Fryns Syndrome

Excerpt

Clinical characteristics: Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia and diaphragm eventration, hypoplasia, or agenesis); characteristic facial appearance (coarse facies, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, long philtrum, low-set and anomalous ears, tented vermilion of the upper lip, wide mouth, and a small jaw); short distal phalanges of the fingers and toes (the nails may also be small); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformations involving the brain, cardiovascular system, gastrointestinal system, and/or genitalia). Survival beyond the neonatal period is rare in those with severe pulmonary hypoplasia and/or multiple malformations. Data on postnatal growth and psychomotor development remain limited; however, severe developmental delays and intellectual disability are common among individuals with PIGN-related Fryns syndrome.

Diagnosis/testing: The clinical diagnosis of Fryns syndrome can be established in a proband based on clinical diagnostic criteria; the molecular diagnosis can be established in a proband with suggestive findings and biallelic loss-of-function variants in PIGN identified by molecular genetic testing.

Management: Treatment of manifestations: For congenital diaphragmatic hernia, the neonate is immediately intubated to prevent inflation of herniated bowel; surgery and/or supportive measures performed as for the general population. Additional anomalies may require consultations and management by a craniofacial specialist, cardiologist, urologist, nephrologist, gastroenterologist, and ophthalmologist. Standardized treatment with anti-seizure medications by an experienced neurologist. Developmental services as needed, including feeding, motor, adaptive, cognitive, and speech-language therapy as well as family and social work support.

Surveillance: Those with successful congenital diaphragmatic hernia repair should be followed in a specialized center with periodic evaluations by a multidisciplinary team (pediatric surgeon, nurse specialist, cardiologist, pulmonologist, nutritionist). Follow up with a craniofacial specialist, cardiologist, urologist, nephrologist, gastroenterologist, and ophthalmologist as needed. Monitor those with seizures as clinically indicated. Assess for new onset of seizures. Monitor developmental progress and educational and family needs.

Genetic counseling: Fryns syndrome is inherited in an autosomal recessive manner. Assuming that both parents are heterozygous for a Fryns syndrome-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If a molecular diagnosis of PIGN-related Fryns syndrome has been established in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.