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Fryns Syndrome

, MBBS, PhD.

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Initial Posting: ; Last Update: January 29, 2015.


Clinical characteristics.

Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, eventration, hypoplasia or agenesis); characteristic facial appearance (coarse facies, ocular hypertelorism, broad and flat nasal bridge, thick nasal tip, long philtrum, low-set and poorly formed ears, tented upper lip, macrostomia, micrognathia); distal digital hypoplasia (nails, terminal phalanges); 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, genitalia). Survival beyond the neonatal period has been rare. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common.


The diagnosis is based on clinical findings. No genes or loci associated with Fryns syndrome have been identified or mapped; however, several different chromosome aberrations have been described in individuals who have previously received a diagnosis of Fryns syndrome.


Treatment of manifestations: Surgery and/or supportive measures as for the general population. For congenital diaphragmatic hernia, the neonate is immediately intubated to prevent inflation of herniated bowel; additional anomalies may require further consultations and management by a craniofacial team and pediatric specialists in neurology, cardiology, gastroenterology, ophthalmology, and nephrology.

Surveillance: Depends on the types of malformations present; 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).

Genetic counseling.

Fryns syndrome is thought to be 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% chance of being neither affected nor a carrier. Because the gene(s) in which pathogenic variants occur have not been identified, carrier testing and prenatal diagnosis using molecular genetic testing are not possible. Two- and three-dimensional ultrasonography and fetal magnetic resonance imaging have been used in the prenatal diagnosis of high-risk pregnancies.


Suggestive Findings

Diagnosis of Fryns syndrome should be suspected in individuals with the following clinical features:

  • Diaphragmatic defect includes 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, ocular hypertelorism, a broad and flat nasal bridge with a thick nasal tip, a long philtrum, low-set and poorly formed ears, a tented upper lip, macrostomia, and micrognathia
  • Distal digital hypoplasia involving the nails and/or terminal phalanges
  • Pulmonary hypoplasia of a significant degree
  • Characteristic associated anomalies, with at least one of the following:
    • Polyhydramnios
    • Cloudy corneas and/or microphthalmia
    • Orofacial clefting
    • Brain malformation
    • Cardiovascular malformation
    • Renal dysplasia/renal cortical cysts
    • Gastrointestinal malformation
    • Genital malformation
  • Affected sibs (or parental consanguinity) suggesting autosomal recessive inheritance. A detailed three-generation family history should be obtained. Special attention should be paid to similarly affected sibs, other family members with birth defects or physical anomalies, miscarriages, stillbirths or early perinatal deaths, and consanguinity.

Establishing the Diagnosis

The gene(s) in which mutation causes Fryns syndrome are unknown.

Diagnostic criteria for Fryns syndrome were reformulated by Lin et al [2005] based on the clinical features listed above. The six proposed criteria are not obligatory (see Note below).

Using these criteria, three categories of individuals with Fryns syndrome are recognized:

  • Narrow definition: Presence of four out of six clinical features
  • Broad definition: Presence of three of the six clinical features (without facies characteristic of another syndrome)
  • Atypical: Fryns syndrome with atypical features exceeding the current diagnostic spectrum of Fryns syndrome, such as radial aplasia and pterygia (see following Note)

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 [Jog et al 2002], limb shortening, and multiple pterygia [Ramsing et al 2000] have been labeled as Fryns syndrome by some authors, but not by others.

Exclusionary criteria. Because chromosome aberrations have been associated with congenital diaphragmatic hernia (CDH) and additional major malformations/dysmorphology (see Differential Diagnosis), the diagnosis of Fryns syndrome can only be considered after appropriate chromosome studies have been performed to exclude the following:

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 chromosome studies to evaluate for many of the chromosome abnormalities associated with a Fryns syndrome-like phenotype (see Diagnosis).

Prenatal findings. Polyhydramnios, noted in the second trimester, has been reported in 56% of cases [Peron et al 2014]. 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 can rarely be established unequivocally prior to birth [Peron et al 2014].

Survival/prognosis. Although survival beyond the neonatal period is uncommon, the phenotype of 11 children with Fryns syndrome who survived the first year of life has been reviewed [Dentici et al 2009]. All exhibited neurologic impairment that ranged from mild to severe. 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 [Alessandri et al 2005]. No sex differences have been noted.

