Fryns Syndrome

Anne Slavotinek

Fryns Syndrome

Slavotinek A.

Publication Details

Estimated reading time: 23 minutes

Summary

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.

Diagnosis

Diagnostic criteria for Fryns syndrome were reformulated by Lin et al [2005] to include the six proposed clinical 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: Controversies regarding diagnostic criteria include the extent to which phenotypic deviation from the original case reports of Fryns syndrome is tolerable. For example, cases 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.

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, wide mouth, 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 clinical finding can accompany diaphragmatic hernia.
Characteristic associated anomalies including at least one of the following:
- Polyhydramnios
- Cloudy corneas and/or microphthalmia
- Orofacial clefting
- Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
- Cardiovascular malformation
- Renal dysplasia / renal cortical cysts
- Gastrointestinal malformation
- Genital malformation
Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Laboratory findings. Absence of a copy number variant associated with congenital diaphragmatic hernia, including chromosome deletions at 15q26.2 and 8p23.1 and mosaic trisomy 1q [Bone et al 2017]. See Differential Diagnosis and Yu et al [2012] and Yu et al [2020] for review.

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], or the molecular diagnosis can be established in proband with suggestive findings and biallelic pathogenic variants in PIGN identified by molecular genetic testing (see Table 1).

Clinical 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.

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: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any 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.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings can be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with multiple congenital anomalies are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of PIGN is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. 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 gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

A multigene panel that includes PIGN and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the 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

When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is most likely to be used. Exome sequencing is most common; genome sequencing is also possible.

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

Table 1.

Molecular Genetic Testing Used in Fryns Syndrome

Clinical Characteristics

Clinical Description

The term "Fryns syndrome" was first used to describe the clinical findings in two stillborn female sibs, each with a coarse facial appearance, cloudy corneas, a cleft of the soft palate, a small thorax with hypoplastic nipples, proximal insertion of the thumbs, hypoplasia of the terminal phalanges and nails, lung hypoplasia, and congenital diaphragmatic hernia (CDH) with bilateral agenesis of the posterolateral diaphragms [Fryns et al 1979]. As both of the sibs were stillborn, Fryns syndrome was initially considered likely to be a lethal disorder. It is now known that this is not so. However, the natural history of Fryns syndrome is difficult to determine because of the high early mortality. In addition, earlier reports of Fryns syndrome may have mislabeled individuals who either did not have chromosome analysis or did not have adequate laboratory studies to evaluate for copy number variants associated with a Fryns syndrome-like phenotype (see Differential Diagnosis).

Recently, biallelic variants in PIGN have been identified in individuals who met the strict diagnostic criteria for Fryns syndrome [Brady et al 2014, McInerney-Leo et al 2016, Alessandri et al 2018] as described in Establishing the Diagnosis [Lin et al 2005]. As only ten individuals have been identified with biallelic pathogenic variants in PIGN and a Fryns syndrome phenotype [Alessandri et al 2018], the extent of the contribution of this gene to the etiology of Fryns syndrome is not yet known; in addition, it is also unclear if the clinical description of this syndrome should be modified based on the phenotype associated with PIGN variants.

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 [Brady et al 2014, McInerney-Leo et al 2016, Alessandri et al 2018].

Table 2.

Fryns Syndrome: Frequency of Select Features

Prenatal findings. CDH and the other malformations found in Fryns syndrome can be visualized by ultrasound scan in the prenatal period, usually from the second trimester, but the diagnosis of Fryns syndrome is rarely established prior to birth [Peron et al 2014] and requires appropriate cytogenetic and molecular genetic testing. 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].

Survival/prognosis. The prognosis in Fryns syndrome is influenced by the malformations present and has been described as more promising 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). No sex differences have been noted.

Diaphragmatic abnormality / respiratory concerns. CDH is found in more than 90% of individuals with a clinical diagnosis of Fryns syndrome [Peron et al 2014]. 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.

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.

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 Bowman's 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.

