Fryns Syndrome

Anne Slavotinek

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Fryns Syndrome

Anne Slavotinek, MBBS, PhD.

Author Information and Affiliations

Initial Posting: April 18, 2007; Last Update: December 4, 2025.

Estimated reading time: 32 minutes

Summary

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.

Diagnosis

Diagnostic criteria for Fryns syndrome were reformulated by Lin et al [2005] to include the six proposed criteria described in Suggestive Findings: diaphragmatic defect, characteristic facial appearance, distal digital hypoplasia, pulmonary hypoplasia, at least one characteristic associated anomaly, and family history consistent with autosomal recessive inheritance.

Note: Controversy regarding diagnostic criteria include the extent to which phenotypic deviation from the original case reports of Fryns syndrome is tolerable. For example, individuals with atypical limb manifestations such as ectrodactyly, radial ray aplasia, limb shortening, and multiple pterygia have been labeled as Fryns syndrome by some authors but not by others.

Suggestive Findings

Diagnosis of Fryns syndrome should be suspected in individuals with the following clinical and laboratory findings and family history.

Clinical findings

Diaphragmatic defects including diaphragmatic hernia in any location (most commonly a posterolateral Bochdalek hernia), diaphragmatic eventration, significant diaphragm hypoplasia, or diaphragm agenesis
Characteristic facial appearance with a coarse face, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, a long philtrum, low-set and anomalous ears, a tented vermilion of the upper lip, macrostomia, and a small jaw
Short distal phalanges of the fingers and toes. The nails may also be small.
Pulmonary hypoplasia of a significant degree. This finding can accompany diaphragmatic hernia.
Characteristic associated anomalies (at least one of the following):
- Polyhydramnios
- Orofacial clefting
- Cardiovascular malformation
- Genitourinary malformation
- Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
- Gastrointestinal malformation
- Cloudy corneas and/or microphthalmia

Laboratory findings. Absence of a copy number variant associated with congenital diaphragmatic hernia and other phenotypic features similar to Fryns syndrome, including chromosome deletions at 8p23.1 and mosaic trisomy 1q [Bone et al 2017]. See Differential Diagnosis, Yu et al [2012], and Yu et al [2020] for review.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history and/or absence of consanguinity does not preclude the diagnosis.

Establishing the Diagnosis

The clinical diagnosis of Fryns syndrome can be established in a proband based on clinical diagnostic criteria [Slavotinek 2004, Lin et al 2005]. The molecular diagnosis can be established in proband with suggestive clinical findings and biallelic pathogenic variants in PIGN identified by molecular genetic testing (see Table 1).

Clinical Diagnosis

The clinical diagnosis of Fryns syndrome can be established in a proband with four of the six criteria described in Suggestive Findings (diaphragmatic defect, characteristic facial appearance, distal digital hypoplasia, pulmonary hypoplasia, at least one characteristic associated anomaly, and family history consistent with autosomal recessive inheritance [Lin et al 2005]) and absence of a copy number variant associated with congenital diaphragmatic hernia.

Molecular Diagnosis

The molecular diagnosis of Fryns syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in PIGN identified by molecular genetic testing (see Table 1). Note: Truncating PIGN pathogenic variants are observed more commonly in individuals with clinical features of Fryns syndrome compared to missense variants, which are more often associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) (see Genetically Related Disorders).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic PIGN variants of uncertain significance (or of one known PIGN pathogenic variant and one PIGN variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

Single-gene testing. Sequence analysis of PIGN is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform (1) gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications or (2) exome or genome sequencing (short or long read) to investigate for a second PIGN pathogenic variant including noncoding PIGN pathogenic variants.

A multigene panel that includes PIGN and other genes of interest (see Differential Diagnosis) can identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. However, multigene panels focused on Fryns syndrome and related phenotypes such as congenital diaphragmatic hernia are rare and exome or genome sequencing is recommended. Note: (1) The genes included in a panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely to be involved. Genome sequencing is replacing exome sequencing as the most commonly used test. ACMG and the American Academy of Pediatrics recommend exome/genome sequencing as first- or second-tier diagnostic testing for children with developmental delay, intellectual disability, and/or multiple congenital anomalies [Manickam et al 2021, Rodan et al 2025]. To date, the majority of PIGN pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing; deep intronic variants that are pathogenic have not yet been reported [A Slavotinek, personal observation].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Fryns Syndrome: Molecular Genetic Testing

Gene ¹	Method	Proportion of Pathogenic Variants ² Identified by Method
PIGN	Sequence analysis ³	15 individuals ⁴
PIGN	Gene-targeted deletion/duplication analysis ⁵	1 reported ⁶
Unknown	NA	See footnote 7.