Diaphragmatic abnormality/respiratory concerns. Diaphragmatic hernia is found in more than 90% of individuals with Fryns syndrome [Peron et al 2014]. A unilateral, left-sided Bochdalek hernia is most commonly observed, although bilateral and right-sided hernias have been noted in around 20% and 10% of affected individuals respectively [Slavotinek 2004]. Pulmonary hypoplasia has been found in approximately two thirds of individuals [Slavotinek 2004], although it is not commonly present in the absence of diaphragmatic defects.

Fryns syndrome has also been reported without CDH [Vasudevan & Stewart 2004, Alessandri et al 2005].

Neurologic findings. Structural brain malformations (ventriculomegaly, agenesis of the corpus callosum, and Dandy-Walker malformation) were identified in 7/9 (88%). Seizures were identified in four individuals. Other brain malformations have included arhinencephaly, hydrocephalus, and absence of the olfactory bulbs and tracts.

Ocular findings. Eye findings 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].

Cardiac findings. Ventricular septal defect was the most frequently observed cardiac malformation (40%), with atrial septal defects and aortic abnormalities present in slightly more than 10% each [Slavotinek 2004].

Gastrointestinal findings. Abdominal defects have included omphalocele, anal malformations, and intestinal malrotation that can be associated with CDH without additional syndromic manifestations [Slavotinek 2004].

Genitourinary findings. Clinical features present in more than 10% of affected individuals comprise renal cysts, mega-, hydro- or cystic ureter, and renal dysplasia [Slavotinek 2004]. In males, cryptorchidism and micropenis are also common, whereas females may have a bicornuate uterus [Slavotinek 2004]. Hypospadias has also been reported.

Dysmorphic findings. The most characteristic facial features have been listed as a coarse face, hypertelorism with cloudy corneae, a broad and flat nasal bridge with anteverted nares, dysplastic and low-set ears, macrostomia, and microretrognathia [Slavotinek 2004].

Cleft palate was present in 50% and cleft lip in 25% [Slavotinek 2004].

Skeletal findings. Nail hypoplasia and hypoplasia of the terminal phalanges are frequent and useful diagnostic findings and are present in around 60% of cases [Slavotinek 2004]. Other limb findings present in more than 10% of individuals include proximal thumbs, broad first digits/metacarpals, and camptodactyly [Slavotinek 2004].

Growth. Postnatal growth was normal in a child at age 14 months and in another at age seven years; an 18-month old male had macrocephaly with head circumference in the 90th centile, weight in the third centile, and normal stature [Slavotinek 2004]. Growth data were not reported in several other children who survived the neonatal period.

Development. In the past, severe developmental delay and intellectual disability were considered invariable in Fryns syndrome. However, a few individuals with milder learning disabilities have been reported, including a one-year old twin who was able to stand with support and to transfer objects, and a two-year old male with hypotonia and mild developmental delay [Slavotinek 2004]. One child began walking at age four years and another walked independently at age six years, but remained nonverbal at age nine years. Seizures occurred in at least one child [Cunniff et al 1990]. One male, who had had skills at the 13-month level at age 20 months, could babble and understand language but was not able to speak at age six years [Dentici et al 2009].


Fryns syndrome was present in seven cases per 100,000 live births in a French population [Aymé et al 1989]. No more recent estimates of prevalence have been published.

The incidence of Fryns syndrome has been estimated in large cohorts of individuals with congenital diaphragmatic hernia (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 at 4%-10% of persons with CDH.

Differential Diagnosis

Fryns syndrome is the most common autosomal recessive syndrome associated with congenital diaphragmatic hernia (CDH; see Congenital Diaphragmatic Hernia Overview). Many individuals with CDH and multiple malformations or dysmorphic features have been diagnosed with Fryns syndrome, and there is substantial clinical heterogeneity in the patient group reported to have Fryns syndrome in the published literature. Although an associated gene has not yet been established for Fryns syndrome, it is reasonable to assume that genetic heterogeneity is highly likely. The following conditions are distinguishable from Fryns syndrome because of their recognizable patterns of anomalies and the absence of characteristic nail or digital hypoplasia found in Fryns syndrome. In addition, molecular genetic testing is available for some of these conditions.

