Fryns syndrome (ORPHA:2059)
A rare multiple congenital anomaly syndrome characterized by congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia, distal limb hypoplasia and facial anomalies in addition to variable expression of additional birth defects.
Epidemiology
The birth prevalence of Fryns syndrome (FS) has been estimated at 1/14,000 births. FS has been estimated to be present in 4-10% of patients with CDH.
Clinical description
Polyhydramnios is often noted during pregnancy and neonates present with a spectrum of anomalies at birth. The classical features of FS include CDH (unilateral in 75% of cases) together with the associated complications such as lung hypoplasia and left heart hypoplasia. Craniofacial anomalies include a 'coarse' facial appearance, widely spaced eyes, microphthalmia, low-set and anomalous ears, a wide and flat nasal bridge, thick nasal tip with anteverted nares, long philtrum, tented vermilion of the upper lip, wide mouth and small jaw. Distal limb hypoplasia is characteristic and includes short and broad hands, short digits and short terminal phalanges, small or absent nails, and clinodactyly. The thorax can be small with widely spaced nipples. Brain anomalies (ventricular dilation, hydrocephalus, Dandy-Walker malformation) and cardiac malformations (atrial and ventricular septal defects, aortic abnormalities) are reported frequently in affected individuals. Additional anomalies include orofacial clefting, malrotation of the gastrointestinal tract, anal atresia, omphalocele, uro-genital anomalies (renal cysts, ureteral dilation and cryptorchidism), talipes and broad clavicles. In those that survive the neonatal period, severe developmental delay and intellectual disability have been reported.
Etiology
The etiology in many cases is not clear. Several recurrent chromosome aberrations, including microdeletions involving chromosome bands 15q26.2 and 8p23.1, have been reported in probands with clinical presentations similar to FS, but the causal genes in these intervals are yet to be identified. More recently, bi-alleic variants in PIGN have been associated with a FS phenotype. Variants in other genes involved in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway (PIGV and PIGA) have also been identified in several patients with a phenotype overlapping FS.
Diagnostic methods
Diagnosis is primarily based on clinical findings and six clinical criteria have been suggested, comprising CDH, pulmonary hypoplasia, characteristic facial anomalies, distal limb hypoplasia, at least one other characteristic additional anomaly and a family history consistent with autosomal recessive inheritance. FS is classically associated with a normal karyotype; thus array comparative genomic hybridization and copy number variation analysis can be useful in differentiating FS from other chromosomal conditions. Exome sequencing (particularly for PIGN variants or genes of the GPI-anchor biosynthesis pathway), skin biopsy and karyotyping can also be performed to rule out overlapping conditions.
Differential diagnosis
Differential diagnosis includes Donnai-Barrow syndrome, Matthew-Wood syndrome, Simpson-Golabi-Behmel syndrome, craniofrontonasal syndrome, Cornelia de Lange syndrome, tetrasomy 12p, distal monosomy 15q and other chromosome aberrations. Bi-allelic variants in PIGN can also cause multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1) that is not typically associated with CDH.
Antenatal diagnosis
CDH and the other anomalies associated with FS can be diagnosed by ultrasound scanning during a pregnancy.
Genetic counseling
Classically, FS has been inherited as an autosomal recessive (AR) condition. If no cytogenetic or molecular defect is identified, ultrasound scanning can be recommended in future pregnancies of at-risk couples.
Management and treatment
Management is multidisciplinary and may necessitate pediatric specialists in neurology, cardiology, gastroenterology, and nephrology as well as clinical geneticists, developmental pediatricians and regular follow-up in a specialized center. Supportive treatments are directed at the management of the CDH and include extra-corporeal membrane oxygenation (ECMO), nitric oxide and surfactant as therapies for persistent pulmonary hypertension. Other malformations are managed with standard treatment.
Prognosis
Prognosis depends on the severity of the anomalies present, although it is generally guarded with survival beyond the neonatal period being relatively rare. Patients without diaphragmatic defects have a better prognosis.

                            Last update: 
                            July 2021


                            - Expert reviewer(s): 
                            Pr Anne SLAVOTINEK