: NA = not applicable
1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Brady et al [2014], McInerney-Leo et al [2016], Alessandri et al [2018], Siavrienė et al [2022], Loong et al [2023], Marchetto et al [2024]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
6.: 5.07-kb deletion with breakpoints in exon 5 and intron 7 (See Table 9.)
7.: Genetic heterogeneity for Fryns syndrome remains highly probable, as some individuals with a clinical diagnosis of Fryns syndrome have not had PIGN pathogenic variants identified [McInerney-Leo et al 2016]. The number of individuals meeting the clinical diagnostic criteria for Fryns syndrome with negative testing for PIGN variants is unknown.

Clinical Characteristics

Clinical Description

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 has been rare. To date, 15 individuals have been identified with biallelic pathogenic variants in PIGN and a clinical diagnosis of Fryns syndrome [Brady et al 2014 (n=1), McInerney-Leo et al 2016 (n=3), Alessandri et al 2018 (n=6), Siavrienė et al 2022 (n=2), Loong et al 2023 (n=1), Marchetto et al 2024 (n=2)]. The following description of the phenotypic features associated with this condition is based on reports of individuals with a clinical diagnosis of Fryns syndrome and those with a molecular diagnosis of Fryns syndrome caused by biallelic pathogenic variants in PIGN.

Table 2.

Fryns Syndrome: Frequency of Select Features

Feature	Proportion of Persons w/PIGN-Related Fryns w/Feature ^1, 2
Polyhydramnios or cystic hygroma / nuchal fold abnormalities	15/17 (88%)
Dysmorphic features	12/17 (71%)
Cleft lip/palate	12/17 (71%)
Cardiac anomalies	12/17 (71%)
Diaphragmatic hernia	11/17 (65%)
Genitourinary anomalies	11/17 (65%)
Distal digital hypoplasia	10/17 (59%)
Structural brain malformations	8/17 (47%)
Gastrointestinal anomalies	8/17 (47%)
Ocular anomalies	2/17 (12%)
Prenatal/neonatal lethal	17/17 (100%)

1.: Only individuals with biallelic PIGN pathogenic variants and a Fryns syndrome phenotype are included [Brady et al 2014 (n=1), McInerney-Leo et al 2016 (n=3), Alessandri et al 2018 (n=6), Sun et al 2021 (n=2), Siavrienė et al 2022 (n=2), Loong et al 2023 (n=1), Marchetto et al 2024 (n=2)].
2.: The frequency of clinical findings associated with bilateral truncating variants in PIGN may have been influenced by ascertainment and the small numbers of reported affected individuals. Diaphragmatic hernia may be less common in those from La Réunion and other nearby islands [Alessandri et al 2018].

Prenatal findings. Congenital diaphragmatic hernia (CDH) and the other malformations found in Fryns syndrome can be visualized by ultrasound in the prenatal period, usually from the second trimester. Previously, the diagnosis of Fryns syndrome was rarely established prior to birth, but detailed imaging and molecular genetic testing are becoming more common during pregnancy and there are several reports of Fryns syndrome being suspected in the prenatal period [Marchetto et al 2024]. Prenatal findings in those with PIGN variants have included nuchal translucency, severe septated cystic hygromata, fetal ascites, a small exomphalos, moderately hyperechogenic bowel, echogenic kidneys, and femur length at the fifth centile [McInerney-Leo et al 2016]. Polyhydramnios has also been noted in the second and third trimester and has been described as "massive" [Alessandri et al 2018].

Diaphragmatic abnormalities / respiratory concerns. CDH is found in more than 90% of individuals with a clinical diagnosis of Fryns syndrome but may be less common in those with Fryns syndrome caused by biallelic truncating variants in PIGN. A unilateral, left-sided Bochdalek hernia is most commonly observed. Diaphragmatic defects were identified in 50% of individuals with PIGN pathogenic variants. Abnormal pulmonary lobation was also noted in one individual.

Dysmorphic findings. The most characteristic facial features for individuals with a clinical diagnosis of Fryns syndrome include a coarse face, wide-spaced eyes with cloudy corneas, a wide and depressed nasal bridge with anteverted nares, anomalous and low-set ears, macrostomia, and a small jaw. Facial features in individuals with PIGN pathogenic variants have been described as coarse with wide-spaced eyes, a small nose, depressed nasal bridge, anteverted nares, a long philtrum, macrostomia, and small, low-set, anomalous ears. Clefts of the lip and palate are common. One fetus had mild axillary pterygia and a synovial cyst attached to the left heel [Brady et al 2014].

Cardiac findings. In individuals diagnosed clinically with Fryns syndrome, ventricular septal defect was the most frequently observed cardiac malformation; atrial septal defects and aortic abnormalities have also been reported. In individuals with PIGN pathogenic variants, tetralogy of Fallot, ventricular septal defect, patent ductus arteriosus, overriding aorta, hypoplastic pulmonary trunk, and an aberrant retroesophageal right subclavian artery have been described. One fetus had a mildly hypoplastic right ventricle with pulmonary valve stenosis and narrowed pulmonary trunk, membranous ventricular septal defect, and an aberrant right subclavian artery arising distal to the left subclavian artery.