Single-gene disorders in which CDH is observed include the following:

  • Simpson-Golabi-Behmel syndrome (SGBS), an X-linked disorder associated with pathogenic variants in GPC3 or GPC4, is characterized by pre- and postnatal macrosomia, distinctive craniofacies (including macrocephaly, coarse facial features, macrostomia, macroglossia, palatal abnormalities), and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti/umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and GI anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies comprise large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, and hepatocellular carcinoma.
    In one study, five (17.8%) of 28 individuals with molecularly confirmed SGBS had CDH [Li et al 2001]. More recently, a smaller report of seven individuals with SGBS included two with CDH (29%) who both had pathogenic variants (p.Arg254Ter and p.Trp260Ter) predicting loss of GPC3 function [Sakazume et al 2007]. A recent case report described a male with a left-sided diaphragmatic defect and multiple anomalies (including left coronal craniosynostosis, enlarged prostatic utricle, and penoscrotal hypospadias) associated with a frameshift variant in GPC3 [Villarreal et al 2013]. In addition to X-linked inheritance (and hence typically more severe manifestations in males) and use of molecular genetic testing in diagnosis, SGBS can be distinguished from Fryns syndrome based on the higher frequency of overgrowth, skeletal anomalies, and tumors in SGBS.
  • Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; <5th centile throughout life), hirsutism, and upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. CDH was identified in one (7.7%) of 13 individuals with CdLS from the Spanish Collaborative Study of Congenital Malformations.
    CdLS differs from Fryns syndrome in its distinctive craniofacial features, growth retardation, upper limb defects, and inheritance patterns. NIPBL, SMC1A, SMC3, RAD21, and HDAC8 are the genes currently known to be associated with CdLS. Pathogenic variants in NIPBL have been reported in individuals with Cornelia de Lange syndrome who have CDH; however, no phenotype-genotype correlation with respect to CDH has been determined [Hosokawa et al 2010].
  • Donnai-Barrow syndrome is characterized by typical craniofacial features (ocular hypertelorism, enlarged fontanelle), ocular findings (high myopia, retinal detachment, progressive vision loss, and iris coloboma), sensorineural deafness, agenesis of the corpus callosum, intellectual disability, and congenital diaphragmatic hernia (CDH) and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.
    Inheritance is autosomal recessive. The gene in which pathogenic variants are causative, LRP2, encodes the low-density lipoprotein receptor-related protein 2 precursor (megalin). Diaphragmatic hernia has been identified in 15 (56%) of 27 persons with Donnai-Barrow syndrome [Pober et al 2009].
    Donnai-Barrow syndrome can be clinically distinguished from Fryns syndrome by ocular hypertelorism and colobomas, enlarged anterior fontanelle, and deafness in the former condition. In addition, a characteristic pattern of low molecular weight proteinuria which has shown a strong correlation with LRP2 pathogenic variants can be sought in individuals suspected of having Donnai-Barrow syndrome [Pober et al 2009].
  • Matthew-Wood syndrome (OMIM 601186), also known as PDAC (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) syndrome, is an autosomal recessive condition. Pathogenic variants in STRA6 have been described in individuals with Matthew-Wood syndrome and related phenotypes [Pasutto et al 2007]. STRA6 encodes a transmembrane protein that has been shown to be involved in cellular uptake of retinol [Kawaguchi et al 2007]. Diaphragmatic defects are common (14/19; 74%) and have ranged in type from left- and right-sided defects to bilateral diaphragmatic eventration [Chitayat et al 2007]. A second and more recent review found diaphragmatic defects in 10 (48%) of 21 affected individuals [Chassaing et al 2009], but suggested that phenotypic heterogeneity may be present in this syndrome.
    Matthew-Wood syndrome is distinguished from Fryns syndrome by the severe ocular and pulmonary malformations in Matthew-Wood syndrome, combined with absence of the characteristic digital defects found in Fryns syndrome. Molecular genetic testing of STRA6 can confirm a diagnosis of Matthew-Wood syndrome.
    In the same developmental pathway concerning retinoic acid synthesis, individuals with PDAC who do not have pathogenic variants in STRA6 have been found to have pathogenic variants in retinoic acid receptor beta (RARb; OMIM 180220) [Srour et al 2013]. Deleterious sequence variants were most likely in those with anophthalmia or microphthalmia in addition to other features of PDAC such as CDH, and variants could be either recessive (loss of function) or dominant (activating) [Srour et al 2013]. This gene has not been systematically screened in patients with Fryns syndrome, but anophthalmia/microphthalmia are uncommon in this condition.

