Fryns Syndrome
Summary
Clinical characteristics.
Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, eventration, hypoplasia, or agenesis); characteristic facial appearance (coarse facies, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, long philtrum, low-set and anomalous ears, tented vermilion of the upper lip, wide mouth, and a small jaw); short distal phalanges of the fingers and toes (the nails may also be small); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformations involving the brain, cardiovascular system, gastrointestinal system, and/or genitalia). Survival beyond the neonatal period is rare. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common.
Diagnosis/testing.
The clinical diagnosis of Fryns syndrome can be established in a proband based on six proposed criteria (diaphragmatic defect, characteristic facial appearance, distal digital hypoplasia, pulmonary hypoplasia, at least one characteristic associated anomaly, and a family history consistent with autosomal recessive inheritance). The molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic variants in PIGN identified by molecular genetic testing.
Management.
Treatment of manifestations: For congenital diaphragmatic hernia, the neonate is immediately intubated to prevent inflation of herniated bowel, surgery, and/or supportive measures as for the general population. Standardized treatment with anti-seizure medications by an experienced neurologist. Additional anomalies may require consultations and management by ophthalmology, cardiology gastroenterology, nephrology, urology, and craniofacial specialists. Developmental services as needed including feeding, motor, adaptive, cognitive, and speech/language therapy.
Surveillance: Those with successful congenital diaphragmatic hernia repair should be followed in a specialized center with periodic evaluations by a multidisciplinary team (pediatric surgeon, nurse specialist, cardiologist, pulmonologist, nutritionist). Monitor those with seizures as clinically indicated.
Assess for new onset of seizures. Monitor developmental progress and educational needs. Follow up with ophthalmology, cardiology, gastroenterology, nephrology, urology, and craniofacial specialists as needed.
Genetic counseling.
Fryns syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PIGN pathogenic variants in the family are known.
Diagnosis
Diagnostic criteria for Fryns syndrome were reformulated by Lin et al [2005] to include the six proposed clinical criteria described in Suggestive Findings: diaphragmatic defect, characteristic facial appearance, distal digital hypoplasia, pulmonary hypoplasia, at least one characteristic associated anomaly, and family history consistent with autosomal recessive inheritance.
Note: Controversies regarding diagnostic criteria include the extent to which phenotypic deviation from the original case reports of Fryns syndrome is tolerable. For example, cases with atypical limb manifestations such as ectrodactyly, radial ray aplasia, limb shortening, and multiple pterygia have been labeled as Fryns syndrome by some authors, but not by others.
Suggestive Findings
Diagnosis of Fryns syndrome should be suspected in individuals with the following clinical and laboratory findings.
Clinical findings
- Diaphragmatic defects including diaphragmatic hernia in any location (most commonly a posterolateral Bochdalek hernia), diaphragmatic eventration, significant diaphragm hypoplasia, or diaphragm agenesis
- Characteristic facial appearance with a coarse face, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, a long philtrum, low-set and anomalous ears, a tented vermilion of the upper lip, wide mouth, and a small jaw
- Short distal phalanges of the fingers and toes. The nails may also be small.
- Pulmonary hypoplasia of a significant degree. This clinical finding can accompany diaphragmatic hernia.
- Characteristic associated anomalies including at least one of the following:
- Polyhydramnios
- Cloudy corneas and/or microphthalmia
- Orofacial clefting
- Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
- Cardiovascular malformation
- Renal dysplasia / renal cortical cysts
- Gastrointestinal malformation
- Genital malformation
- Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Laboratory findings. Absence of a copy number variant associated with congenital diaphragmatic hernia, including chromosome deletions at 15q26.2 and 8p23.1 and mosaic trisomy 1q [Bone et al 2017]. See Differential Diagnosis and Yu et al [2012] and Yu et al [2020] for review.
Establishing the Diagnosis
The clinical diagnosis of Fryns syndrome can be established in a proband based on clinical diagnostic criteria [Slavotinek 2004, Lin et al 2005], or the molecular diagnosis can be established in proband with suggestive findings and biallelic pathogenic variants in PIGN identified by molecular genetic testing (see Table 1).