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 retro-esophageal 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.

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.

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.

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 flat 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, flat nasal bridge, anteverted nares, a long philtrum, macrostomia, and small low-set anomalous ears. Clefts of the lip and palate have also been noted. One fetus had mild axillary pterygia and a synovial cyst attached to the left heel [Brady et al 2014].

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].

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.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for PIGN-related Fryns syndrome have been identified.

Prevalence

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. No more recent prevalence estimates have been published.

Fryns syndrome may be the most common autosomal recessive disorder associated with congenital diaphragmatic hernia (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 also known to cause multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1) (OMIM 614080). Both MCAHS1 and Fryns syndrome are associated with polyhydramnios, coarse facies with a high-arched palate, flat nasal bridge and anomalous ears, short phalanges and small nails, and genitourinary, gastrointestinal, and cardiac defects. MCAHS1 can be differentiated from Fryns syndrome by the absence of diaphragmatic hernia and a less severe presentation [Alessandri et al 2018].

Almost all known MCAHS1-related PIGN pathogenic variants are missense or compound missense/loss-of-function variants, whereas PIGN pathogenic variants associated with Fryns syndrome are predicted to result in loss of function [McInerney-Leo et al 2016, Alessandri et al 2018].

Differential Diagnosis

Disorders associated with complex congenital diaphragmatic hernia (CDH) may resemble Fryns syndrome, but are distinguishable from Fryns syndrome by their recognizable patterns of anomalies and an absence of characteristic nail or digital hypoplasia. See Table 3.

Table 3.

Monogenic Disorders Associated with Complex Congenital Diaphragmatic Hernia of Interest in the Differential Diagnosis of Fryns Syndrome

Table 4.

Chromosome Anomalies Associated With Congenital Diaphragmatic Hernia and Additional Major Malformations/Dysmorphology

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 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Fryns Syndrome

Treatment of Manifestations

Table 6.

Treatment of Manifestations in Individuals with Fryns Syndrome

Surveillance

Table 7.

Recommended Surveillance for Individuals with Fryns Syndrome

Evaluation of Relatives at Risk

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

Pregnancy Management

Pregnancies are managed according to the malformations that have been diagnosed. One literature review concluded that fetoscopic endoluminal tracheal occlusion used as a prenatal interventional strategy can increase survival in cases with severe CDH [Cundy et al 2014], although this technique has most frequently been used for isolated CDH rather than Fryns syndrome.

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 caused by pathogenic variants in PIGN is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Fryns syndrome-causing pathogenic variant based on family history).
If biallelic PIGN pathogenic variants have been identified in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a PIGN pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

Assuming that both parent are heterozygous for a Fryns syndrome-causing pathogenic 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. Individuals with Fryns syndrome have not typically been 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 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives is possible if biallelic PIGN pathogenic variants have been identified in an affected family member.

Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk, clarification of carrier status, 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 biallelic PIGN pathogenic variants have been identified 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). Newer, 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, renal 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. However, it is possible that Fryns syndrome will be missed during pregnancy without a prior index case [Peron et al 2014].

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. 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 [Peron et al 2014], pending evaluation with complete physical examination and other imaging studies.

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)
PO Box 341
Los Gatos CA 95031
Phone: 888-908-HAND (4263)
www.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

Table B.

OMIM Entries for Fryns Syndrome (View All in OMIM)

Molecular Pathogenesis

PIGN 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]. PIGN encodes GPI-ethanolaminetransferase I (ETI) and transfers EtNP from phosphatidylethanolamine to the 2-position of the first, α4 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 and references therein].

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 8.

