Fryns syndrome is a rare congenital disorder characterized by multiple birth defects affecting various body systems. It is recognized by a combination of physical features and internal organ malformations that develop before birth. With fewer than 100 cases reported, the syndrome often leads to severe health complications. This condition presents a wide range of anomalies.
Clinical Manifestations
Individuals with Fryns syndrome exhibit a combination of physical features. A hallmark characteristic is a congenital diaphragmatic hernia (CDH), a hole in the diaphragm that allows abdominal organs to move into the chest cavity, impacting lung development. This defect is observed in approximately 95% of cases and can lead to underdeveloped lungs, known as pulmonary hypoplasia, causing severe breathing difficulties immediately after birth.
Craniofacial anomalies are also commonly seen, including widely spaced eyes (hypertelorism), a broad and flat nasal bridge, and a thick nasal tip. Affected individuals may also have a long philtrum, a large mouth (macrostomia), and a small lower jaw (micrognathia). Low-set and abnormally shaped ears are additional frequent findings.
Limb abnormalities are another recurring feature, particularly affecting the fingers and toes. The tips of the digits may be underdeveloped, appearing short, stubby, or having small or absent nails. Other reported limb anomalies include short fingers (brachydactyly) and webbed fingers or toes (syndactyly).
Beyond these external features, Fryns syndrome can involve various internal organ malformations. These may include structural abnormalities of the brain, such as an underdeveloped corpus callosum or fluid accumulation (hydrocephalus). Heart defects, kidney malformations, and issues with the digestive and genitourinary systems are also observed.
Genetic Basis and Inheritance
Fryns syndrome is primarily understood as an autosomal recessive disorder, meaning an individual must inherit two copies of a mutated gene—one from each parent—to develop the condition. Parents who carry one copy of the mutated gene are typically asymptomatic, but they have a 25% chance with each pregnancy of having a child affected by the syndrome.
While the precise genetic causes are still being investigated, variants in the PIGN gene have been identified in some cases of Fryns syndrome. The PIGN gene provides instructions for an enzyme involved in creating a glycophosphatidylinositol (GPI) anchor, which helps attach proteins to the cell membrane. When the PIGN gene is mutated, the GPI anchor cannot properly deliver proteins, disrupting developmental pathways and leading to the syndrome’s signs and symptoms.
Beyond PIGN, researchers are exploring other genes involved in the GPI-anchor biosynthesis pathway, such as PIGV and PIGA, which may also contribute to a phenotype resembling Fryns syndrome. Chromosomal changes, including deletions of genetic material, have also been observed in some individuals with Fryns syndrome-like features. Genetic counseling is an important resource for families, offering insights into inheritance patterns, recurrence risks, and available options for future family planning.
Diagnosis and Management
The diagnosis of Fryns syndrome can occur both before and after birth. Prenatal diagnosis may be suspected through ultrasound examinations that reveal characteristic anomalies such as a diaphragmatic hernia, pulmonary hypoplasia, or other structural malformations. If suspected prenatally, further genetic testing can be performed to confirm the diagnosis by identifying specific gene variants.
Following birth, a diagnosis is based on a comprehensive clinical evaluation of the newborn’s physical features and internal anomalies. Confirmation often involves molecular genetic testing to identify pathogenic variants in genes like PIGN. Clinical criteria for diagnosis include:
The presence of a diaphragmatic defect
Distinctive facial features
Underdeveloped fingers and toes
Pulmonary hypoplasia
At least one other characteristic associated anomaly
A family history consistent with autosomal recessive inheritance
Managing Fryns syndrome requires a multidisciplinary approach due to the wide range of affected body systems. Medical interventions often begin immediately after birth, with surgical repair of the diaphragmatic hernia being a common procedure to address severe respiratory issues. Respiratory support, such as mechanical ventilation or extracorporeal membrane oxygenation (ECMO), may also be necessary to assist lung function.
Supportive care is tailored to individual needs and may involve consultations with various specialists, including cardiologists for heart defects, nephrologists for kidney issues, and neurologists for any brain anomalies or seizures. Developmental services such as physical therapy, occupational therapy, and speech therapy are provided to address developmental delays. Feeding interventions and special education programs are also implemented to support development.
Prognosis and Family Support
The prognosis for individuals with Fryns syndrome varies significantly, largely depending on the severity and combination of malformations present. The presence and severity of congenital diaphragmatic hernia and the extent of lung underdevelopment are major factors influencing outcomes. Many affected infants face severe health challenges and may not survive beyond the neonatal period, often due to respiratory complications.
However, some individuals with Fryns syndrome can survive into childhood and beyond, particularly those with less severe malformations or without a diaphragmatic defect. These survivors often experience severe developmental delays and intellectual disabilities, requiring ongoing comprehensive medical care and supportive therapies. The long-term outlook for these individuals requires sustained medical management and developmental support.
For families navigating a diagnosis of Fryns syndrome, connecting with support groups and advocacy organizations specializing in rare diseases is beneficial. These groups provide a community for shared experiences, emotional support, and access to valuable resources and information. Organizations such as the National Organization for Rare Disorders (NORD) offer assistance programs and connect families with others facing similar challenges, fostering a sense of community and reducing feelings of isolation.