Clinical diagnosis. Diagnostic criteria for Fryns syndrome were reformulated by Lin et al [2005] to include the six proposed criteria described in Suggestive Findings: diaphragmatic defect, characteristic facial appearance, distal digital hypoplasia, pulmonary hypoplasia, at least one characteristic associated anomaly and family history consistent with autosomal recessive inheritance.
Molecular diagnosis. The molecular diagnosis of Fryns syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in PIGN identified by molecular genetic testing (see Table 1).
Note: Identification of biallelic PIGN variants of uncertain significance (or identification of one known PIGN pathogenic variant and one PIGN variant of uncertain significance) does not establish or rule out the diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings can be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with multiple congenital anomalies are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of PIGN is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A multigene panel that includes PIGN and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is most likely to be used. Exome sequencing is most common; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Fryns Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| PIGN | Sequence analysis 3 | 10 individuals 4 |
| Gene-targeted deletion/duplication analysis 5 | 1 reported 6 | |
| Unknown | NA | See footnote 7. |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Brady et al [2014], McInerney-Leo et al [2016], Alessandri et al [2018]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
5.07-kb deletion with breakpoints in exon 5 and intron 7 (See Table 8.)
- 7.
Genetic heterogeneity for Fryns syndrome remains highly probable, as some individuals with a clinical diagnosis of Fryns syndrome have not had PIGN pathogenic variants identified [McInerney-Leo et al 2016]. The number of individuals meeting the clinical diagnostic criteria for Fryns syndrome with negative testing for PIGN variants is unknown.
Clinical Characteristics
Clinical Description
The term "Fryns syndrome" was first used to describe the clinical findings in two stillborn female sibs, each with a coarse facial appearance, cloudy corneas, a cleft of the soft palate, a small thorax with hypoplastic nipples, proximal insertion of the thumbs, hypoplasia of the terminal phalanges and nails, lung hypoplasia, and congenital diaphragmatic hernia (CDH) with bilateral agenesis of the posterolateral diaphragms [Fryns et al 1979]. As both of the sibs were stillborn, Fryns syndrome was initially considered likely to be a lethal disorder. It is now known that this is not so. However, the natural history of Fryns syndrome is difficult to determine because of the high early mortality. In addition, earlier reports of Fryns syndrome may have mislabeled individuals who either did not have chromosome analysis or did not have adequate laboratory studies to evaluate for copy number variants associated with a Fryns syndrome-like phenotype (see Differential Diagnosis).
Recently, biallelic variants in PIGN have been identified in individuals who met the strict diagnostic criteria for Fryns syndrome [Brady et al 2014, McInerney-Leo et al 2016, Alessandri et al 2018] as described in Establishing the Diagnosis [Lin et al 2005]. As only ten individuals have been identified with biallelic pathogenic variants in PIGN and a Fryns syndrome phenotype [Alessandri et al 2018], the extent of the contribution of this gene to the etiology of Fryns syndrome is not yet known; in addition, it is also unclear if the clinical description of this syndrome should be modified based on the phenotype associated with PIGN variants.
The following description of the phenotypic features associated with this condition is based on reports of individuals with a clinical diagnosis of Fryns syndrome and those with a molecular diagnosis of Fryns syndrome caused by biallelic pathogenic variants in PIGN [Brady et al 2014, McInerney-Leo et al 2016, Alessandri et al 2018].
Table 2.
Fryns Syndrome: Frequency of Select Features
| Feature | Proportion of Persons w/Feature | Comment | |
|---|---|---|---|
| Persons w/a clinical diagnosis of Fryns syndrome 1 | Persons w/biallelic PIGN pathogenic variants 2 | ||
| Polyhydramnios | 56% | 6/10 | |
| Diaphragmatic hernia | >90% | 7/10 | |
| Structural brain malformations | 88% | 3/10 | |
| Ocular anomalies | >6% 3 | 2/6 | |
| Cardiac anomalies | >40% 3 | 6/10 | |
| Gastrointestinal anomalies | >15% 3 | Not established | |
| Genitourinary anomalies | >25% 3 | 5/10 | |
| Dysmorphic features | >55% 3 | 8/10 | |
| Distal digital hypoplasia | >60% 3 | 8/10 | |
| Developmental delay | Unknown due to poor survival | NA | Perinatal death in 10/10 persons w/PIGN pathogenic variants |
- 1.