Genitourinary findings. Renal pyelectasis, segmental renal dysplasia, micropenis, and cryptorchidism have been reported in individuals with PIGN pathogenic variants. Hypospadias and bicornuate uterus as seen in individuals diagnosed clinically with Fryns syndrome have not been reported to date in association with PIGN pathogenic variants.

Skeletal findings. Small nails and short terminal phalanges of the fingers and toes are frequent and useful diagnostic findings in Fryns syndrome. In individuals with PIGN pathogenic variants, short thumbs and fingers (most pronounced for the fifth finger), short toes, and small or absent nails were reported. Unilateral talipes was also described. One male with PIGN pathogenic variants had oligodactyly of the left foot, with absence of rays three to five, hypoplasia of the remaining toes, and absent toenails [Brady et al 2014], which would be considered atypical for Fryns syndrome. Nail defects were not present in all individuals [McInerney-Leo et al 2016].

Neurologic findings. Structural brain malformations in those with PIGN pathogenic variants have included thinning and shortening of the corpus callosum, hypoplasia of the cerebellar vermis, and agenesis of the olfactory bulbs. Seizures can be present in individuals with Fryns syndrome and biallelic PIGN variants who survive the neonatal period [Alessandri et al 2018]. The seizures may be refractory [Siavrienė et al 2022].

Gastrointestinal findings. Abdominal defects have included exomphalos and intestinal malrotation in individuals with PIGN pathogenic variants. Anal malformations have been noted in individuals with a clinical diagnosis of Fryns syndrome but not reported in those with PIGN pathogenic variants.

Ocular findings. Eye findings previously associated with Fryns syndrome have included central/paracentral corneal clouding that may result from abnormal corneal endothelium, microphthalmia, irregularities of the Bowman layer, thickened posterior lens capsule, and retinal dysplasia [Cursiefen et al 2000]. In those with PIGN pathogenic variants, cloudy corneas and cataracts have been described. One baby with diaphragmatic eventration and a clinical diagnosis of Fryns syndrome was reported to have septo-optic dysplasia, but genetic testing was unable to be performed [Imdadoglu et al 2025].

Development. Developmental delay ranging from relatively mild impairment to severe intellectual disability has been reported in individuals with clinically diagnosed Fryns syndrome. Due to impaired survival, the developmental course is not known for those with Fryns syndrome caused by PIGN pathogenic variants.

Survival/prognosis. The prognosis in Fryns syndrome is influenced by the malformations present and has been described as more favorable in those without CDH than in those with CDH. Survival beyond the neonatal period is uncommon both in those with a clinical diagnosis of Fryns syndrome and in individuals with biallelic PIGN variants (none of whom survived the neonatal period). Of those with PIGN-related Fryns syndrome, two died in utero, four pregnancies were terminated, and nine died after birth (from day 1 to age 2.5 months).

Genotype-Phenotype Correlations

Clinical severity has been postulated to correlate with the predicted functional severity of the PIGN pathogenic variants [Fleming et al 2016].

Biallelic truncating PIGN variants are more likely to be associated with Fryns syndrome compared to allelic phenotypes (see Genetically Related Disorders) and are associated with a significantly increased relative risk of polyhydramnios, congenital anomalies, distal digital hypoplasia, and facial anomalies compared to other genotypes [Loong et al 2023]. Biallelic truncating variants in PIGN are also correlated with an increased mortality in the prenatal and neonatal periods; of 16 individuals with biallelic PIGN variants, two died in utero, six pregnancies were terminated, and four died in the first two months of life [Loong et al 2023].

To date, there have been few functional studies to classify PIGN variants.

Pathogenic PIGN variant p.Ser893Arg was classified as a null variant, as it failed to restore cell surface expression of GPI-anchored complement inhibitors CD59 glycoprotein and complement decay-accelerating factor (also called CD55 or DAF), as well as fluorescein-labeled proaerolysin (FLAER) [Loong et al 2023]. This pathogenic variant is in the last exon of PIGN, and it was hypothesized that this exon contains a functionally important region [Loong et al 2023]. One individual homozygous for p.Ser893Arg was diagnosed with Fryns syndrome [Loong et al 2023].
PIGN pathogenic variant p.Leu311Trp partially restored CD59, DAF, and FLAER expression and thus was considered to demonstrate partial function [Loong et al 2023].
RNA analysis also showed that putative splice site variants c.548_549+6del and c.2180+1G>T were both associated with abnormal transcripts that were likely to result in loss of function [Loong et al 2023].

Prevalence

Fryns syndrome is rare; only approximately 15 individuals with PIGN-related Fryns syndrome have been reported to date. Fryns syndrome was present in seven of 100,000 live births in a French population [Aymé et al 1989], but this prevalence was established before the advent of many genetic testing methodologies.