Notable PIGN Pathogenic Variants

Chapter Notes

Revision History

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

References

Literature Cited

Alessandri JL, Gordon CT, Jacquemont ML, Gruchy N, Ajeawung NF, Benoist G, Oufadem M, Chebil A, Duffourd Y, Dumont C, Gérard M, Kuentz P, Jouan T, Filippini F, Nguyen TTM, Alibeu O, Bole-Feysot C, Nitschké P, Omarjee A, Ramful D, Randrianaivo H, Doray B, Faivre L, Amiel J, Campeau PM, Thevenon J. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome. Eur J Hum Genet. 2018;26:340–9. [PMC free article: PMC5839001] [PubMed: 29330547]
Aymé S, Julian C, Gambarelli D, Mariotti B, Luciani A, Sudan N, Maurin N, Philip N, Serville F, Carles D, Rolland M, Giraud F. Fryns syndrome: report on 8 new cases. Clin Genet. 1989;35:191–201. [PubMed: 2650934]
Bone KM, Chernos JE, Perrier R, Innes AM, Bernier FP, McLeod R, Thomas MA. Mosaic trisomy 1q: a recurring chromosome anomaly that is a diagnostic challenge and is associated with a Fryns-like phenotype. Prenat Diagn. 2017;37:602–10. [PubMed: 28437579]
Brady PD, Moerman P, De Catte L, Deprest J, Devriendt K, Vermeesch JR. Exome sequencing identifies a recessive PIGN splice site mutation as a cause of syndromic congenital diaphragmatic hernia. Eur J Med Genet. 2014;57:487–93. [PubMed: 24852103]
Cundy TP, Gardener GJ, Andersen CC, Kirby CP, McBride CA, Teague WJ. Fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia in Australia and New Zealand: are we willing, able, both or neither? J Paediatr Child Health. 2014;50:226–33. [PubMed: 24372875]
Cursiefen C, Schlötzer-Schrehardt U, Holbach LM, Vieth M, Kuchelmeister K, Stolte M. Ocular findings in Fryns syndrome. Acta Ophthalmol Scand. 2000;78:710–3. [PubMed: 11167240]
Fryns JP, Moerman F, Goddeeris P, Bossuyt C, Van den Berghe H. A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Hum Genet. 1979;50:65–70. [PubMed: 381161]
Goumy C, Laffargue F, Eymard-Pierre E, Kemeny S, Gay-Bellile M, Gouas L, Gallot D, Francannet C, Tchirkov A, Pebrel-Richard C, Vago P. Congenital diaphragmatic hernia may be associated with 17q12 microdeletion syndrome. Am J Med Genet A. 2015;167A:250–3. [PubMed: 25425496]
Hong Y, Maeda Y, Watanabe R, Ohishi K, Mishkind M, Riezman H, Kinoshita T. Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol. J Biol Chem. 1999;274:35099–106. [PubMed: 10574991]
Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
Izumi K, Krantz ID. Pallister-Killian syndrome. Am J Med Genet C Semin Med Genet. 2014;166C:406–13. [PubMed: 25425112]
Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
Kinoshita T. Biosynthesis and biology of mammalian GPI-anchored proteins. Open Biol. 2020;10:190290. [PMC free article: PMC7125958] [PubMed: 32156170]