PIGN testing status is not known for these individuals.
- 2.
Alessandri et al [2018]
- 3.
Slavotinek [2004]
Prenatal findings. CDH and the other malformations found in Fryns syndrome can be visualized by ultrasound scan in the prenatal period, usually from the second trimester, but the diagnosis of Fryns syndrome is rarely established prior to birth [Peron et al 2014] and requires appropriate cytogenetic and molecular genetic testing. Prenatal findings in those with PIGN variants have included nuchal translucency, severe septated cystic hygromata, fetal ascites, a small exomphalos, moderately hyperechogenic bowel, echogenic kidneys, and femur length at the fifth centile [McInerney-Leo et al 2016]. Polyhydramnios has also been noted in the second and third trimester and has been described as "massive" [Alessandri et al 2018].
Survival/prognosis. The prognosis in Fryns syndrome is influenced by the malformations present and has been described as more promising in those without CDH than in those with CDH. Survival beyond the neonatal period is uncommon both in those with a clinical diagnosis of Fryns syndrome and in individuals with biallelic PIGN variants (none of whom survived the neonatal period). No sex differences have been noted.
Diaphragmatic abnormality / respiratory concerns. CDH is found in more than 90% of individuals with a clinical diagnosis of Fryns syndrome [Peron et al 2014]. A unilateral, left-sided Bochdalek hernia is most commonly observed. Diaphragmatic defects were identified in 50% of individuals with PIGN pathogenic variants. Abnormal pulmonary lobation was also noted in one individual.
Neurologic findings. Structural brain malformations in those with PIGN pathogenic variants have included thinning and shortening of the corpus callosum, hypoplasia of the cerebellar vermis, and agenesis of the olfactory bulbs.
Ocular findings. Eye findings previously associated with Fryns syndrome have included central/paracentral corneal clouding that may result from abnormal corneal endothelium, microphthalmia, irregularities of Bowman's layer, thickened posterior lens capsule, and retinal dysplasia [Cursiefen et al 2000]. In those with PIGN pathogenic variants, cloudy corneas and cataracts have been described.
Cardiac findings. In individuals diagnosed clinically with Fryns syndrome, ventricular septal defect was the most frequently observed cardiac malformation; atrial septal defects and aortic abnormalities have also been reported. In individuals with PIGN pathogenic variants, tetralogy of Fallot, ventricular septal defect, patent ductus arteriosus, overriding aorta, hypoplastic pulmonary trunk, and an aberrant retro-esophageal right subclavian artery have been described. One fetus had a mildly hypoplastic right ventricle with pulmonary valve stenosis and narrowed pulmonary trunk, membranous ventricular septal defect, and an aberrant right subclavian artery arising distal to the left subclavian artery.
Gastrointestinal findings. Abdominal defects have included exomphalos and intestinal malrotation in individuals with PIGN pathogenic variants. Anal malformations have been noted in individuals with a clinical diagnosis of Fryns syndrome, but not reported in those with PIGN pathogenic variants.
Genitourinary findings. Renal pyelectasis, segmental renal dysplasia, micropenis, and cryptorchidism have been reported in individuals with PIGN pathogenic variants. Hypospadias and bicornuate uterus as seen in individuals diagnosed clinically with Fryns syndrome have not been reported to date in association with PIGN pathogenic variants.
Dysmorphic findings. The most characteristic facial features for individuals with a clinical diagnosis of Fryns syndrome include a coarse face, wide-spaced eyes with cloudy corneas, a wide and flat nasal bridge with anteverted nares, anomalous and low-set ears, macrostomia, and a small jaw. Facial features in individuals with PIGN pathogenic variants have been described as coarse with wide-spaced eyes, a small nose, flat nasal bridge, anteverted nares, a long philtrum, macrostomia, and small low-set anomalous ears. Clefts of the lip and palate have also been noted. One fetus had mild axillary pterygia and a synovial cyst attached to the left heel [Brady et al 2014].