Fryns syndrome may be the most common autosomal recessive disorder associated with CDH (see Congenital Diaphragmatic Hernia Overview). The incidence of Fryns syndrome has been estimated in large cohorts of individuals with CDH.

In one study, 23 (1.3%) of 1,833 persons with CDH observed over a six-year period were diagnosed with Fryns syndrome [Neville et al 2002].
Earlier studies estimated the incidence of Fryns syndrome at 4%-10% of persons with CDH.

Some individuals with PIGN-related Fryns syndrome have shared ancestry from La Réunion and other Indian Ocean islands, with a founder effect considered likely for a pathogenic intragenic deletion [Alessandri et al 2018] (see Molecular Genetics).

Genetically Related (Allelic) Disorders

Biallelic pathogenic variants in PIGN are known to be associated with three distinct phenotypes: Fryns syndrome [Slavotinek 2004, Lin et al 2005], multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1), and a neurologic presentation [Loong et al 2023] (see Table 3). Clinical severity has been postulated to correlate with the predicted functional severity of the PIGN pathogenic variants [Fleming et al 2016].

Table 3.

PIGN-Related Disorders

Disorder	MOI	Predicted Mechanism of Disease Causation / Class of Variants	Comment
Fryns syndrome	AR	Loss of function Pathogenic variants incl intragenic deletions, splice site variants, frameshift variants, & nonsense variants predicted to cause premature protein truncation or a null allele. ^1, 2 1 person had biallelic missense variants. ³	Biallelic truncating PIGN variants are more likely to be assoc w/Fryns syndrome compared to MCAHS1 & PIGN-related neurologic disorder (see Genotype-Phenotype Correlations). ³
Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) (OMIM 614080)	AR	Loss of function Almost all persons w/MCAHS1 reported to date have biallelic missense variants or compound heterozygosity for a missense variant & a loss-of-function variant. ^1, 2	Both MCAHS1 & Fryns syndrome are assoc w/polyhydramnios, coarse facies w/high-arched palate, depressed nasal bridge, anomalous ears, short phalanges, small nails, & genitourinary, gastrointestinal, & cardiac defects. MCAHS1 can be differentiated from Fryns syndrome by absence of diaphragmatic hernia & a less severe presentation overall w/fewer anomalies. ^2, 3
PIGN-related neurologic disorder	AR	Loss of function Missense variants & loss of function variants, incl splicing, nonsense, & frameshift variants 1 person had an inframe deletion. ³	Neurologic presentation w/developmental delays, hypotonia, & seizures w/mild anomalies but lacking diaphragmatic hernia & other visceral malformations. ³

: AR = autosomal recessive; MOI = mode of inheritance
1.: McInerney-Leo et al [2016]
2.: Alessandri et al [2018]
3.: Loong et al [2023]

Differential Diagnosis

Disorders associated with complex congenital diaphragmatic hernia (CDH) may resemble Fryns syndrome but are distinguishable from Fryns syndrome by their recognizable and distinct patterns of anomalies and an absence of characteristic nail or digital hypoplasia (see Table 4).

Note: There are a number of glycosylphosphatidylinositol (GPI) anchor pathway genes that have been associated with clinical features that overlap with PIGN-related Fryns syndrome. These include PIGA, PIGL, PIGV, and PIGW (see Table 4).

Table 4.