Chromosomal conditions associated with CDH and additional major malformations/dysmorphology in which two or more individuals with similar chromosome abnormalities have had CDH are summarized below. It has been hypothesized that the deleted chromosomal regions may harbor a gene in which mutation is causative of Fryns syndrome such that the associated gene is deleted on one allele and mutated on the other allele; to date, however, sequence analysis of candidate genes in persons with the chromosome aberration and CDH has not identified any associated genes.

  • Isochromosome 12p or tetrasomy 12p (Pallister-Killian syndrome, PKS) (OMIM 601803). Of all the conditions to be considered in the differential diagnosis, PKS most closely resembles Fryns syndrome. Diaphragmatic hernia can occur in 10%-50% of individuals with PKS; the facial phenotype is coarse and similar to that of Fryns syndrome.
    Sparse hair is characteristic of PKS, in contrast to Fryns syndrome in which the sisters originally described by Fryns had low hairlines and hypertrichosis. Other features observed in PKS but not in Fryns syndrome are syndactyly and streaky skin pigmentation, whereas distal digital hypoplasia, cloudy corneas, and internal malformations are more commonly observed in Fryns syndrome than in individuals with PKS.
    In some persons, only chromosome analysis and/or the inheritance pattern can distinguish between PKS and Fryns syndrome [Paladini et al 2000, 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.
  • Monosomy 15q26. More than 25 persons with CDH and an interstitial or terminal deletion of distal chromosome 15q have been reported [Biggio et al 2004, Castiglia et al 2005, Klaassens et al 2005a Klaassens et al 2005b, López et al 2006, Slavotinek et al 2006, Klaassens et al 2007, Brady et al 2013]. Deletions of chromosome 15q have been estimated to account for up to 1% of persons with CDH [Klaassens et al 2005b]. The phenotype associated with 15q26 deletions is recognized as a contiguous gene deletion syndrome. The cardinal clinical findings are diaphragmatic defects (19/21; 90%; most commonly left-sided herniation, but hypoplasia of the diaphragm has also been described); pulmonary hypoplasia (8/16; 50%); severe growth retardation (16/17; 94%); cardiovascular malformations comprising ventricular septal defect (8/19; 42%), aortic stenosis (4/19; 21%) and hypoplasia of the left heart (2/19; 11%); facial dysmorphism (8/16; 50%); talipes and/or rockerbottom feet (13/21; 62%); and a single umbilical artery (5/16 or 31%) [Slavotinek et al 2006, Klaassens et al 2007]. Nail hypoplasia was present in only two (13%) of 16 in an earlier case series [Slavotinek et al 2006]; however, it has been found more commonly in subsequent reports [Klaassens et al 2007]. Coarse facies, ocular hypertelorism, and posteriorly rotated ears can suggest Fryns syndrome [Klaassens et al 2007]; however, distinctive findings in 15q26 deletion syndrome are severe prenatal growth retardation, specific types of cardiac defects, talipes equinovarus and/or rockerbottom feet, and single umbilical artery. NR2F2 (COUP-TFII; OMIM 107773) has been considered to be the best candidate gene for the diaphragmatic defects in this region [Brady et al 2013] and conditional null mice for this gene have had CDH [You et al 2005].
  • Monosomy 8p23.1. Interstitial and terminal deletions that include 8p23.1 have also been associated with CDH and additional anomalies [Borys & Taxy 2004, Shimokawa et al 2005, Slavotinek et al 2005, López et al 2006, Wat et al 2009]. Diaphragmatic hernia was present in four (22%) of 18 individuals with interstitial deletions and five (8.3%) of 60 individuals with terminal deletions [Wat et al 2009]. Most hernias have been left-sided and presumed to have a posterior diaphragmatic location. The critical region for CDH has been localized between 8p-OR-REPD and 8pOR-REPP [Wat et al 2009]. Haploinsufficiency for GATA4 and/or SOX7 [Wat et al 2012] has been suggested to cause the diaphragmatic defects and missense variants in GATA4 have been implicated in familial CDH with incomplete penetrance and in patients with sporadic CDH [Yu et al 2013].
    The broader phenotype associated with 8p23.1 deletions commonly includes congenital heart defects (atrioventricular septal defects and atrial and ventricular septal defects), genitourinary anomalies with cryptorchidism, developmental delays and mild-to-moderate cognitive impairment, growth retardation, facial dysmorphism, and strabismus [Shimokawa et al 2005, Slavotinek et al 2005, López et al 2006, Wat et al 2009]. Heart malformations are the most characteristic finding.
  • Monosomy 1q41-1q42. A third locus for a Fryns syndrome-like phenotype was identified in a study of 29 individuals with CDH and normal karyotypes using array CGH [Kantarci et al 2006]. A 5-Mb de novo deletion between clones RP11-553F10 and RP11-275O4 at chromosome 1q41-1q42.13 was identified in a child with: a large left-sided congenital diaphragmatic hernia (CDH) and a small right-sided diaphragmatic eventration; pulmonary hypoplasia; facial dysmorphism with large fontanelles, ocular hypertelorism, broad nasal tip, tented upper lip and cleft of the soft palate; small muscular ventricular septal defect; hypoplasia of the nails; talipes equinovarus; and possible partial supraglottic and glottic luminal stenosis [Kantarci et al 2006].
    A 1q41-1q42 deletion was described in seven individuals with: developmental delays (often severe); short stature with microcephaly; facial dysmorphism with coarse facies, frontal bossing, deep-set eyes, depressed nasal bridge, broad nasal tip, and anteverted nares; cleft palate; seizures; and talipes equinovarus [Shaffer et al 2007]. Two of the seven with CDH and pulmonary hypoplasia had been diagnosed with Fryns syndrome prior to the detection of the 1q41-1q42 deletion [Shaffer et al 2007]. The gene responsible for the diaphragmatic defects within this interval remains unknown, although HLX (OMIM 141995) and DISP1 have been suggested as candidate gene [Slavotinek et al 2009, Kantarci et al 2010].