Skeletal findings. Small nails and short terminal phalanges of the fingers and toes are frequent and useful diagnostic findings in Fryns syndrome. In individuals with PIGN pathogenic variants, short thumbs and fingers (most pronounced for the fifth finger), short toes, and small or absent nails were reported. Unilateral talipes was also described. One male with PIGN pathogenic variants had oligodactyly of the left foot, with absence of rays three to five, hypoplasia of the remaining toes, and absent toenails [Brady et al 2014], which would be considered atypical for Fryns syndrome. Nail defects were not present in all individuals [McInerney-Leo et al 2016].
Development. Developmental delay ranging from relatively mild impairment to severe intellectual disability has been reported in individuals with clinically diagnosed Fryns syndrome. Due to impaired survival, the developmental course is not known for those with Fryns syndrome caused by PIGN pathogenic variants.
Genotype-Phenotype Correlations
No genotype-phenotype correlations for PIGN-related Fryns syndrome have been identified.
Prevalence
Fryns syndrome was present in seven of 100,000 live births in a French population [Aymé et al 1989], but this prevalence was established before the advent of many genetic testing methodologies. No more recent prevalence estimates have been published.
Fryns syndrome may be the most common autosomal recessive disorder associated with congenital diaphragmatic hernia (CDH); see Congenital Diaphragmatic Hernia Overview). The incidence of Fryns syndrome has been estimated in large cohorts of individuals with CDH.
- In one study, 23 (1.3%) of 1,833 persons with CDH observed over a six-year period were diagnosed with Fryns syndrome [Neville et al 2002].
- Earlier studies estimated the incidence of Fryns syndrome at 4%-10% of persons with CDH.
Some individuals with PIGN-related Fryns syndrome have shared ancestry from La Réunion and other Indian Ocean islands, with a founder effect considered likely for a pathogenic, intragenic deletion [Alessandri et al 2018] (see Molecular Genetics).
Differential Diagnosis
Disorders associated with complex congenital diaphragmatic hernia (CDH) may resemble Fryns syndrome, but are distinguishable from Fryns syndrome by their recognizable patterns of anomalies and an absence of characteristic nail or digital hypoplasia. See Table 3.
Table 3.
Monogenic Disorders Associated with Complex Congenital Diaphragmatic Hernia of Interest in the Differential Diagnosis of Fryns Syndrome
| Gene(s) | Disorder | MOI | CDH 1 | Other Characteristic Features |
|---|---|---|---|---|
| GPC3 GPC4 2 | Simpson-Golabi-Behmel syndrome type 1 (SGBS1) | XL | Rare |
|
| EFNB1 | Craniofrontonasal syndrome (CFNS) (OMIM 304110) | XL | Rare (can occur in both males & females w/CFNS) | Coronal synostosis, facial anomalies (wide-set eyes, wide nasal tip), & skeletal anomalies |
| PORCN | Focal dermal hypoplasia (Goltz syndrome) | XL | Rare | Linear skin pigmentation, fat herniation, eye anomalies incl microphthalmia, small teeth, digital anomalies |
| BRD4 HDAC8 NIPBL 4 RAD21 SMC1A SMC3 | Cornelia de Lange syndrome (CdLS) | AD XL | Rare | Facial anomalies (high-arched &/or joined eyebrows, long eyelashes, short nose w/anteverted nares, small & widely spaced teeth), microcephaly, growth restriction, hirsutism, upper-limb reduction defects, ID, autistic features, self-destructive behavior |
| WT1 | WT1 disorder (incl Denys-Drash syndrome, Frasier syndrome, Meacham syndrome) 5 | AD | Rare | Urogenital anomalies, Wilms tumor, nephropathy, glomerulopathy, disorders of sexual development |
| FBN1 | Marfan syndrome | AD | Rare | Musculoskeletal, cardiac, & ocular defects; diaphragmatic eventration & hernia can be assoc w/early-onset Marfan syndrome. 6 |
| NR2F2 | Congenital heart defects, multiple types, 4 (OMIM 615779) | AD | Variable | Fryns syndrome-like craniofacial anomalies, cardiovascular malformations, hypoplastic genitalia or cryptorchidism, severe prenatal growth deficiency, ID, talipes equinovarus &/or rockerbottom feet, single umbilical artery |
| LRP2 | Donnai-Barrow syndrome | AR | Core feature | Facial anomalies (wide-set eyes, enlarged anterior fontanelle); high myopia, retinal detachment, progressive vision loss, iris coloboma, sensorineural deafness; agenesis of corpus callosum; omphalocele; ID |
| RARB STRA6 | Matthew-Wood syndrome (PDAC syndrome; syndromic microphthalmia) (OMIM 615524, 601186) | AR AD | Core |
|
AD = autosomal dominant; AR = autosomal recessive; CDH = congenital diaphragmatic hernia; CHD = congenital heart defect; ID = intellectual disability; MOI = mode of inheritance; PDAC = pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, & cardiac defect; XL = X-linked
- 1.