Fryns Syndrome: Differential Diagnosis

Gene(s)	Disorder	MOI	CDH	Other Characteristic Features
Glycosylphosphatidylinositol (GPI) deficiency disorders
PIGA	Multiple congenital anomalies-hypotonia-seizures syndrome 2 (OMIM 300868)	XL	2/16 affected persons ¹	Facial anomalies, brachytelephalangy w/nail hypoplasia, kidney & brain malformations, cleft palate, seizures, hypotonia, ID
PIGL	Mabry syndrome / CHIME syndrome ²	AR	CDH in 1 family ²	Facial anomalies, brachytelephalangy w/nail hypoplasia, kidney & brain malformations, cleft palate, ambiguous genitalia, seizures, hypotonia, ID
PIGV	Hyperphosphatasia w/impaired intellectual development syndrome 1 (OMIM 239300)	AR	1/5 affected persons ³	Facial anomalies, cleft palate, malformations affecting heart, gut & other organs, hypotonia, ID, seizures
PIGW	Glycosylphosphatidylinositol biosynthesis defect 11 (OMIM 616025)	AR	1/6 affected persons ⁴	Facial anomalies, kidney & skeletal anomalies, seizures, ID
Other disorders
ALDH1A2	Diaphragmatic hernia 4 w/cardiovascular defects (OMIM 620025)	AR	CDH in 1 person & diaphragmatic eventration in 3/6 affected persons ⁵	Pulmonary hypoplasia/atresia w/respiratory failure, complex cardiac malformations, macrocephaly, facial anomalies, syndactyly, & other findings that overlap w/Fryns syndrome
BRD4 HDAC8 NIPBL RAD21 SMC1A SMC3	Cornelia de Lange syndrome	AD XL	Rare ⁶	Facial anomalies (high-arched brows &/or synophrys, long eyelashes, short nose w/anteverted nares, small & widely spaced teeth), microcephaly, growth restriction, hirsutism, upper-limb reduction defects, ID, autistic features, self-destructive behavior
EFNB1	Craniofrontonasal syndrome (OMIM 304110)	XL	Rare (can occur in both males & females)	Coronal synostosis, facial anomalies (wide-set eyes, wide nasal tip), skeletal anomalies
FBN1	FBN1-related Marfan syndrome	AD	Rare	Musculoskeletal, cardiac, & ocular defects Diaphragmatic eventration & hernia can be assoc w/early-onset Marfan syndrome. ⁷
GPC3 pathogenic variant or intragenic or whole-gene deletion of GPC3 ⁸	Simpson-Golabi-Behmel syndrome type 1 (SGBS1)	XL	Seen in up to 30% of affected persons	Overgrowth (pre- & postnatal), macrocephaly, dysmorphic features (coarse facies, macrostomia, wide-set eyes, palatal abnormalities), polydactyly, syndactyly, congenital heart defects, mild-to-severe ID, ± structural brain anomalies ⁹ Overgrowth, skeletal anomalies, & tumors distinguish SGBS1 from Fryns syndrome.
LRP2	Donnai-Barrow syndrome	AR	Core feature	Facial anomalies (wide-set eyes, enlarged anterior fontanelle), high myopia, retinal detachment, progressive vision loss, iris coloboma, sensorineural hearing loss, agenesis of corpus callosum, omphalocele, ID
MED12	Hardikar syndrome & nonspecific ID (MED12-Related Disorders)	XL	Variable; reported in 3/7 affected females ¹⁰	Hardikar syndrome: cleft lip &/or cleft palate, biliary anomalies, pigmentary retinopathy, intestinal malrotation, coarctation of aorta, normal cognition Nonspecific ID: wide range of features that often overlap w/ but are not reported to be consistent w/other MED12-related disorders.
NR2F2	Congenital heart defects, multiple types, 4 (OMIM 615779)	AD	Variable	Fryns syndrome-like craniofacial anomalies, cardiovascular malformations, hypoplastic genitalia or cryptorchidism, severe prenatal growth deficiency, ID, talipes equinovarus &/or rocker bottom feet, single umbilical artery
PORCN	PORCN-related developmental disorders (focal dermal hypoplasia, Goltz syndrome)	XL	Rare	Linear skin pigmentation, fat herniation, eye anomalies (incl microphthalmia), small teeth, digital anomalies
RARB STRA6	Matthew-Wood syndrome (PDAC syndrome; syndromic microphthalmia) (OMIM 615524, 601186)	AR AD	Core feature	Micro- & anophthalmia, pulmonary agenesis or hypoplasia, congenital heart defects, genitourinary anomalies Matthew-Wood syndrome is not assoc w/small nails or small digits.
WT1	WT1 disorder ¹¹	AD	Rare	Urogenital anomalies, Wilms tumor, nephropathy, glomerulopathy, disorders of sexual development

: AD = autosomal dominant; AR = autosomal recessive; CDH = congenital diaphragmatic hernia; CHIME = coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies; ID = intellectual disability; MOI = mode of inheritance; PDAC = pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect; XL = X-linked
1.: Bayat et al [2020], Ronzoni et al [2022], Crenshaw et al [2023]
2.: Winter-Paquette et al [2022]
3.: Reynolds et al [2017], Ronzoni et al [2022]
4.: Hendrix et al [2012], Goumy et al [2015]
5.: Beecroft et al [2021], Leon et al [2023]
6.: CDH occurring in Cornelia de Lange syndrome is typically associated with pathogenic variants in NIPBL [Yu et al 2020].
7.: Veiga-Fernández et al [2020]
8.: Contiguous deletions of GPC3 and GPC4 have been identified in multiple families with Simpson-Golabi-Behmel syndrome type 1 (SGBS1). There are case reports of multigene deletions that extend into GPC4, and a single individual with SGBS1 with a pathogenic variant in GPC4; however, the role of GPC4 in SGBS1 pathogenesis remains unknown.
9.: Individuals with SGBS1 are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.
10.: Kao et al [2025]
11.: While various combinations of kidney and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past (the most common being Denys-Drash and Frasier syndromes), those designations are now recognized to be part of a phenotypic continuum and are no longer clinically useful.

Copy Number Variants Associated with Congenital Diaphragmatic Hernia

The differential diagnosis of Fryns syndrome should include copy number variants that are associated with congenital diaphragmatic hernia and other phenotypic features similar to Fryns syndrome, including chromosome deletions at 8p23.1 and mosaic trisomy 1q [Bone et al 2017, Yu et al 2012, Yu et al 2020] (see Table 5).

Table 5.