Other chromosome aberrations that have been implicated in the pathogenesis of diaphragmatic defects include:

  • 15q24 microdeletion syndrome is characterized by: global developmental delay; mild to severe (usually at least moderate) intellectual disability; facial dysmorphism; congenital malformations of the hands and feet, eye, and genitalia; joint laxity; and growth retardation and failure to thrive. Less common findings include: seizures; conductive and sensorineural hearing loss; hypospadias and/ or micropenis. Males and females are affected equally. Of six reported individuals, one manifest a late-presenting, anterior diaphragmatic hernia (Morgagni hernia) with organ herniation at age 30 years [van Esch et al 2009] and one other had a diaphragmatic hernia, type unknown [Sharp et al 2007]. This microdeletion may include STRA6, which is well known to be associated with CDH [Magoulas & El-Hattab 2012], although usually with autosomal recessive inheritance.
  • 16p11.2 deletion and duplication. A male age seven months with CDH, cleft palate, heart disease (patent foramen ovale and patent ductus arteriosus), and weight and height below the 3rd centile had a 546-kb de novo deletion of 16p11.2 [Shinawi et al 2010]. A male age 15 years with a de novo 16p11.2 duplication involving the same chromosome region had autism with cognitive delays and anxiety, epilepsy, CDH, height and weight below the 5th centile, scoliosis, and joint laxity [Fernandez et al 2010]; it is known that a dosage-sensitive gene or genes can cause diaphragmatic defects in this chromosome interval [Brady et al 2013]. However, 16p11.2 deletions and duplications should be clearly distinguishable from Fryns syndrome, as the chromosome aberrations are more likely to present with a neurocognitive or neuropsychiatric phenotype without major malformations or nail hypoplasia.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Fryns syndrome, the following evaluations are recommended:

  • Chest and abdominal radiographs
  • Cranial ultrasound examination
  • Echocardiogram
  • Abdominal ultrasound examination
  • Examination for dysmorphic features and digital anomalies by a clinical geneticist

Depending on the clinical situation, further evaluation with a cranial magnetic resonance imaging (MRI) scan, a complete radiographic skeletal survey, and a detailed ophthalmologic examination should be considered to evaluate for other physical findings that could be present.

