality rate associated with Fryns syndrome.

The gastrointestinal consequences of a diaphragmatic hernia include displacement and compression of the abdominal organs, leading to impaired digestion and nutrient absorption. Newborns with Fryns syndrome and CDH often present with feeding difficulties and vomiting, leading to failed survival due to these complications. 

Surgical intervention to repair the diaphragmatic defect may be necessary, however, it is often complicated by the associated lung hypoplasia and other congenital anomalies.^1,4

Gastrointestinal malrotation

Gastrointestinal malrotation is another common abnormality in Fryns syndrome. This condition refers to the abnormal rotation and fixation of the intestines during foetal development, resulting in abnormal abdominal positioning of the intestines. Malrotation can lead to several complications, including volvulus (twisting of the intestines), bowel obstruction, and ischemia (reduced blood flow to the intestines).

Children with Fryns syndrome and gastrointestinal malrotation may present with symptoms such as:

• Bilious vomiting
• Abdominal distension
• Feeding intolerance
• Signs of intestinal obstruction

Early diagnosis and surgical correction are crucial to prevent life-threatening complications. The surgical procedure typically involves correcting the malrotation, removing necrotic bowel segments, and establishing proper intestinal positioning to reduce the risk of volvulus recurrence.^1,4

Omphalocele

An omphalocele is a congenital defect in the abdominal wall. In this defect, the intestines and other abdominal organs herniate into the base of the umbilical cord, which is covered by a thin membrane. This defect is commonly associated with Fryns syndrome, and its presence can further complicate the already challenging clinical management of affected infants. Omphalocele occurs in approximately 20-30% of individuals with Fryns syndrome.

The presence of an omphalocele in Fryns syndrome may also indicate additional underlying abnormalities, such as cardiac and neural tube defects, which can be common. Surgical repair of the omphalocele is often necessary, but the timing and approach depend on the size of the defect and the overall condition of the infant. Large omphaloceles may be associated with a higher risk of complications, including infection, respiratory distress, and feeding difficulties.^1,4

Intestinal atresia and stenosis

Intestinal atresia and stenosis are congenital abnormalities characterised by the partial or complete obstruction of the intestines due to the narrowing or absence of a portion of the intestinal lumen. These conditions can affect any part of the GI tract but are most commonly seen in the small intestine. Intestinal atresia or stenosis has been reported in some cases of Fryns syndrome, contributing to the severe digestive complications observed in these patients.

Infants with this condition present with symptoms such as vomiting, abdominal distension, and failure to pass meconium (the first stool passed by a newborn). Surgical intervention is typically required to remove the atretic or stenotic segment of the intestine and restore bowel continuity. 

Early diagnosis and treatment are essential to prevent complications such as bowel perforation, peritonitis, and sepsis.^1,4

Gastroesophageal reflux disease (GERD)

Gastroesophageal reflux disease (GERD) is characterised by the backflow of stomach contents into the oesophagus, causing symptoms such as vomiting, irritability, and feeding difficulties. GERD is a common gastrointestinal issue in infants with Fryns syndrome, likely due to the presence of associated anomalies such as diaphragmatic hernia, abnormal oesophageal motility, and delayed gastric emptying.

Management of GERD in Fryns syndrome may include medical therapies such as acid suppression medications, feeding modifications like food thickener, and positioning strategies to reduce reflux episodes. In severe cases, surgical intervention, such as fundoplication, may be considered to prevent reflux and its complications, including aspiration pneumonia and oesophagitis.^1,4

Anorectal malformations

Anorectal malformations (ARM) are congenital abnormalities involving the anus and rectum, ranging from mild defects, such as anal stenosis where the opening is too narrow, to more severe conditions, like imperforate anus where the anal opening is absent or misplaced. 

Anorectal malformations have been reported in some cases of Fryns syndrome, contributing to the complex gastrointestinal presentation of the syndrome. These malformations can lead to significant challenges in bowel management, including constipation, faecal incontinence, and recurrent infections. 

Surgical correction is often required to create a functional anorectal opening and establish normal bowel function. Long-term follow-up is necessary to monitor bowel habits, prevent complications, and address any associated urological abnormalities that may coexist with anorectal malformations.^1,4

Other gastrointestinal anomalies

In addition to the specific gastrointestinal abnormalities mentioned above, Fryns syndrome may also be associated with other digestive system issues. These may include:

• Hepatobiliary anomalies: liver and biliary tract abnormalities, such as biliary atresia (narrowing or absence of bile ducts) or hepatic fibrosis, which can affect liver function and lead to jaundice and liver disease
• Pancreatic abnormalities: abnormalities in the development or function of the pancreas (pancreatic hypoplasia or agenesis) can impact digestion and nutrient absorption, leading to malnutrition and failure to thrive
• Splenic anomalies: abnormalities of the spleen, including polysplenia (multiple small spleens) or asplenia (absence of the spleen), which can affect immune function and increase susceptibility to infections
• Oesophagal atresia and tracheoesophageal fistula: conditions that involve abnormal connections between the oesophagus and trachea, leading to feeding difficulties, choking, and respiratory complications. Surgical repair is required to separate the oesophagus and trachea and establish a normal swallowing mechanism^1,4

Diagnosis, management and prognosis

Diagnosing gastrointestinal abnormalities in Fryns syndrome typically involves a combination of clinical assessment, imaging studies, and sometimes genetic testing. Prenatal ultrasound may reveal congenital diaphragmatic hernia, omphalocele, or other structural anomalies, prompting further investigation and monitoring. After birth, imaging modalities, such as X-rays, ultrasound, and MRI, can help assess the extent and severity of gastrointestinal abnormalities.⁵

Genetic testing may identify genetic mutations associated with Fryns syndrome and exclude other syndromes with similar manifestations. However, as the genetic basis of Fryns syndrome is not yet fully understood, a definitive genetic diagnosis may not always be possible.

Managing gastrointestinal abnormalities in Fryns syndrome requires a multidisciplinary approach, involving neonatologists, paediatric surgeons, gastroenterologists, and other specialists. The primary goals of management are to address life-threatening anomalies, support nutrition and growth, and improve the quality of life for affected individuals.

Surgical interventions are often necessary to correct GI abnormalities. The timing and extent of surgery depend on the severity of the anomalies, the infant's overall condition, and the presence of associated anomalies. Postoperative care involves monitoring for complications, ensuring adequate respiratory support, and managing feeding and nutritional needs.

Nutritional support is a critical aspect of care for infants with Fryns syndrome, as feeding difficulties and malabsorption are common. Enteral nutrition via feeding tubes may be required to ensure adequate caloric intake and promote growth. In cases of severe malnutrition or feeding intolerance, parenteral nutrition (intravenous nutrition) may be necessary.^1,4

Summary

Fryns Syndrome is a rare disease that affects the lungs, kidneys, brain, heart and digestive system, among others. The prognosis is usually poor, with most children not surviving. Those who do survive often face significant ongoing medical challenges. Support with feeding is generally necessary due to feeding difficulties and poor nutrient absorption. Additionally, surgery may be required to repair structural anomalies.