Copy Number Variants Associated with Congenital Diaphragmatic Hernia

Copy Number Variant	Critical Genes Included	Facial Phenotype	Other Clinical Characteristics (in addition to CDH)
Mosaic tetrasomy 12p (Pallister-Killian syndrome [PKS]) (OMIM 601803)		Coarse w/wide-set eyes, prominent cheeks, & eversion of vermilion of lower lip Considered similar to Fryns syndrome ^1, 2	Sparse hair, ³ syndactyly, & streaky skin pigmentation Hypotonia, seizures, & ID common ² Short distal phalanges of fingers & toes, small nails, cloudy corneas, congenital heart defects, & internal malformations may be seen but are typically less frequent in PKS than in Fryns syndrome.
Mosaic trisomy 1q ⁴		Abnormal ears, micrognathia, microphthalmia	CDH in 6/18 persons (33%) Cleft palate, omphalocele, cardiac, brain, & genitourinary malformations, hypoplastic nails, camptodactyly/syndactyly Growth restriction
1q41-q42 deletion (OMIM 612530)	HLX DISP ⁵		Limb anomalies (e.g., talipes), cleft lip & palate, seizures, ID
4p16.3 deletion (OMIM 194190)	FGFRL1 ⁶	Typical facial anomalies assoc w/Wolf-Hirschhorn syndrome	Skeletal anomalies, ID, growth delays
5q26.1 deletion (OMIM 142340)	NR2F2 ⁵	Fryns syndrome-like craniofacial anomalies	Congenital heart defects, hypoplastic genitalia or cryptorchidism, severe prenatal growth deficiency, ID, talipes equinovarus &/or rocker bottom feet, single umbilical artery
8p23.1 deletion (OMIM 222400)	GATA4 SOX7 ⁵	Mild facial anomalies	Congenital heart defects (e.g., heterotaxy), kidney anomalies, ID
8q22-q23 deletion	ZFPM2 ⁶	Blepharophimosis, widely spaced eyes, epicanthus, flat malar region, thin vermilion of upper lip, downturned corners of mouth, ↓ facial movements	ID w/absent speech, microcephaly, seizures, growth delays ⁶
15q24 deletion (OMIM 613406)		Typical craniofacial features	Malformations of hands & feet, growth delays, ID w/marked speech delay
17q12 deletion		Facial anomalies (See 17q12 Recurrent Deletion Syndrome.)	Structural or functional abnormalities of kidney & urinary tract, MODY, neurodevelopmental or neuropsychiatric disorders
22q11.2 deletion		Typical facial anomalies assoc w/22q11.2 deletion syndrome, cleft palate	Congenital heart defects, skeletal anomalies, immune deficiency, learning difficulties, hypocalcemia CDH is present in 0.8% of persons w/22q11.2 deletion. ⁷

: AD = autosomal dominant; AR = autosomal recessive; CDH = congenital diaphragmatic hernia; ID = intellectual disability; MODY = maturity-onset diabetes of the young
1.: In some persons, only chromosome analysis and/or the inheritance pattern can distinguish between PKS and Fryns syndrome [Veldman et al 2002]. To evaluate for PKS, skin fibroblasts, chorionic villus cells, or amniocytes should be karyotyped because of the phenomenon of tissue-specific mosaicism in which the isochromosome 12p can be present in some cells (e.g., fibroblasts) but not others (e.g., lymphocytes). It is important to note that a normal karyotype or CMA on peripheral blood lymphocytes does not exclude PKS, although CMA may detect PKS when the percentage of tetrasomic cells is relatively high.
2.: Izumi & Krantz [2014]
3.: Sparse hair is characteristic of PKS, in contrast to Fryns syndrome, in which the sisters originally described by Fryns had low hairlines and hypertrichosis.
4.: Bone et al [2017]
5.: Yu et al [2020]
6.: Kuechler et al [2011]
7.: Unolt et al [2017]

Management

No clinical practice guidelines for Fryns syndrome have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual with Fryns syndrome, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Fryns Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
CDH	Chest & abdominal radiographs CT or MRI can also be used to diagnose CDH.
Ears/Nose/Throat	Eval w/ENT &/or craniofacial team if cleft palate is suspected
Cardiovascular	Echocardiogram
Genitourinary	Kidney US exam
Neurologic	Cranial US exam to evaluate for structural brain malformations Neurologic eval & EEG if seizures are suspected Brain MRI exam
Gastrointestinal	Upper gastrointestinal imaging to evaluate for intestinal malrotation
Eyes	Ophthalmology exam incl fundoscopy
Development	Developmental assessment	To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education
Genetic counseling	By genetics professionals ¹	To obtain a pedigree & inform affected persons & families re nature, MOI, & implications of Fryns syndrome to facilitate medical & personal decision making
Family support & resources	By clinicians, wider care team, & family support organizations	Assessment of family & social structure to determine need for: Community or online resources such as Parent to Parent Social work involvement for parental support Home nursing referral

: CDH = congenital diaphragmatic hernia; ENT = ears/nose/throat specialist; MOI = mode of inheritance; US = ultrasound
1.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 7).