Kuechler A, Buysse K, Clayton-Smith J, Le Caignec C, David A, Engels H, Kohlhase J, Mari F, Mortier G, Renieri A, Wieczorek D. Five patients with novel overlapping interstitial deletions in 8q22.2q22.3. Am J Med Genet A. 2011;155A:1857–64. [PubMed: 21739578]
Lin AE, Pober BR, Mullen MP, Slavotinek AM. Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells? Am J Med Genet A. 2005;139:186–93. [PubMed: 16283673]
Losty PD. Congenital diaphragmatic hernia: where and what is the evidence? Semin Pediatr Surg. 2014;23:278–82. [PubMed: 25459012]
McInerney-Leo AM, Harris JE, Gattas M, Peach EE, Sinnott S, Dudding-Byth T, Rajagopalan S, Barnett CP, Anderson LK, Wheeler L, Brown MA, Leo PJ, Wicking C, Duncan EL. Fryns syndrome associated with recessive mutations in PIGN in two separate families. Hum Mutat. 2016;37:695–702. [PubMed: 27038415]
Neville HL, Jaksic T, Wilson JM, Lally PA, Hardin WD Jr, Hirschl RB, Langham MR Jr, Lally KP. Fryns syndrome in children with congenital diaphragmatic hernia. J Pediatr Surg. 2002;37:1685–7. [PubMed: 12483630]
Peron A, Bedeschi MF, Fabietti I, Baffero GM, Fogliani R, Ciralli F, Mosca F, Rizzuti T, Leva E, Lalatta F. Prenatal and postnatal findings in five cases of Fryns syndrome. Prenat Diagn. 2014;34:1227–30. [PubMed: 24996149]
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
Slavotinek AM. Fryns syndrome: a review of the phenotype and diagnostic guidelines. Am J Med Genet A. 2004;124A:427–33. [PubMed: 14735597]
Unolt M, DiCairano L, Schlechtweg K, Barry J, Howell L, Kasperski S, Nance M, Adzick NS, Zackai EH, McDonald-McGinn DM. Congenital diaphragmatic hernia in 22q11.2 deletion syndrome. Am J Med Genet A. 2017;173:135–42. [PubMed: 27682988]
Veiga-Fernández A, Joigneau Prieto L, Álvarez T, Ruiz Y, Pérez R, Gámez F, Ortega Abad V, Yllana F, De León-Luis J. Perinatal diagnosis and management of early-onset Marfan syndrome: case report and systematic review. J Matern Fetal Neonatal Med. 2020;33:2493–504. [PubMed: 30652519]
Veldman A, Schlosser R, Allendorf A, Fischer D, Heller K, Schaeff B, Fuchs S. Bilateral congenital diaphragmatic hernia: differentiation between Pallister-Killian and Fryns syndromes. Am J Med Genet. 2002;111:86–7. [PubMed: 12124742]
Yu L, Hernan RR, Wynn J, Chung WK. The influence of genetics in congenital diaphragmatic hernia. Semin Perinatol. 2020;44:151169. [PMC free article: PMC6994346] [PubMed: 31443905]
Yu L, Wynn J, Ma L, Guha S, Mychaliska GB, Crombleholme TM, Azarow KS, Lim FY, Chung DH, Potoka D, Warner BW, Bucher B, LeDuc CA, Costa K, Stolar C, Aspelund G, Arkovitz MS, Chung WK. De novo copy number variants are associated with congenital diaphragmatic hernia. J Med Genet. 2012;49:650–9. [PMC free article: PMC3696999] [PubMed: 23054247]

