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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Fryns Syndrome

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

Initial Posting: ; Last Update: June 1, 2010.


Disease 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 malformation involving 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.

Diagnosis/testing. 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.

Management. 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, 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 disease-causing mutations 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.


Clinical Diagnosis

Diagnostic criteria for Fryns syndrome were recently reformulated [Lin et al 2005]. Using these criteria, three categories of individuals with Fryns syndrome are recognized:

  • Narrow definition: Presence of four out of six features
  • Broad definition: Presence of three of the six features (without facies characteristic of another syndrome)
  • Atypical

Note: These categories and the new diagnostic criteria have not yet been prospectively evaluated.

The six proposed criteria are not obligatory (see *Note). They are:

  • Diaphragmatic defect (diaphragmatic hernia in any location, 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.

* 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 chromosomal 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:

Molecular Genetic Testing

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

Loci. No locus for Fryns syndrome has been mapped, and no linkage data have been reported.

Clinical Description

Natural History

The term Fryns syndrome was first used to describe the clinical findings in two stillborn female siblings, 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. Polyhydramnios was noted in the second trimester of each pregnancy.

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

No sex differences have been noted.

Although survival beyond the neonatal period is uncommon; nonetheless, the phenotype of 11 children with Fryns syndrome who survived the first year of life has been reviewed [Dentici et al 2009]. All exhibited neurological impairment that ranged from mild to severe. 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 variable features included central/paracentral corneal clouding, coarsening of facial features, intestinal malrotation, Hirschsprung disease, gastroesophageal reflux, hydronephrosis, and vesico-ureteral reflux.

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.

In the past, severe developmental delay and cognitive impairment were considered invariable in Fryns syndrome. However, more recently, 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].

The prognosis in Fryns syndrome is influenced by the malformations present. Early reports of Fryns syndrome included arhinencephaly, agenesis of the corpus callosum, absence of the olfactory bulbs and tracts, hydrocephalus, Dandy-Walker malformation, cleft lip, renal cysts, and hypospadias.

Fryns syndrome has also been reported without CDH [Vasudevan & Stewart 2004, Alessandri et al 2005]. In one review six individuals with Fryns syndrome without CDH (but with a normal karyotype) had characteristic facial features, five had distal limb hypoplasia, four had cleft lip and/or palate, and four had cardiac defects [Vasudevan & Stewart 2004]. There were two sib pairs. In another review, the prognosis of individuals with Fryns syndrome was described as more promising in those without CDH than in those with CDH [Alessandri et al 2005].


Fryns syndrome was present in seven cases per 100,000 live births in a French population [Aymé et al 1989].

The incidence of Fryns syndrome has been estimated in large cohorts of individuals with congenital diaphragmatic hernia (CDH).

  • In one study, 23 of 1,833 persons with CDH observed over a six-year period were diagnosed with Fryns syndrome (1.3%) [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 a genetic etiology 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.

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

  • Simpson-Golabi-Behmel syndrome (SGBS), an X-linked disorder associated with mutations in GPC3, is characterized by pre- and postnatal macrosomia, distinctive craniofacies (macrocephaly, ocular hypertelorism, 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, renal defects (nephromegaly, multicystic kidneys, hydronephrosis, hydroureter, duplicated ureters), and GI anomalies (pyloric ring, Meckel's diverticulum, intestinal malrotation, hepatosplenomegaly, hyperplasia of islets of Langerhans, choledochal cysts, polysplenia). Skeletal anomalies can include vertebral fusion, scoliosis, pectus excavatum, rib anomalies, winged scapula, and congenital hip dislocation. Hand anomalies comprise large hands, broad thumbs, brachydactyly, syndactyly, clinodactyly, and postaxial polydactyly. Tumor frequency is about 10%; reported tumors include Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, and hepatocellular carcinoma.
    In one study, 5/28 (17.8%) of 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 mutations (p.Arg254* and p.Trp260*) predicting loss of GPC3 function [Sakazume et al 2007]. 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. Craniofacial features include synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 with an average of 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 1/13 (7.7%) of 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, SMC1L1, and SMC1A are the genes currently known to be associated with CdLS. Mutations 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 [OMIM 222448] comprises diaphragmatic defects, omphalocele, agenesis of the corpus callosum, ocular hypertelorism, severe myopia, and sensorineural deafness [Pober et al 2009]. Cardiac defects, iris coloboma, dysmorphic features with a wide anterior fontanelle, downslanting palpebral fissures, epicanthic folds, a short nose with a broad tip and low-set, posteriorly angulated ears, and proteinuria have also been described. Inheritance is autosomal recessive. The gene in which mutations are causative, LRP2, encodes the low-density lipoprotein receptor-related protein 2 precursor (megalin). Diaphragmatic hernia has been identified in 15/27 (56%) of 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 mutations can be sought in individuals suspected to have 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. Mutations 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 10/21 (48%) of 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.

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 chromosome 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 causative genes.