Table 7.

Fryns Syndrome: Treatment of Manifestations

Manifestation/ Concern	Treatment	Considerations/Other
CDH	Neonates w/CDH require immediate intubation to prevent inflation of herniated bowel. See Wild et al [2024] for mgmt guidelines for CDH.	CDH in Fryns syndrome may be amenable to prenatal surgical repair. Survival in a controlled trial of open hysterotomy-guided fetal endoscopic tracheal occlusion vs conventional care was not improved; percutaneous fetal endoluminal tracheal occlusion is still being evaluated. ¹ VEGF expression was downregulated in the distal pulmonary epithelium of human fetuses w/CDH & exogenous administration of VEGF may be promising as a therapy. ² To date, there are no reports of VEGF therapy use in infants w/Fryns syndrome.
Cleft palate	Mgmt per craniofacial team
Congenital heart defects	Mgmt per pediatric cardiologist
Genitourinary malformations	Mgmt per pediatric nephrologist &/or urologist
Epilepsy	Standardized treatment w/ASM by experienced neurologist	Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ³
Gastrointestinal malformations	Surgical repair per pediatric gastroenterologist & pediatric surgeon
Cataracts / Other ocular anomalies	Mgmt per ophthalmologist
Developmental delay	Developmental services as needed incl feeding, motor, adaptive, cognitive, & speech-language
Family/Community	Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.	Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics.

: ASM = anti-seizure medication; CDH = congenital diaphragmatic hernia; VEGF = vascular endothelial growth factor
1.: Losty [2014]
2.: Loukogeorgakis et al [2025]
3.: Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

Table 8.

Fryns Syndrome: Recommended Surveillance

System/Concern	Evaluation	Frequency
Following successful CDH repair	Evals by pediatric surgeon, nurse specialist, cardiologist, pulmonologist, & nutritionist	As recommended by specialist(s)
Cleft palate	Follow up w/craniofacial specialist
Congenital heart defects	Follow up w/cardiologist
Genitourinary malformations	Follow up w/nephrologist or pediatric urologist
Neurologic	Monitor those w/seizures as clinically indicated; assess for new onset of seizures.	At each visit
Development	Monitor developmental progress & educational needs.
Gastrointestinal malformations	Follow up w/gastroenterologist
Ocular anomalies	Ophthalmology eval
Family/Community	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

: CDH = congenital diaphragmatic hernia

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Many different treatments are currently being evaluated for the management of congenital diaphragmatic hernia.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Fryns syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected child are presumed to be heterozygous for a Fryns syndrome-causing variant.
If a molecular diagnosis of PIGN-related Fryns syndrome has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a PIGN pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
- A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
- Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with Fryns syndrome are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a Fryns syndrome-causing variant.

Carrier Detection

Carrier testing for at-risk relatives is possible if a molecular diagnosis of PIGN-related Fryns syndrome has been established in an affected family member.

Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with Fryns syndrome and young adults who are at risk of being carriers.
If the reproductive partner of an individual known to be heterozygous for a PIGN pathogenic variant has ancestry from La Réunion or other Indian Ocean islands, they may choose to have carrier screening for a PIGN intragenic deletion, which is considered likely to be a founder variant in this population [Alessandri et al 2018].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

A Priori High-Risk Pregnancy – Sib with Fryns Syndrome

Molecular genetic testing. If a molecular diagnosis of PIGN-related Fryns syndrome has been established in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound examination. Fryns syndrome has been diagnosed by two- and three-dimensional ultrasonography and fetal magnetic resonance imaging (MRI). Three-dimensional scans may also allow a more detailed assessment of facial features. Findings on ultrasound examination in addition to a diaphragmatic hernia and pulmonary hypoplasia that may suggest a diagnosis of Fryns syndrome include polyhydramnios in the second or third trimester, nuchal translucency / cystic hygroma, hyperechogenic bowel, echogenic kidneys, cardiac malformations, kidney cysts, hydroureter, ventricular dilatation / hydrocephalus, agenesis of the corpus callosum, and Dandy-Walker malformation. Thus, a detailed sonographic examination of the fetus with echocardiography and measurement of growth parameters and amniotic fluid levels is recommended. Fetal MRI can be considered to confirm the presence of a diaphragmatic defect and to search for other anomalies.

A Priori High-Risk Pregnancy – Sib with Possible Fryns Syndrome

Chromosome analysis. If the possibility of a chromosomal syndrome associated with CDH and additional major malformations/dysmorphology has not been ruled out in a sib with possible Fryns syndrome, chromosome analysis and CMA of fetal cells may both be warranted.