Treatment of Manifestations

The physical manifestations of Fryns syndrome are treated by surgery and/or supportive measures in the same way that the same manifestations are treated when they are not part of a syndrome. However, treatment of the diaphragmatic hernia often takes precedence over the management of other anomalies present.

For congenital diaphragmatic hernia (CDH), the neonate is immediately intubated to prevent inflation of herniated bowel.

Medical therapies are used to stabilize the infant prior to surgical repair. High-frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO) have achieved recent popularity in the treatment of CDH [Fallon et al 2013] but proof of improved survival with ECMO has not been established [Losty 2014]. Nitric oxide and surfactant have also been trialed as therapies for persistent pulmonary hypertension of the newborn (PPHN).

In Fryns syndrome, additional anomalies may dictate further consultations; management by a pediatric neurologist, pediatric cardiologist, pediatric gastroenterologist, pediatric nephrologist, and a craniofacial team may be appropriate.

See also Congenital Diaphragmatic Hernia Overview.

Prevention of Primary Manifestations

The diaphragmatic defects in Fryns syndrome may be amenable to surgical repair in the prenatal period. Survival in a controlled trial of open hysterotomy-guided fetal endoscopic tracheal occlusion versus conventional care was not improved; an experimental, minimally invasive approach called percutaneous fetal endoluminal tracheal occlusion is still being evaluated [Losty 2014].

Prevention of Secondary Complications

For those with prenatally detected CDH, it is important to prevent lung injury that can result from inflation of bowel that has herniated into the chest and immediate intubation at birth has been recommended as above.


There are no specific surveillance guidelines for Fryns syndrome. In those who survive the neonatal period, surveillance depends on the types of malformations present and is specific to the individual.

Infants with successful CDH repair should be followed by a multidisciplinary team at a specialized center, with periodic evaluations by a pediatric surgeon, nurse specialist, cardiologist, pulmonologist, and nutritionist.

Evaluation of Relatives at Risk

Testing of sibs at risk for Fryns syndrome requires an evaluation for physical anomalies (see Diagnosis and Management, Evaluations Following Initial Diagnosis). If chromosome studies were not obtained on the proband, CMA to evaluate for the possibility of a chromosome disorder (see Differential Diagnosis) could be performed in the sib(s) at risk. A high index of suspicion for a chromosome aberration should prompt evaluation for deletions of the chromosomal loci associated with a Fryns syndrome-like phenotype.

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 (FETO) 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 in the US and 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Fryns syndrome is thought to be inherited in an autosomal recessive manner. See Table 1.

Table 1.

Fryns Syndrome: Selected Evidence in Support of Autosomal Recessive Inheritance

# of SibsConsanguineous RelationshipType of Chromosome Study PerformedCitation
1 maleSecond cousinsCAFitch et al [1978]
1 femaleFirst cousins once removedCA, karyotype 1Meinecke & Fryns [1985]
1 maleFirst cousinsCADix et al [1991]
1 brother, 1 sisterSecond cousinsCAKershisnik et al [1991]
1 brother, 1 sisterFirst cousinsCA on affected male, karyotype 1 on affected femaleWilgenbus et al [1994]
2 affected sibs: 1 male & 1 of unknown sexSecond cousinsCA w/FISH for 22q11 deletions on affected maleVasudevan & Stewart [2004]
cases with >1 affected sib
3 brothers, 1 sisterN/ACA in both parents & 2 affected sibsSamueloff et al [1987]
1 brother, 1 sisterCA in both affected sibsMoerman et al [1988]
1 brother, 1 sisterCA in both affected sibsAymé et al [1989]
2 brothersCA & karyotype 1 in 1 affected maleCunniff et al [1990]
2 brothersKaryotype 1 in 1 affected male; CGH 2 in bothRamsing et al [1991] (family 1)
3 affected sibs: 2 sisters, 1 brotherKaryotype 1; exclusion of tetrasomy 12p & trisomy 22 by microsatellite markersRamsing et al [1991] (family 2)
3 affected sibs: 2 brothers & 1 of unknown sexCA in both malesLanger et al [1994]
Monozygous male twinsCA on 1 male, karyotype 1 on bothVargas et al [2000]
2 sistersNo chromosome studies doneAboud & Al-Shamsy [2011]
1 male, 1 unknown sexCA on 1 maleArora et al [2014]