Publication Details

Author Information and Affiliations

Anne Slavotinek, MBBS, PhD

Professor of Clinical Pediatrics
Division of Medical Genetics
Department of Pediatrics
University of California San Francisco
San Francisco, California

Publication History

Initial Posting: April 18, 2007; Last Update: September 17, 2020.

Copyright

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Publisher

University of Washington, Seattle, Seattle (WA)

NLM Citation

Slavotinek A. Fryns Syndrome. 2007 Apr 18 [Updated 2020 Sep 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Gene ¹	Method	Proportion of Pathogenic Variants ² Detectable by Method
PIGN	Sequence analysis ³	10 individuals ⁴
PIGN	Gene-targeted deletion/duplication analysis ⁵	1 reported ⁶
Unknown	NA	See footnote 7.

Feature	Proportion of Persons w/Feature		Comment
Feature	Persons w/a clinical diagnosis of Fryns syndrome ¹	Persons w/biallelic PIGN pathogenic variants ²	Comment
Polyhydramnios	56%	6/10
Diaphragmatic hernia	>90%	7/10
Structural brain malformations	88%	3/10
Ocular anomalies	>6% ³	2/6
Cardiac anomalies	>40% ³	6/10
Gastrointestinal anomalies	>15% ³	Not established
Genitourinary anomalies	>25% ³	5/10
Dysmorphic features	>55% ³	8/10
Distal digital hypoplasia	>60% ³	8/10
Developmental delay	Unknown due to poor survival	NA	Perinatal death in 10/10 persons w/PIGN pathogenic variants

Gene(s)	Differential Disorder	MOI	CDH ¹	Other Characteristic Features
GPC3 GPC4 ²	Simpson-Golabi-Behmel syndrome type 1 (SGBS1)	XL	Rare	Overgrowth (pre- & postnatal), macrocephaly, dysmorphic features (coarse facies, macrostomia, wide-set eyes, palatal abnormalities), polydactyly, syndactyly, CHD & mild-to-severe ID ± structural brain anomalies Overgrowth, skeletal anomalies, & tumors distinguish SGBS1 from Fryns syndrome. ³
EFNB1	Craniofrontonasal syndrome (CFNS) (OMIM 304110)	XL	Rare (can occur in both males & females w/CFNS)	Coronal synostosis, facial anomalies (wide-set eyes, wide nasal tip), & skeletal anomalies
PORCN	Focal dermal hypoplasia (Goltz syndrome)	XL	Rare	Linear skin pigmentation, fat herniation, eye anomalies incl microphthalmia, small teeth, digital anomalies
BRD4 HDAC8 NIPBL ⁴ RAD21 SMC1A SMC3	Cornelia de Lange syndrome (CdLS)	AD XL	Rare	Facial anomalies (high-arched &/or joined eyebrows, 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
WT1	WT1 disorder (incl Denys-Drash syndrome, Frasier syndrome, Meacham syndrome) ⁵	AD	Rare	Urogenital anomalies, Wilms tumor, nephropathy, glomerulopathy, disorders of sexual development
FBN1	Marfan syndrome	AD	Rare	Musculoskeletal, cardiac, & ocular defects; diaphragmatic eventration & hernia can be assoc w/early-onset Marfan syndrome. ⁶
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 rockerbottom feet, single umbilical artery
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 deafness; agenesis of corpus callosum; omphalocele; ID
RARB STRA6	Matthew-Wood syndrome (PDAC syndrome; syndromic microphthalmia) (OMIM 615524, 601186)	AR AD	Core	Micro-/anophthalmia, pulmonary agenesis or hypoplasia, CHD, genitourinary anomalies Matthew-Wood syndrome is not assoc w/small nails or small digits.

Chromosome Abnormality	Critical Genes Included	Facial Phenotype	Other Clinical Characteristics (in addition to CDH)
Pallister-Killian syndrome (PKS) ¹ (mosaic tetrasomy 12p) (OMIM 601803)		Coarse w/wide-set eyes, prominent cheeks, & eversion of vermilion of lower lip Considered similar to Fryns syndrome ^2, 3	Sparse hair, ⁴ syndactyly, & streaky skin pigmentation Hypotonia, seizures, & ID common ³ Short distal phalanges of fingers & toes, small nails, cloudy corneas, CHD, & internal malformations may be seen but are typically less frequent in PKS than in Fryns syndrome.
Del 15q26.2 (OMIM 142340)	NR2F2 ⁵	Fryns syndrome-like craniofacial anomalies	CHD, hypoplastic genitalia or cryptorchidism, severe prenatal growth deficiency, ID, talipes equinovarus &/or rockerbottom feet, single umbilical artery
Del 8p23.1 (OMIM 222400)	GATA4 SOX7 ⁵	Mild facial anomalies	CHD (e.g., heterotaxy), renal anomalies, ID
Del 8q22-q23	ZFPM2 ⁵	Blepharophimosis, widely spaced eyes, epicanthus, flat malar region, thin vermillion of upper lip, downturned corners of mouth, ↓ facial movement	ID w/absent speech, microcephaly, seizures, growth delays ⁶
Del 1q41-q42 (OMIM 612530)	HLX DISP ⁵		Limb anomalies (e.g., talipes), cleft lip & palate, seizures, ID
Del 15q24 (OMIM 613406)		Typical craniofacial features	Malformations of hands & feet, growth delays, ID w/marked speech delay
Del 4p16.3 (OMIM 194190)	FGFRL1 ⁵	Typical facial anomalies assoc w/Wolf-Hirschhorn syndrome	Skeletal anomalies, ID, growth delays
Del 22q11.2		Typical facial anomalies assoc w/22q11.2 deletion syndrome, cleft palate	CHD, skeletal anomalies, hypocalcemia CDH is present in 0.8% of persons w/22q11 deletion. ⁷
Del 17q12		Facial anomalies (See 17q12 Recurrent Deletion Syndrome.)	MODY, cystic renal disease, pancreatic & liver abnormalities, macrocephaly, ID ⁸

