Fryns syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Fryns syndrome is a condition that affects the development of many parts of the body.

Most people with Fryns syndrome have a defect in the muscle that separates the abdomen from the chest cavity (the diaphragm). The most common defect is a congenital diaphragmatic hernia, which is a hole in the diaphragm that develops before birth. This hole allows the stomach and intestines to move into the chest and crowd the heart and lungs. As a result, the lungs often do not develop properly (pulmonary hypoplasia), which can cause life-threatening breathing difficulties in affected infants.

People with Fryns syndrome typically have abnormalities of the fingers and toes and distinctive facial features. The tips of the fingers and toes tend to be underdeveloped, so they can look short and stubby and have small nails or no nails at all. Affected individuals may have widely spaced eyes (hypertelorism), a broad and flat nasal bridge, a thick nasal tip, a long space between the nose and upper lip (a long philtrum), a large mouth (macrostomia), and a small lower jaw (micrognathia). Many also have low-set and abnormally shaped ears.

Additional features of Fryns syndrome include small eyes (microphthalmia), clouding of the clear outer covering of the eye (the cornea), and an opening in the roof of the mouth (cleft palate) with or without a split in the lip (cleft lip). Fryns syndrome can also affect the development of the brain, heart, digestive system, kidneys, and genitalia.

Because there are significant health problems associated with congenital diaphragmatic hernias, most children with Fryns syndrome do not survive past infancy. Affected individuals who do survive into childhood often have severe developmental delays and intellectual disabilities.

The features of this condition often overlap with those of other disorders. As a result, Fryns syndrome can be difficult to diagnose.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the PIGN gene have been found to cause some cases of Fryns syndrome. The PIGN gene provides instructions for making an enzyme called GPI ethanolamine phosphate transferase 1. This enzyme takes part in a series of steps that produce a molecule called a glycophosphatidylinositol (GPI) anchor. The GPI anchor transports many different proteins to the cell membrane, ensuring that these proteins are available when needed.

The PIGN gene variants that cause Fryns syndrome are known as "loss-of-function variants" because they reduce the amount of functional GPI ethanolamine phosphate transferase 1 enzyme that is available to modify the GPI anchor. As a result, the GPI anchor cannot deliver proteins to their proper places on the cell membrane. This disrupts critical developmental pathways, which leads to the signs and symptoms seen in people with Fryns syndrome.

Researchers are trying to determine other possible genetic causes for Fryns syndrome. Chromosomal changes, such as missing (deleted) chromosomal material, that can cause features similar to those seen in people with Fryns syndrome are of particular interest to investigators.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Fryns syndrome appears to be inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The exact prevalence of Fryns syndrome is unknown; fewer than 100 individuals with this condition have been reported in the medical literature. Studies suggest that up to 10 percent of all cases of congenital diaphragmatic hernia may be due to Fryns syndrome.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Broad forehead · Very frequent (99-80%)

Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.

Congenital diaphragmatic hernia · Very frequent (99-80%)

The presence of a hernia of the diaphragm present at birth.

High palate · Very frequent (99-80%)

Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).

Hypoplastic fingernail · Very frequent (99-80%)

Underdevelopment of a fingernail.

Intellectual disability · Very frequent (99-80%)

The term intellectual disability or intellectual developmental disorder is used to describe significantly sub-average intellectual and adaptive functioning based on clinical assessment and as measured by individually administered, appropriately normed, standardized and validated tests of intellectual functioning and adaptive behavior, with onset during the developmental period from infancy through adolescence.

Long philtrum · Very frequent (99-80%)

Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.

Micrognathia · Very frequent (99-80%)

Developmental hypoplasia of the mandible.

Multicystic kidney dysplasia · Very frequent (99-80%)

Multicystic dysplasia of the kidney is characterized by multiple cysts of varying size in the kidney and the absence of a normal pelvicaliceal system. The condition is associated with ureteral or ureteropelvic atresia, and the affected kidney is nonfunctional.

Other findings in the same source

From: Orphanet

Additional reported features include Posteriorly rotated ears (Very frequent (99-80%)); Severe global developmental delay (Very frequent (99-80%)); Short neck (Very frequent (99-80%)); Tented upper lip vermilion (Very frequent (99-80%)); Wide nasal bridge (Very frequent (99-80%)); Aplasia/Hypoplasia of the nipples (Very frequent (99-80%)); Pulmonary hypoplasia (Very frequent (99-80%)); Abnormal cardiac septum morphology (Frequent (79-30%)); Agenesis of corpus callosum (Frequent (79-30%)); Anteverted nares (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Fryns syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Fryns syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.