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A prenatal ultrasound at 22 weeks shows a left-sided diaphragmatic hernia, polyhydramnios, and cystic hygroma. The fetus has shortened distal phalanges of fingers and toes on imaging. After delivery, the neonate has coarse facial features, cleft lip and palate, and severe pulmonary hypoplasia.
AR; PIGN and PIGA (genes in the GPI-anchor biosynthesis pathway) account for a subset; molecular cause unidentified in many clinically diagnosed cases. Diagnosis remains primarily clinical.
Diagnosis requires ≥4 of 6 cardinal features:
- Diaphragmatic defect (CDH, hernia, eventration, hypoplasia): present in ~90%
- Distal limb hypoplasia: small distal phalanges, especially nails
- Pulmonary hypoplasia: major cause of perinatal mortality
- Coarse facies: broad nasal bridge, thick alveolar ridges, macrostomia, large mouth
- Cloudy corneas / anterior chamber anomalies
- Either: positive family history OR characteristic associated anomalies (cardiac, renal, GU, CNS)
- Clinical (Lin-Fryns criteria)
- Prenatal: CDH + cystic hygroma + distal limb anomalies on US should prompt suspicion
- Karyotype/CMA + multigene panel including PIGN/PIGA to exclude mimics
- Diaphragm-CDH + GPI-anchor disorder differential
- Isolated congenital diaphragmatic hernia: no associated anomalies
- Pallister-Killian syndrome (mosaic 12p tetrasomy): CDH + characteristic facies; karyotype/FISH from fibroblasts (mosaic)
- Donnai-Barrow syndrome: CDH + ocular and ear anomalies + agenesis of corpus callosum
- Cornelia de Lange syndrome: overlapping limb and facial features but no CDH
- Prognosis is poor: most affected infants die in the perinatal period from pulmonary hypoplasia
- Survivors have severe intellectual disability and need lifelong support
- Family planning: AR with ~25% recurrence (when PIGN/PIGA identified); offer prenatal diagnosis
"Fryns = Frying pan-flat distal phalanges + diaphragmatic Failure + Facies coarse": three F's that capture the major recognition features.