Clinical characteristics: Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, 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. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common.
Diagnosis/testing: The clinical diagnosis of Fryns syndrome can be established in a proband based on six proposed criteria (diaphragmatic defect, characteristic facial appearance, distal digital hypoplasia, pulmonary hypoplasia, at least one characteristic associated anomaly, and a family history consistent with autosomal recessive inheritance). The molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic 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 as for the general population. Standardized treatment with anti-seizure medications by an experienced neurologist. Additional anomalies may require consultations and management by ophthalmology, cardiology gastroenterology, nephrology, urology, and craniofacial specialists. Developmental services as needed including feeding, motor, adaptive, cognitive, and speech/language therapy.
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). Monitor those with seizures as clinically indicated.
Assess for new onset of seizures. Monitor developmental progress and educational needs. Follow up with ophthalmology, cardiology, gastroenterology, nephrology, urology, and craniofacial specialists as needed.
Genetic counseling: Fryns syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PIGN pathogenic variants in the family are known.
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