System/Concern	Evaluation	Comment
CDH	Chest & abdominal radiographs
Neurologic	Cranial US exam to evaluate for structural brain malformations Neurologic eval & EEG if seizures are suspected Brain MRI exam
Eyes	Ophthalmology exam incl fundoscopy
Cardiovascular	Echocardiogram
Gastrointestinal	Upper gastrointestinal imaging to evaluate for intestinal malrotation
Genitourinary	Renal US exam
Ears/Nose/Throat	Eval w/ENT &/or craniofacial team if cleft palate is suspected
Development	Developmental assessment	To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education
Genetic counseling	By genetics professionals ¹	To inform affected persons & families re nature, MOI, & implications of Fryns syndrome to facilitate medical & personal decision making
Family support & resources	Assess: Use of community or online resources such as Parent to Parent; Need for social work involvement for parental support; Need for home nursing referral.

Manifestation/ Concern	Treatment	Considerations/Other
CDH	Neonates w/CDH require immediate intubation to prevent inflation of herniated bowel. See also Congenital Diaphragmatic Hernia Overview.	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 [Losty 2014].
Seizures	Standardized treatment w/antiseizure medications by experienced neurologist
Cataracts / Other ocular anomalies	Management per ophthalmologist
Congenital heart defects	Management per pediatric cardiologist
Gastrointestinal malformations	Surgical repair per pediatric gastroenterologist & pediatric surgeon
Genitourinary malformations	Management per pediatric nephrologist &/or urologist
Cleft palate	Management per craniofacial team
Developmental delay	Developmental services as needed incl feeding, motor, adaptive, cognitive, & speech/language

System/Concern	Evaluation	Frequency
Following successful CDH repair	Evals by pediatric surgeon, nurse specialist, cardiologist, pulmonologist, & nutritionist	As recommended by specialist(s)
Neurologic	Monitor those w/seizures as clinically indicated; assess for new onset of seizures.	At each visit
Development	Monitor developmental progress & educational needs.	At each visit
Ocular anomalies	Ophthalmology eval	As needed
Congenital heart defects	Follow up w/cardiologist
Gastrointestinal malformations	Follow up w/gastroenterologist
Genitourinary malformations	Follow up w/nephrologist or pediatric urologist
Cleft palate	Follow up w/craniofacial specialists

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

Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NM_176787.5 NP_789744.1	c.421dup	p.Ile141AsnfsTer10	Homozygous [Alessandri et al 2018]
NM_176787.5 NP_789744.1	c.694A>T	p.Lys232Ter	Homozygous [McInerney-Leo et al 2016]
NM_176787.5	c.1574+1G>A	--	Homozygous [Brady et al 2014]
NM_176787.5	c.1674+1G>C	--	Compound heterozygous ¹ [McInerney-Leo et al 2016]
NM_176787.5 NP_789744.1	c.1966C>T	p.Glu656Ter	Compound heterozygous ¹ [McInerney-Leo et al 2016]
GRCh37	Chr18:59819870–59824934 deletion ²	See footnote 3.	Homozygous; likely founder effect in La Réunion & other Indian Ocean islands [Alessandri et al 2018]