Fryns syndrome

Overview

Fryns Syndrome is a rare, autosomal recessive congenital disorder characterized by multiple birth defects, most notably congenital diaphragmatic hernia (CDH), facial dysmorphism, and distal limb anomalies. First described by Dr. Jean Pierre Fryns in 1979, the syndrome is usually identified in the neonatal period due to severe respiratory distress. Fryns Syndrome often leads to perinatal death, although a few long-term survivors with milder forms have been reported.

Causes

Fryns Syndrome is inherited in an autosomal recessive manner, meaning both parents must carry one copy of the mutated gene for their child to be affected. Although the exact genetic cause is not fully understood, recent studies suggest mutations in genes such as PIGN and others involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis may be implicated. However, no single gene has been definitively identified as the sole cause in all cases.

Symptoms

The clinical features of Fryns Syndrome vary but commonly include a combination of the following abnormalities:

Major Features

• Congenital diaphragmatic hernia (CDH): Leading to severe respiratory distress due to herniation of abdominal organs into the chest cavity.

• Facial dysmorphism:

  • Coarse facial features

  • Broad nasal bridge

  • Hypertelorism (wide-set eyes)

  • Thick lips and micrognathia (small jaw)

• Limb abnormalities:

  • Hypoplasia of distal phalanges and nails

  • Polydactyly (extra fingers or toes) in some cases

Other Features

• Low-set ears

• Cleft lip and/or palate

• Genital anomalies

• Cardiac defects

• Renal malformations (e.g., cystic or hypoplastic kidneys)

• Brain anomalies (e.g., agenesis of the corpus callosum)

• Severe developmental delays in survivors

Diagnosis

Diagnosis of Fryns Syndrome is primarily clinical and made based on the combination of characteristic physical features, especially in the presence of CDH. Key diagnostic steps include:

• Prenatal imaging: Ultrasound or fetal MRI may detect CDH and other anomalies.

• Physical examination: Identification of facial, limb, and internal malformations at birth.

• Radiologic studies: Chest and abdominal imaging to confirm diaphragmatic hernia and organ position.

• Genetic testing: Whole-exome or genome sequencing may reveal mutations in candidate genes, though a specific diagnostic marker may not always be identified.

• Autopsy findings: In fatal cases, postmortem examination helps confirm the diagnosis and differentiate from other syndromes with overlapping features.

Treatment

There is no cure for Fryns Syndrome. Treatment is supportive and focused on managing life-threatening complications, particularly those due to diaphragmatic hernia and pulmonary hypoplasia. Management strategies include:

Neonatal Intensive Care

• Respiratory support, including mechanical ventilation

• Extracorporeal membrane oxygenation (ECMO) in severe cases

• Surgical repair of congenital diaphragmatic hernia

Supportive Therapies

• Cardiac and renal monitoring

• Feeding support, including gastrostomy if needed

• Rehabilitation and developmental therapies for long-term survivors

Genetic Counseling

• Essential for affected families due to autosomal recessive inheritance

• Carrier testing and prenatal diagnosis should be offered to at-risk couples

Prognosis

The prognosis for Fryns Syndrome is generally poor. Most affected infants die in the neonatal period due to severe pulmonary hypoplasia resulting from CDH. However, a few individuals with milder forms have survived beyond infancy and into adolescence or adulthood with significant developmental disabilities. Early diagnosis and multidisciplinary care can improve outcomes for those with less severe manifestations.