Overview

Fryns Syndrome is an extremely rare genetic developmental disorder characterized by anomalies in several organs of the body. It is a congenital disorder, and fetuses as well as infants show an increased mortality. It is autosomal recessive; thus, the defective gene needs to be inherited from one's parent, and only then in the case of both parents, will they cause the condition. The gene causing the disorder has not yet been identified¹.

An underdeveloped diaphragm with a severe hernia, certain characteristic facial appearance, and lung and limb abnormalities are typical features of this anomaly. In Fryns Syndrome, symptomatic treatment and support are afforded to the individual depending on that individual's problem. Generally, the prognosis for Fryns Syndrome is not very good.  

Despite being reported first in 1979, its exact aetiology has yet to be established. 

Risk factor

The following are the risk factors for Fryns Syndrome:

It runs in families, and children are at risk of Fryns Syndrome if they are born in families with a previous medical history of the condition.¹

Individuals with a diaphragmatic hernia, which involves a malformation of the separating diaphragm membrane between the abdomen and pulmonary region, are high at risk. Incidences have reportedly shown that among children with CDH, approximately 1 in every 10-75 cases has been found to have Fryns Syndrome.

Causes

The specific gene/s responsible for Fryns syndrome are not known but, because of patterns detected within families, it is considered to be an autosomal recessive condition.

A genetic disorder can be recessive if an individual receives two copies of the altered genes responsible for the condition-one copy from either parent. If one normal gene and one disease gene are inherited, the person will not usually show symptoms but be a carrier for the disease. Sharing parents means that with every pregnancy, there is a 25% chance the altered gene will be passed on to a child and that the child will be affected. With every pregnancy, there is a 50% risk of having a child who is a carrier like both parents.²

There is a 25% chance the child will receive normal genes from both parents. The risk for males and females is equal. The risk in every pregnancy is equal.

All individuals in the general population are carriers of 4-5 abnormal genes. Consanguineous parents are more likely than unrelated parents to share the same abnormal gene, thereby increasing the chance of having children affected with a recessive genetic disorder.

Clinical features

Generally, Fryns syndrome is characterized by the presence of multiple congenital anomalies of variable severity in different individuals.² Though not all patients appear with the following features, the most common clinical manifestations of this condition include the following:

• Over 90 percent with Fryns syndrome have a congenital diaphragmatic hernia: the diaphragm does not fully develop and allows contents like the small intestine, liver, and stomach to migrate into the chest cavity. The most frequent hernia seen is a unilateral, left-sided hernia. Underdevelopment of the lung, or lung hypoplasia, along with other respiratory issues often accompanies this
• Individuals with Fryns syndrome generally have typical physical manifestations such as a coarse face, widely set eyes, the cloudy outer layer of the eyes, the wide and flat nasal bridge with nostrils facing towards the top of the head, malformed and low-set ears, wide mouth, and small jaw. A cleft palate or incomplete closure of the two sides of the roof of the mouth has been reported in 50% of individuals. Incomplete closure of the two sides of the lip has been reported in 25% of patients
• Hypoplasia of nails and finger bones has been described in 60% of individuals with Fryns syndrome. First digits have been reported to be broad in 10%, with a hand deformity known as camptodactyly, or bent fingers. Scoliosis, extra ribs, and abnormalities of the development of bone and cartilage, termed osteochondrodysplasias have also been described
• Other associated anomalies have also been sometimes reported in individuals with Fryns syndrome
  • Most of the affected children showed neurological abnormalities due to structural brain malformations, including seizures in at least one child
    • The dilatation of the lateral ventricles in the brain are cavities through which cerebrospinal fluid flows is called ventriculomegaly. The Corpus callosum connects the two halves of the cerebrum with nerve fibres
    • Dandy-Walker malformation consists of an enlarged fourth ventricle of the brain and the fluid space around the brain over the area of the base of the skull known as the posterior fossa, with an underdevelopment of the midline cerebellar vermis responsible for coordination and arrangement of the body
  • Cardiac defects are not infrequent; 40% have a ventricular septal defect, 10% an atrial septal defect, and 10% abnormalities of the aorta. In both VSD and ASD, there is an opening of the heart in different parts; whereas in the case of VSD, there is the appearance of the lower two-chamber of the heart; The upper two chambers have an opening that may be seen in the case of ASD
  • Although in most cases the diaphragmatic defect occurs in isolation, due to the abnormality in the diaphragm in patients with CDH other abdominal defects may occur. These include omphalocele, an outpouching of the abdominal wall where intestines, liver, and other organs develop outside the abdominal wall; anal malformations; and intestinal malrotation, when intestines are twisted, preventing passage of food
  • About 10% of individuals with Fryns syndrome also have genital and urinary abnormalities. There can be cysts in the kidneys (renal cysts) and the connected structure, the ureter may be big or dilated (mega- or hydro-ureter), or even contain cysts. The development of the kidney may not be proper: renal dysplasia
  • Males may have one or both testes undescended in the scrotum-hypospadias, or a small penis; often an abnormal position of the urethral opening is found. Females may have an abnormal heart-shaped uterus, which contains two rather than a single large cavity called a bicornuate uterus
  • Survival beyond the neonatal period seldom occurs, and survivors beyond the neonatal period are reported to have developmental delays

