Fraser syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Fraser syndrome is a rare disorder that affects development before birth. Characteristic features of this condition include:

Cryptophthalmos is the most common abnormality in people with Fraser syndrome. In most cases, both eyes are completely covered by skin. However, in some affected individuals, only one eye is covered, or one or both eyes are partially covered. Additional eye abnormalities may include:

Because of these eye abnormalities, people with Fraser syndrome may have partial or complete vision loss.

Individuals with Fraser syndrome often have abnormalities in their reproductive and urinary tracts. These can include:

Affected individuals may also have other kidney problems or abnormalities of other parts of the urinary tract, such as the bladder.

A variety of other signs and symptoms can be associated with Fraser syndrome:

Intellectual disabilities sometimes occur, although many people with Fraser syndrome have normal intelligence. The specific features and the severity of Fraser syndrome can vary widely. In severe cases, abnormalities of the airway or kidneys can be fatal before or shortly after birth.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the FRAS1, FREM2, or GRIP1 genes can cause Fraser syndrome. FRAS1 gene variants are the most common cause of Fraser syndrome. FREM2 and GRIP1 gene variants are each responsible for a small percentage of cases.

The proteins that are produced from the FRAS1 and FREM2 genes are part of a group of proteins called the FRAS/FREM complex. The protein that is produced from the GRIP1 gene ensures that the FRAS1 and FREM2 proteins get to the correct location to form the FRAS/FREM complex.

The FRAS/FREM complex is found in basement membranes, which are thin, sheet-like structures that separate and support the cells in many tissues. One of the roles of the FRAS/FREM complex is to anchor the basement membrane of the top layer of skin to the layer of skin below. The FRAS/FREM complex is also involved in the proper organization and development of certain organs and tissues, including the kidneys.

The pathogenic variants in the FRAS1, FREM2, or GRIP1 genes that cause Fraser syndrome interfere with the proper formation of the FRAS/FREM complex. This disrupts the connection between tissue layers, including the connection between the top layer of skin and the layer of skin underneath. Disrupting the interactions between tissue layers impairs cellular movement and communication during early development, which can lead to the cryptophthalmos and cutaneous syndactyly seen in affected individuals.

Through a mechanism that is not well understood, the pathogenic variants that cause Fraser syndrome appear to interfere with the self-destruction of cells that are no longer needed (apoptosis), which may contribute to the additional abnormalities seen in people with Fraser syndrome.

In some people with Fraser syndrome, a pathogenic variant cannot be identified. In these cases, the cause of the disorder is unknown.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. Usually, 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

Fraser syndrome is a rare condition. It is believed to affect up to 1 in 250,000 newborns. More than 250 cases have been reported in the scientific literature.

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.

Abnormality of the urinary system · Very frequent (99-80%)

An abnormality of the urinary system.

Blindness · Very frequent (99-80%)

Blindness is the condition of lacking visual perception defined as a profound reduction in visual perception. On the 6m visual acuity scale, blindness is defined as less than 3/60. On the 20ft visual acuity scale, blindness is defined as less than 20/400. On the decimal visual acuity scale, blindness is defined as less than 0.05. Blindness is typically characterized by a visual field of no greater than 10 degrees in radius around central fixation.

Cryptophthalmos · Very frequent (99-80%)

Cryptophthalmos is a condition of total absence of eyelids and the skin of forehead is continuous with that of cheek, in which the eyeball is completely concealed by the skin, which is stretched over the orbital cavity.

Cutaneous syndactyly · Very frequent (99-80%)

A soft tissue continuity in the A/P axis between two digits that extends distally to at least the level of the proximal interphalangeal joints, or a soft tissue continuity in the A/P axis between two digits that lies significantly distal to the flexion crease that overlies the metacarpophalangeal or metatarsophalangeal joint of the adjacent digits.

Finger syndactyly · Very frequent (99-80%)

Webbing or fusion of the fingers, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" Syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers in a proximo-distal axis are referred to as "Symphalangism".

Lacrimal duct aplasia · Very frequent (99-80%)

A congenital defect resulting in absence of the lacrimal duct.

Malformed lacrimal ducts · Very frequent (99-80%)

Congenital malformation of the lacrimal duct associated with incomplete development of the bony nasolacrimal canal or craniofacial anomalies.

Renal hypoplasia/aplasia · Very frequent (99-80%)

Absence or underdevelopment of the kidney.

Other findings in the same source

From: Orphanet

Additional reported features include Abnormal pinna morphology (Frequent (79-30%)); Abnormality of the middle ear (Frequent (79-30%)); Abnormality of the outer ear (Frequent (79-30%)); Abnormality of the vagina (Frequent (79-30%)); Ambiguous genitalia (Frequent (79-30%)); Anal atresia (Frequent (79-30%)); Anal stenosis (Frequent (79-30%)); Anophthalmia (Frequent (79-30%)); Anorectal anomaly (Frequent (79-30%)); Bifid tongue (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 Fraser 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 Fraser 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.