NORD gratefully acknowledges Stephanie Koo, NORD Editorial Intern from the University of Connecticut, and Angela Peron, MD, Clinical Geneticist, Child Neurology Unit, San Paolo Hospital, Department of Health Sciences, Università degli Studi, Milan, Italy; Research Associate, Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, for assistance in the preparation of this report.
Fryns syndrome is a rare genetic condition in which multiple abnormalities are present at birth. Characteristics of the syndrome are broadly categorized into diaphragmatic defects (diaphragmatic hernia) with incomplete development of the lungs, distinctive facial features, underdevelopment of the ends of the fingers and toes (distal digital hypoplasia), and other associated abnormalities of the brain, eyes, heart, gastrointestinal and genitourinary system. Fryns syndrome is thought to be inherited as an autosomal recessive condition, but the specific causal gene or genes have not yet been identified.
Fryns syndrome was described for the first time in 1979, and about 50 patients have been reported in the medical literature since then. While originally thought to be a lethal disorder, there are few documented individuals that have survived into childhood, although survival beyond the neonatal period is extremely are. Since there is a wide variety of signs and symptoms, treatment and prognosis for the condition vary greatly from person to person.
Fryns syndrome is characterized by multiple congenital anomalies that vary in severity from person to person. Although not all patients present with the following characteristics, the most common clinical features in this condition are:
1.Diaphragmatic defects and pulmonary hypoplasia
2.Distinctive facial appearance
3.Distal digital hypoplasia
4.Characteristic associated anomalies: excess amniotic fluid (polyhydramnios), cloudy corneas and/or abnormally small eyes (microphthalmia), orofacial clefting, brain malformation, cardiovascular malformation, gastrointestinal malformation, renal dysplasia/renal cortical cysts, genital malformation
1. More than 90% of individuals with Fryns syndrome have congenital diaphragmatic hernia (CDH): this means that the diaphragm is not completely formed, resulting in contents like the small intestine, liver, and stomach moving into the chest cavity. The most common hernia is a unilateral, left-sided hernia. Underdevelopment of the lung (lung hypoplasia) and other respiratory concerns are commonly associated.
2. Individuals with Fryns syndrome commonly have characteristic facial features such as coarse face, widely spaced eyes (hypertelorism), and a cloudy outer layer of the eye (cloudy cornea), broad and flat nasal bridge with nostrils that face the top of the head (anteverted nares), malformed (dysplastic) and low-set ears, wide mouth (macrostomia), and small jaw (microretrognathia). Cleft palate, or incomplete closure of the two sides of the roof of the mouth, has been reported in 50% of individuals. Cleft lip was reported in 25% of patients.
3. Individuals with Fryns syndrome can have underdevelopment (hypoplasia) of nails and finger bones, reported in 60% of those affected. 10% of the patients have broad first digits, and bent fingers (camptodactyly). Side-to-side curvature of the spine (scoliosis), extra ribs, abnormalities of development of bone and cartilage (osteochondrodysplasia) have also been described.
4. Other associated anomalies have been reported in some individuals with Fryns syndrome.
Neurological abnormalities due to structural brain malformations were found in the majority of affected children, with seizures presenting in at least one child. Examples of abnormalities are ventriculomegaly, failure of development (agenesis) of the corpus callosum, and Dandy-Walker malformation. Ventriculomegaly is the enlargement of the lateral ventricles of the brain, the cavities where cerebrospinal fluid flows. The corpus callosum connects the two halves of the brain with nerve fibers. In Dandy-Walker malformation, the fourth ventricle of the brain and the base of the skull (posterior fossa) are enlarged, and the cerebellar vermis, an area of the brain responsible for coordination of body arrangement, is underdeveloped. More information on these syndromes and how they can be diagnosed and treated may be found in the Rare Disease Database.