A Priori Low-Risk Pregnancy – No Family History of Fryns Syndrome

A routine prenatal ultrasound examination may identify a diaphragmatic hernia and/or other malformations, raising the possibility of Fryns syndrome in a fetus not known to be at increased risk. (Note: In the absence of a family history of Fryns syndrome, it is possible that Fryns syndrome-related features will be missed on prenatal ultrasound examination.) In such situations, chromosome analysis, including karyotype (for evaluation for mosaicism for isochromosome 12p or tetrasomy 12p associated with Pallister-Killian syndrome) and CMA (for other chromosome abnormalities) (see A Priori High-Risk Pregnancy – Sib with Possible Fryns Syndrome) is strongly recommended. Confirmation of the diagnosis of Fryns syndrome, however, may not be possible prior to delivery unless biallelic PIGN pathogenic variants are identified on prenatal molecular genetic testing. After delivery, a complete physical examination and other imaging studies and evaluations can be undertaken.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

CDH International
Email: info@cdhi.org
cdhi.org
Compassionate Friends
Supporting Family After a Child Dies
Phone: 877-969-0010
compassionatefriends.org
Helping After Neonatal Death (HAND)
Phone: 650-367-6993
Email: info@handsupport.org
handonline.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Fryns Syndrome: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
PIGN	18q21.33	GPI ethanolamine phosphate transferase 1	PIGN @ LOVD	PIGN	PIGN

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Fryns Syndrome (View All in OMIM)

229850	FRYNS SYNDROME; FRNS
606097	PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS N PROTEIN; PIGN

Molecular Pathogenesis

PGIN encodes GPI ethanolamine phosphate transferase 1, which is one of a family of proteins responsible for the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors proteins to the outer leaflet of the lipid bilayer of the cell membrane, enabling diverse cellular functions including signal transduction, cell adhesion, and antigen presentation [Brady et al 2014, McInerney-Leo et al 2016, Kinoshita 2020]. GPI ethanolamine phosphate transferase 1 transfers phosphoethanolamine (EtNP) from phosphatidylethanolamine to the second position of the first alpha-4 linked mannose, generating Manα6(EtNP)2Manα4GlcN-(acyl)phosphatidylinositol [Hong et al 1999]. The defective GPI anchor proteins (GPI-APs) caused by pathogenic variants in PIGN and other genes involved in GPI anchor biosynthesis result in cellular mislocalization of GPI-APs with subsequent impairment of cell function [Brady et al 2014, Kinoshita 2020]. Aberrant GPI-APs can also disrupt critical developmental pathways such as Wnt signaling, Hedgehog signaling, and BMP signaling [McInerney-Leo et al 2016].

Mechanism of disease causation. Fryns syndrome caused by PIGN variants is considered to result from loss of function. Pathogenic variants have included intragenic deletions, splice site variants, and frameshift variants predicted to cause premature protein truncation or a null allele.

Table 9.

PIGN Pathogenic Variants Referenced in This GeneReview

Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NM_176787.5 NP_789744.1	c.329_549+1907del5064	p.Ser110ArgfsTer15	Likely founder variant in those from La Réunion & other Indian Ocean islands [Alessandri et al 2018]
NM_176787.5	c.548_549+6del	--	Likely to result in loss of function [Loong et al 2023]
NM_176787.5 NP_789744.1	c.932T>G	p.Leu311Trp	Demonstrated partial function [Loong et al 2023]
NM_176787.5	c.2180+1G>T	--	Likely to result in loss of function [Loong et al 2023]
NM_176787.5 NP_789744.1	c.2679C>G	p.Ser893Arg	Classified as null variant [Loong et al 2023]

: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Revision History

4 December 2025 (sw) Comprehensive update posted live
17 September 2020 (sw) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
1 June 2010 (me) Comprehensive update posted live
18 April 2007 (me) Review posted live
8 January 2007 (ams) Original submission

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Slavotinek A. Fryns Syndrome. 2007 Apr 18 [Updated 2025 Dec 4]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.
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GeneReviews® [Internet].

Fryns Syndrome

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

Diagnosis

Suggestive Findings

Establishing the Diagnosis

Clinical Diagnosis

Molecular Diagnosis

Option 1

Option 2

Table 1.

Clinical Characteristics

Clinical Description

Table 2.

Genotype-Phenotype Correlations

Prevalence

Genetically Related (Allelic) Disorders

Table 3.

Differential Diagnosis

Table 4.

Copy Number Variants Associated with Congenital Diaphragmatic Hernia

Table 5.

Management

Evaluations Following Initial Diagnosis

Table 6.

Treatment of Manifestations

Table 7.

Surveillance

Table 8.

Evaluation of Relatives at Risk

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Carrier Detection

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

A Priori High-Risk Pregnancy – Sib with Fryns Syndrome

A Priori High-Risk Pregnancy – Sib with Possible Fryns Syndrome

A Priori Low-Risk Pregnancy – No Family History of Fryns Syndrome

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

Table 9.

Chapter Notes

Revision History

References

Literature Cited

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