The degree of developmental delay and intellectual disability varies among affected individuals. Whereas in the past, all were considered to have severe developmental delays, a few children have been reported with mild learning disabilities. In two cases, growth has been said to be normal; however, growth in most individuals who have survived beyond the neonatal period is not available.

Diagnosis

Fetal testing can be performed to diagnose Fryns Syndrome in pregnant women, or neonatal testing is done on the newborn child. Genetic testing and DNA analysis are not possible as yet, due to the unknown genes related to this syndrome.¹ The major tests include the following:

• Physical examination of the newborn child: 3 or 4 of the key features (out of a set of 6) must be present, for the disorder to be classified as Fryns Syndrome. These include:
  • Diaphragmatic hernia
  • Abnormal facial appearance
  • Distal digital hypoplasia (malformed digits)
  • Significantly underdeveloped lungs (pulmonary hypoplasia)
  • One member present, for example, a parent-family history showing the condition or a sibling with the condition
  • Malformation of any one of the following: Brain, cardiovascular system, GI system, genitals, eyes (cloudy cornea), lips and palate (orofacial cleft), kidney dysplasia, or excess amniotic fluid
• Ultrasonography, which is performed prenatally
• MRI scan of the fetus
• Evaluation of the family medical history; presence of an affected sibling or cousin, or the establishment of consanguineous parents or spouses

Differential diagnosis 

• Donnai-Barrow syndrome
• Matthew-Wood syndrome
• Simpson-Golabi-Behmel syndrome
• Craniofrontonasal syndrome
• Cornelia de Lange syndrome
• Tetrasomy 12p
• Distal monosomy 15q 
• Bi-allelic variants in PIGN may also cause multiple congenital anomalies- hypotonia-seizures syndrome (MCAHS1) unrelated to CDH³

Treatment

Treatment of manifestations

Congenital diaphragmatic hernia-Stabilizing the neonate immediately onto a ventilator to prevent dilatation of the herniated bowel, Surgery, and/or supportive therapy as described for the general population. Medical treatment because the seizures are often resistant to medication should be standardized with anti-seizure medications by an experienced neurologist. Other anomalies may involve ophthalmology, cardiology, gastroenterology, nephrology, urology, and craniofacial specialists. Developmental services, as needed: feeding, motor, adaptive, cognitive, and speech/language therapy.⁴

Surveillance

Survivors of congenital diaphragmatic hernia repair should be followed in a specialized centre with periodic evaluations by a multidisciplinary team of pediatric surgeons, nurse specialists, cardiologists, pulmonologists, and nutritionists. Follow children with seizures as clinically indicated.

Monitor for new onset of seizures Assess developmental progress and educational needs Follow through with ophthalmology, cardiology, gastroenterology, nephrology, urology, and craniofacial specialists as needed.

Genetic counselling

Fryns syndrome is inherited as an autosomal recessive disease. There is a 25% chance at the time of conception that each sibling of an affected individual is affected, a 50% chance that each sibling is an asymptomatic carrier and a 25% chance that each sibling is unaffected and not a carrier. Heterozygotes are asymptomatic. Testing of at-risk relatives for known pathogenic variants in the PIGN gene and prenatal testing, if desired, during pregnancies at increased risk is recommended.

Prognosis

Fryns Syndrome is another lethal genetic condition which has a very bad prognosis. Lately, most of the fetuses are spontaneously aborted, or a lot of babies can be stillborn. A majority of the infants, when born, die during the initial few months due to severe complications.¹

Birth defects and developmental deformities drastically affect the children who survive the initial phase into early adolescence.

The prognosis depends on the number and severity of malformations. Generally, those individuals without difficulties with a diaphragmatic hernia do slightly better.

Summary

Fryns Syndrome is a highly lethal genetic disorder in infancy and fetus, autosomal recessive. Many organs are affected, including an underdeveloped diaphragm, abnormal facies along with other developmental abnormalities. Diagnosis is based on clinical features supported by investigations. Management is symptomatic and supportive. The prognosis is grim as most lives affected by it do not usually survive beyond early adolescence.