Cardiac defects are frequently observed, with 40% presenting with ventricular septal defect, 10% with atrial septal defects, and 10% with abnormalities of the aorta. Ventricular septal defects have an opening in the heart’s lower two chambers, while atrial septal defects are in the upper two chambers.
Due to the abnormality in the diaphragm in CDH patients, other abdominal defects sometimes occur. These can include omphalocele, where intestines, liver, and other organs develop outside of the abdominal wall, anal malformations, and intestinal malrotation, when intestines are twisted preventing passage of food.
About 10% of individuals with Fryns syndrome also present with genital and urinary abnormalities. Cysts in the kidneys (renal cysts) can be present, and the connected structure, the ureter, may be big or dilated (mega- or hydro-ureter) or have cysts. The kidney may not develop properly (renal dysplasia). Males can have one or both testes that have not descended in the scrotum (cryptorchidism) or have a small penis; sometimes the urethral opening is in an unusual position (hypospadias). Females may have an abnormal heart-shaped uterus that is split into two instead of one large cavity, called a bicornuate uterus.
Survival beyond the neonatal period is rare, and those who survive past this stage have documented developmental delays. The degree of developmental delay and intellectual disability varies from individual to individual. While previously it was thought that all individuals had severe developmental delay, a few children have been reported with milder learning disabilities. Growth has been reported to be normal in two children, but growth data for most individuals who survived past the neonatal period is not available.
The specific gene/s that cause Fryns syndrome are not known, but due to patterns detected within families, it is thought that Fryns syndrome is an autosomal recessive condition.
Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same condition, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. The risk is also the same for each pregnancy.
All individuals in the general population carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.
Fryns syndrome is a rare disease that affects both males and females equally. A 1989 French study reported 7 cases per 100,000 live births, but no other recent estimates of prevalence have been published.
Diagnosis of Fryns syndrome is clinical, and based on the following six clinical features:
2.Distinctive facial appearance
3.Distal digital hypoplasia
5.At least one characteristic associated anomaly: polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, brain malformation, cardiovascular malformation, gastrointestinal malformation, renal dysplasia/renal cortical cysts, genital malformation
6.Affected sibs or parental consanguinity
Due to the variability of physical findings associated with the condition, several definitions have been suggested. A narrow definition of Fryns syndrome is if four out of six clinical features are present. A broad definition is the presence of three of the six clinical features (without distinctive facial characteristics of another syndrome). An atypical definition includes unusual features of Fryns syndrome, such as absence of the radius bone in the arm (radial aplasia) or excessive tissue membrane occurring in various parts of the body (pterygia).
It is important to rule out chromosomal disorders, usually by chromosomal microarray analysis, before making a diagnosis of Fryns syndrome.
Recently, three fetuses with Fryns syndrome were found to have two (biallelic) mutations in the PIGN gene, but further studies are needed to confirm whether or not mutations in this gene cause Fryns syndrome in a subset of patients.
The extent of the disease may be evaluated through imaging scans of the chest, brain, abdomen, and more as needed. The diagnosis is usually made after birth. Only rarely, a diagnosis of Fryns syndrome may be suspected before birth based on the results of an ultrasound, where pictures are taken of the fetus using sound waves.
There is currently no cure for Fryns syndrome. Treatment is geared toward addressing the individual’s needs. Surgery for diaphragmatic hernia and/or supportive measures are often suggested.
Due to the life-threatening nature of certain complications such as diaphragmatic hernia, underdevelopment of the lungs, and cardiac defects, procedures shortly after birth may be needed for the newborn. For example, children with diaphragmatic hernia are intubated to prevent inflation of the herniated bowel. Consultation by pediatric neurologists, cardiologists, gastroenterologists, nephrologists, and craniofacial specialists may be appropriate.
Genetic counseling is recommended for parents of a child with Fryns syndrome.
While there are no treatments for Fryns syndrome directly, there are new approaches being evaluated in clinical trials for treatment of congenital diaphragmatic hernia.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources contact: www.centerwatch.com.
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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