  • Isochromosome 12p or tetrasomy 12p (Pallister-Killian syndrome, PKS). 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 seen in Fryns syndrome and not 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 on peripheral blood lymphocytes does not exclude PKS.
  • 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]. 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 recognizable and has been considered to constitute a contiguous gene deletion syndrome. The cardinal clinical findings are diaphragmatic defects (19/21 or 90%; most commonly left-sided herniation, but hypoplasia of the diaphragm has also been described), pulmonary hypoplasia (8/16 or 50%), severe growth retardation (16/17 or 94%), cardiovascular malformations comprising ventricular septal defect (8/19 or 42%), aortic stenosis (4/19 or 21%) and hypoplasia of the left heart (2/19 or 11%), facial dysmorphism (8/16 or 50%), talipes and/or rockerbottom feet (13/21 or 62%), and a single umbilical artery (5/16 or 31%) [Slavotinek et al 2006, Klaassens et al 2007]. Nail hypoplasia was present in only 2/16 (13%) 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.
  • 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 4/18 (22%) of individuals with interstitial deletions and 5/60 (8.3%) of 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 has been suggested as possible mechanisms for the diaphragmatic defects (Dr Daryl Scott, personal communication), but mutations in these genes have not been identified to date.
    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 in which mutation causes the diaphragmatic defects within this interval remains unknown.

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

  • 15q24 microdeletion syndrome. Cardinal findings are developmental delay; facial dysmorphism (high forehead, long face, downslanting palpebral fissures with widened medial eyebrows, low-set ears, a long and smooth philtrum and full cheeks); abnormal connective tissue manifesting as inguinal and umbilical hernias and/or joint laxity; and genital and digital anomalies. 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]. The gene in which mutation causes the diaphragmatic defects within this 70.6- to 73.7-Mb interval remains unknown.
  • 16p11.2 deletion and duplication. A seven-month-old male 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 2009]. A 15-year-old male 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], implying that a dosage-sensitive gene or genes could cause the diaphragmatic defects in this chromosome interval. 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

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

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

Depending on the clinical situation, further cranial evaluation with an 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.

Evaluation by a clinical geneticist and developmental pediatrician is recommended.

Treatment of Manifestations

The physical manifestations of Fryns syndrome can be 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 extra-corporeal membrane oxygenation (ECMO) have achieved recent popularity. Nitric oxide, surfactant, and perflubron have also been tried; the efficacy of these measures has not been systematically evaluated.

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.


In those who survive the neonatal period, surveillance depends on the types of malformations present and is specific to each 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, a high-resolution karyotype 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 chromosomal 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.

Therapies Under Investigation

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

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


For a more detailed discussion on the management of congenital diaphragmatic hernia, see Congenital Diaphragmatic Hernia Overview.

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

Number of SibsConsanguineous RelationshipType of Chromosome Study Performed 1Citation
Consanguineous cases One maleSecond cousins(a)Fitch et al [1978]
One femaleFirst cousins once removed(a), (b)Meinecke & Fryns [1985]
One maleFirst cousins(a)Dix et al [1991]
One brother, one sisterSecond cousins(a)Kershisnik et al [1991]
One brother, one sisterFirst cousins(b) on affected female; (a) on affected maleWilgenbus et al [1994]
Two affected sibs: one male and one with sex unknownSecond cousins(a) with FISH for 22q11 deletions on affected maleVasudevan & Stewart [2004]
Non- consanguineous cases with more than one affected sibling Three brothers, one sisterN/A(a) in both parents and two affected sibsSamueloff et al [1987]
One brother, one sister(a) in both affected sibsMoerman et al [1988]
One brother, one sister(a) in two affected sibsAymé et al [1989]
Two brothers(a), (b) in one affected maleCunniff et al [1990]
Two brothers(b) in one affected male; (c) in bothRamsing et al [1991] (family 1)
Three affected sibs: two sisters, one brother(b); exclusion of tetrasomy 12p and trisomy 22 by microsatellite markersRamsing et al [1991] (family 2)
Three affected sibs: two brothers and one of unknown sex(a) in both malesLanger et al [1994]
Monozygous male twins(a) on one male; (b) on bothVargas et al [2000]

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

1. Type of chromosome study performed:

(a) Chromosome analysis, band resolution not stated

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

(c) 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 mutant 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 disease-causing mutations occur have not been identified, carrier testing is not possible.

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 testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to 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, mutations, 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 disease-causing mutations 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.

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

Chromosome analysis. If chromosome analysis was 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), chromosome analysis 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.

Ideally, the chromosome analysis performed for an evaluation of possible Fryns syndrome should include array comparative genomic hybridization (aCGH), preferably including probes for the 22q11, 15q26, 8p23.1 and 1q41-1q42 regions that are deleted in some individuals with CDH and additional malformations/dysmorphology (see Differential Diagnosis). Microdeletions of 16p11.2 and 15q24 may also be detectable with the appropriate aCGH.

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 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 and aCGH to evaluate the fetus for a chromosome abnormality (see Chromosome analysis) is strongly recommended. Confirmation of the diagnosis of Fryns syndrome, however, may not be possible prior to delivery, 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.

    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
    Email: info@cdhsupport.org
  • 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
    Email: nationaloffice@compassionatefriends.org
  • Helping After Neonatal Death (HAND) - Support Groups
    PO Box 341
    Los Gatos CA 95031
    Phone: 888-908-4263
    Email: info@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 B. OMIM Entries for Fryns Syndrome (View All in OMIM)


Molecular Genetic Pathogenesis

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 mutation in the etiology of Fryns syndrome. In addition, the diversity of the limb malformations in Fryns syndrome suggests that mutations 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

  1. 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

  • 1 June 2010 (me) Comprehensive update posted live
  • 18 April 2007 (me) Review posted to live Web site
  • 8 January 2007 (ams) Original submission
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