See also Congenital Diaphragmatic Hernia Overview.
- 2.
SGBS1 is caused by a pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4.
- 3.
Individuals with SGBS are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, and hepatocellular carcinoma.
- 4.
CDH occurring in CdLS is typically associated with pathogenic variants in NIPBL [Yu et al 2020].
- 5.
Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome were originally described as distinct disorders on the basis of clinical findings but are now understood to represent a continuum of features caused by a WT1 heterozygous pathogenic variant.
- 6.
Veiga-Fernández et al [2020]
Table 4.
Chromosome Anomalies Associated With Congenital Diaphragmatic Hernia and Additional Major Malformations/Dysmorphology
| Chromosome Abnormality | Critical Genes Included | Facial Phenotype | Other Clinical Characteristics (in addition to CDH) |
|---|---|---|---|
| Pallister-Killian syndrome (PKS) 1 (mosaic tetrasomy 12p) (OMIM 601803) |
|
| |
| Del 15q26.2 (OMIM 142340) | NR2F2 5 | Fryns syndrome-like craniofacial anomalies | CHD, hypoplastic genitalia or cryptorchidism, severe prenatal growth deficiency, ID, talipes equinovarus &/or rockerbottom feet, single umbilical artery |
| Del 8p23.1 (OMIM 222400) | GATA4 SOX7 5 | Mild facial anomalies | CHD (e.g., heterotaxy), renal anomalies, ID |
| Del 8q22-q23 | ZFPM2 5 | Blepharophimosis, widely spaced eyes, epicanthus, flat malar region, thin vermillion of upper lip, downturned corners of mouth, ↓ facial movement | ID w/absent speech, microcephaly, seizures, growth delays 6 |
| Del 1q41-q42 (OMIM 612530) | HLX DISP 5 | Limb anomalies (e.g., talipes), cleft lip & palate, seizures, ID | |
| Del 15q24 (OMIM 613406) | Typical craniofacial features | Malformations of hands & feet, growth delays, ID w/marked speech delay | |
| Del 4p16.3 (OMIM 194190) | FGFRL1 5 | Typical facial anomalies assoc w/Wolf-Hirschhorn syndrome | Skeletal anomalies, ID, growth delays |
| Del 22q11.2 | Typical facial anomalies assoc w/22q11.2 deletion syndrome, cleft palate |
| |
| Del 17q12 | Facial anomalies (See 17q12 Recurrent Deletion Syndrome.) | MODY, cystic renal disease, pancreatic & liver abnormalities, macrocephaly, ID 8 |
AD = autosomal dominant; AR = autosomal recessive; CDH = congenital diaphragmatic hernia; CHD = congenital heart defect; ID = intellectual disability; MODY = maturity-onset diabetes of the young
- 1.
See also Congenital Diaphragmatic Hernia Overview.
- 2.
