Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome that is usually lethal in the neonatal period (Alessandri et al., 2005). Fryns (1987) reviewed the syndrome.
Lin et al. (2005) reviewed the clinical features of 112 patients with Fryns syndrome, and categorized them into 3 groups based on the number of diagnostic features. Group I included 82 patients who met narrowly defined criteria (4 ... Lin et al. (2005) reviewed the clinical features of 112 patients with Fryns syndrome, and categorized them into 3 groups based on the number of diagnostic features. Group I included 82 patients who met narrowly defined criteria (4 or more of 6 features); group II included 30 patients who met broader diagnostic criteria (3 of 6 features); and group III included 12 patients with either absence of certain core features or presence of atypical features. - Prenatal Diagnosis Ayme et al. (1989) reported prenatal diagnosis of Fryns syndrome by sonography between 24 and 27 weeks. Manouvrier-Hanu et al. (1996) described the prenatal diagnosis of Fryns syndrome by ultrasonographic detection of diaphragmatic hernia and cystic hygroma. The diagnosis was confirmed after termination of the pregnancy. The fetus also had 2 erupted incisors; natal teeth had not been mentioned in other cases of Fryns syndrome. - Differential Diagnosis McPherson et al. (1993) noted the phenotypic overlap between Fryns syndrome and the Pallister-Killian syndrome (601803), which is a dysmorphic syndrome with tissue-specific mosaicism of tetrasomy 12p. Veldman et al. (2002) discussed the differentiation between Fryns syndrome and Pallister-Killian syndrome, noting that differentiation is important to genetic counseling because Fryns syndrome is an autosomal recessive disorder and Pallister-Killian syndrome is usually a sporadic chromosomal aberration. However, discrimination may be difficult due to the phenotypic similarity. In fact, in some infants with 'coarse face,' acral hypoplasia, and internal anomalies, the initial diagnosis of Fryns syndrome had to be changed because mosaicism of isochromosome 12p was detected in fibroblast cultures or kidney tissue (Rodriguez et al., 1994). Although congenital diaphragmatic hernia is a common finding in both syndromes, bilateral congenital diaphragmatic hernia had been reported only in patients with Fryns syndrome until the report of the patient with Pallister-Killian syndrome by Veldman et al. (2002). Slavotinek (2004) reviewed the phenotypes of 52 reported cases of Fryns syndrome and reevaluated the diagnostic guidelines. She concluded that congenital diaphragmatic hernia and distal limb hypoplasia are strongly suggestive of Fryns syndrome, with other diagnostically relevant findings including pulmonary hypoplasia, craniofacial dysmorphism, polyhydramnios, and orofacial clefting. Slavotinek (2004) stated that other distinctive anomalies not mentioned in previous guidelines include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, abnormalities of the aorta, dilatation of the ureters, proximal thumbs, and broad clavicles.
Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris ... Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris et al. (1980). Fitch (1988) claimed that she and her colleagues were the first to describe this disorder. In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus, arhinencephaly, and cardiovascular anomalies (Fitch et al., 1978). Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period. Facial anomalies included broad nasal bridge, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia, lung hypoplasia, and urogenital abnormalities, including shawl scrotum, uterus bicornis, and renal cysts. They were discordant for diaphragmatic hernia, cleft lip, and Dandy-Walker anomaly. Meinecke and Fryns (1985) reported an affected child; consanguinity of the parents supported recessive inheritance. They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case. The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm as cardinal features. Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality. Features included hypoplastic lungs, cleft palate, retrognathia, micrognathia, small thorax, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins. Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both died shortly after birth with severe respiratory distress. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation of the cerebral ventricles in both infants. Postmortem examination showed Dandy-Walker malformation, ventricular septal defect, and renal cystic dysplasia. Ayme et al. (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain was examined, more than half were found to have Dandy-Walker anomaly and/or agenesis of corpus callosum. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia with rosettes and gliosis of the retina, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane. Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25. One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax, he underwent decortication of the right lung and oversewing of the thoracic duct. Kershisnik et al. (1991) suggested that osteochondrodysplasia is a feature of Fryns syndrome. Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome. They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia. One of these patients was alive at the age of 14 months, but was severely retarded. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period. In the report of Hanssen et al. (1992), 2 older sibs had died in utero. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. However, mental retardation has been present in all surviving patients. In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus appearing shortly after birth, which was well controlled on valproate. Progressive cerebral and brainstem atrophy was noted on serial MRIs made at 3 months and after 6 months of age. Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases). Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment. Their patient had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm associated with profound mental retardation. Fryns and Moerman (1998) reported a second-trimester male fetus with Fryns syndrome and midline scalp defects. The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true malformation syndrome with major involvement of the midline structures. Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly, coarse facial appearance, hypoplasia of distal phalanges, and an extra pair of ribs. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients. Ramsing et al. (2000) described 2 sibships with 4 fetuses and 1 preterm baby of 31 weeks' gestation affected by a multiple congenital disorder suggestive of Fryns syndrome. In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops, cystic hygroma, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial anomalies with bilateral cleft lip and palate and cardiovascular malformation. Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including gastroschisis, central nervous system defects with left arrhinencephaly and cerebellar hypoplasia, midline cleft of the upper lip, alveolar ridge, and maxillary bone, and cleft nose with bilateral choanal atresia. Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of them. They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral microphthalmia and cloudy cornea. Slavotinek et al. (2005) noted that Fryns syndrome may be the most common autosomal recessive syndrome in which congenital diaphragmatic hernia (see DIH2, 222400) is a cardinal feature. The autosomal recessive inheritance in Fryns syndrome contrasts with the sporadic inheritance for most patients with DIH. Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia. They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm. Among 112 patients with Fryns syndrome, Lin et al. (2005) found that about half had a cardiovascular malformation, including an atrial or ventricular septal defect, or conotruncal and aortic arch anomalies. These findings warrant a cardiology evaluation in all patients. The authors postulated a role for aberrant neural crest cell migration in certain features of the disorder, such as craniofacial, gastrointestinal, diaphragmatic, and cardiac defects. Dentici et al. (2009) reported a 6-year-old boy with Fryns syndrome. He was born with congenital diaphragmatic hernia, lung hypoplasia, and intestinal malrotation. He had a coarse facies, large mouth, retrognathia, short neck, corneal leukoma, and narrow thorax with hypoplastic nipples. There were no gross limb anomalies, but he had flexion contractures of the fingers, fifth finger clinodactyly, and malaligned toes. He showed severe psychomotor retardation, with no verbal capacity. Dentici et al. (2009) reviewed proposed diagnostic guidelines for Fryns syndrome, which are based solely on clinical features. The major criteria for a diagnosis of Fryns syndrome is neurologic impairment with mental retardation, often with brain malformations, but other features may be inconstant. Dentici et al. (2009) concluded that their patient fulfilled the criteria for Fryns syndrome even though there was no hypoplasia of distal phalanges.
In France, Ayme et al. (1989) estimated the prevalence of Fryns syndrome to be 0.7 per 10,000 births based on the diagnosis of 6 cases in a series of 112,276 consecutive births (live births and perinatal deaths).
Diagnostic criteria for Fryns syndrome were recently reformulated [Lin et al 2005]. Using these criteria, three categories of individuals with Fryns syndrome are recognized:...
DiagnosisClinical DiagnosisDiagnostic 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: Isochromosome 12p (mosaic tetrasomy 12p; Pallister-Killian syndrome) Partial trisomy for chromosome 22q [de Beaufort et al 2000] Deletion of chromosome 15q26.2 [Slavotinek et al 2005] Deletion of chromosome 8p23.1 [Shimokawa et al 2005, Slavotinek et al 2005] Deletion of chromosome 1q41-1q42 [Shaffer et al 2007] A microdeletion syndrome identified by array comparative genomic hybridization (aCGH). Note: Microdeletion syndromes relatively rarely include a Fryns-like phenotype and multiple malformations.Molecular Genetic TestingGene. 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.
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....
Natural HistoryThe 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 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. ...
Differential DiagnosisFryns 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Fryns syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsThe 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.SurveillanceIn 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 RiskTesting 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 InvestigationMany 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.OtherFor a more detailed discussion on the management of congenital diaphragmatic hernia, see Congenital Diaphragmatic Hernia Overview.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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) View in own window 229850FRYNS SYNDROME; FRNSMolecular Genetic PathogenesisFryns 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.