Using broad diagnostic criteria (i.e., including those without diaphragmatic hernia; see Lin et al [2005])

CA = chromosome analysis; band resolution not stated


Karyotype of skin biopsy or, if anomalies are detected prenatally, of amniocytes or chorionic villus cells


Comparative genomic hybridization (not array)

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore each carry one mutated allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • 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% chance of being neither affected nor a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. No reports of reproduction in individuals with Fryns syndrome have been published.

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

Carrier Detection

Because the gene(s) in which pathogenic variants occur have not been identified, carrier testing is not possible.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Because the gene(s) in which pathogenic variants occur have not been identified, prenatal molecular genetic testing is not possible.

A Priori High-Risk Pregnancy – Sib with Fryns Syndrome

Ultrasound examination. Fryns syndrome has been diagnosed by two- and three-dimensional ultrasonography and fetal magnetic resonance imaging (MRI) [Benacerraf et al 2006]. Characteristic features in one fetus included a right diaphragmatic hernia, cleft soft palate, renal dysgenesis, and a bicornuate uterus with a normal karyotype [Benacerraf et al 2006]. 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 trimester, cardiac malformations such as ventricular and/or atrial septal defects, 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 should 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 chromosome analysis and/or CMA were not performed on the sib with Fryns syndrome (i.e., the diagnosis may be a chromosomal syndrome associated with CDH and additional major malformations/dysmorphology), such testing of fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation) should be considered. Chromosome analysis, for the evaluation for mosaicism for isochromosome 12p or tetrasomy 12p associated with Pallister-Killian syndrome, and CMA, which is likely to include the chromosome regions that are deleted or duplicated in some individuals with CDH and additional malformations/dysmorphology (see Differential Diagnosis), may both be warranted.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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, Chromosome analysis) 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.


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.

  • Breath of Hope: Congenital Diaphragmatic Hernia (CDH) Awareness
    A support group for parents of children with CDH
    PO Box 6627
    Charlottesville VA 22906-6627
    Phone: 888-264-2340 (toll-free)
    The Association of Congenital Diaphragmatic Hernia Research, Awareness and Support
    3650 Rogers Road
    Wake Forest NC 27587
    Phone: 919-610-0129
    Fax: 815-425-9155
  • Compassionate Friends
    Supporting Family After a Child Dies
    PO Box 3696
    Oak Brook IL 60522
    Phone: 877-969-0010 (toll free); 630-990-0010
    Fax: 630-990-0246
  • Helping After Neonatal Death (HAND)
    PO Box 341
    Los Gatos CA 95031
    Phone: 888-908-HAND (4263)

Molecular Genetics

Molecular Genetic Pathogenesis

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

Table B.

OMIM Entries for Fryns Syndrome (View All in OMIM)


Fryns syndrome is most likely inherited in an autosomal recessive manner (see Table 1). The observations summarized in Table 1 support the involvement of at least one autosomal recessively inherited pathogenic variant in the etiology of Fryns syndrome. In addition, the diversity of the limb malformations in Fryns syndrome suggests that pathogenic variants in more than one gene could be causative. However, no published data to support either hypothesis are available.

Chromosome deletions involving chromosomes 15q26.2, 8p23.1, or 1q41-1q42 [Holder et al 2007] in individuals with CDH and additional major malformations/dysmorphology have led to the hypothesis that in some instances Fryns syndrome may result from a contiguous gene deletion syndrome involving genes at these loci.


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Suggested Reading

  • Alkuraya FS, Lin AE, Irons MB, Kimonis VE. Fryns syndrome with Hirschsprung disease: support for possible neural crest involvement. Am J Med Genet A. 2005;132A:226–30. [PubMed: 15580636]

Chapter Notes

Revision History

  • 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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