In some persons, only chromosome analysis and/or the inheritance pattern can distinguish between PKS and Fryns syndrome [Veldman et al 2002]. To evaluate for PKS, skin fibroblasts, chorionic villus cells, or amniocytes should be karyotyped because of the phenomenon of tissue-specific mosaicism in which the isochromosome 12p can be present in some cells (e.g., fibroblasts), but not others (e.g., lymphocytes). It is important to note that a normal karyotype or CMA on peripheral blood lymphocytes does not exclude PKS, although CMA may detect PKS when the percentage of tetrasomic cells is relatively high.
- 3.
Izumi & Krantz [2014]
- 4.
Sparse hair is characteristic of PKS, in contrast to Fryns syndrome, in which the sisters originally described by Fryns had low hairlines and hypertrichosis.
- 5.
Yu et al [2020]
- 6.
Kuechler et al [2011]
- 7.
Unolt et al [2017]
- 8.
Goumy et al [2015]
Management
No clinical practice guidelines for Fryns syndrome have been published.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual with Fryns syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with Fryns Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| CDH | Chest & abdominal radiographs | |
| Neurologic |
| |
| Eyes | Ophthalmology exam incl fundoscopy | |
| Cardiovascular | Echocardiogram | |
| Gastrointestinal | Upper gastrointestinal imaging to evaluate for intestinal malrotation | |
| Genitourinary | Renal US exam | |
| Ears/Nose/Throat | Eval w/ENT &/or craniofacial team if cleft palate is suspected | |
| Development | Developmental assessment |
|
| Genetic counseling | By genetics professionals 1 | To inform affected persons & families re nature, MOI, & implications of Fryns syndrome to facilitate medical & personal decision making |
| Family support/ resources | Assess:
|
CDH = congenital diaphragmatic hernia; MOI = mode of inheritance; US = ultrasound
- 1.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations
Table 6.
Treatment of Manifestations in Individuals with Fryns Syndrome
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| CDH | Neonates w/CDH require immediate intubation to prevent inflation of herniated bowel. See also Congenital Diaphragmatic Hernia Overview. | CDH in Fryns syndrome may be amenable to prenatal surgical repair. Survival in a controlled trial of open hysterotomy-guided fetal endoscopic tracheal occlusion vs conventional care was not improved; percutaneous fetal endoluminal tracheal occlusion is still being evaluated [Losty 2014]. |
| Seizures | Standardized treatment w/antiseizure medications by experienced neurologist | |
| Cataracts / Other ocular anomalies | Management per ophthalmologist | |
| Congenital heart defects | Management per pediatric cardiologist | |
| Gastrointestinal malformations | Surgical repair per pediatric gastroenterologist & pediatric surgeon | |
| Genitourinary malformations | Management per pediatric nephrologist &/or urologist | |
| Cleft palate | Management per craniofacial team | |
| Developmental delay | Developmental services as needed incl feeding, motor, adaptive, cognitive, & speech/language |
CDH = congenital diaphragmatic hernia
Surveillance
Table 7.
Recommended Surveillance for Individuals with Fryns Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Following successful CDH repair | Evals by pediatric surgeon, nurse specialist, cardiologist, pulmonologist, & nutritionist | As recommended by specialist(s) |
| Neurologic | Monitor those w/seizures as clinically indicated; assess for new onset of seizures. | At each visit |
| Development | Monitor developmental progress & educational needs. | |
| Ocular anomalies | Ophthalmology eval | As needed |
| Congenital heart defects | Follow up w/cardiologist | |
| Gastrointestinal malformations | Follow up w/gastroenterologist | |
| Genitourinary malformations | Follow up w/nephrologist or pediatric urologist | |
| Cleft palate | Follow up w/craniofacial specialists |
CDH = congenital diaphragmatic hernia
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Pregnancies are managed according to the malformations that have been diagnosed. One literature review concluded that fetoscopic endoluminal tracheal occlusion used as a prenatal interventional strategy can increase survival in cases with severe CDH [Cundy et al 2014], although this technique has most frequently been used for isolated CDH rather than Fryns syndrome.
Therapies Under Investigation
Many different treatments are currently being evaluated for the management of congenital diaphragmatic hernia.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.