Fraser syndrome is a rare, severe congenital disorder that affects development across multiple body systems, beginning before birth. It is sometimes referred to as Cryptophthalmos-Syndactyly syndrome, referencing its two most common physical manifestations. The syndrome takes its name from Canadian geneticist George R. Fraser, who first provided a comprehensive description of the disorder in 1962. Because of its broad range of effects on the eyes, skin, and internal organs, Fraser syndrome presents significant medical challenges for affected individuals. This article explains the clinical presentation of this condition, explores its genetic causes, details the methods used for identification, and outlines the approach to medical management and long-term outlook.
Defining the Syndrome
The physical signs of Fraser syndrome, known as its phenotype, are highly variable but consistently involve malformations in the eyes, skin, and genitourinary tract. The most distinguishing and common feature is cryptophthalmos, which means “hidden eyes.” This anomaly involves the complete or partial fusion of the eyelids, where the skin passes continuously from the forehead to the cheek without the typical palpebral fissure.
In cases of cryptophthalmos, the underlying eye structures are often malformed, such as being abnormally small (microphthalmia) or entirely missing (anophthalmia). These ocular abnormalities frequently lead to severe visual impairment or total loss of vision. Malformations of the tear ducts and an increased distance between the eyes (hypertelorism) are also commonly observed.
A second major characteristic is cutaneous syndactyly, which is the webbing or fusion of the skin between the fingers and toes. While the severity varies, the middle three digits are most often involved, and this can affect both the hands and the feet. The combination of cryptophthalmos and syndactyly is central to the clinical definition of the syndrome.
Internal malformations, particularly those affecting the genitourinary system, are highly prevalent and often determine the severity of the condition. The most serious urinary tract defect is renal agenesis, the complete absence of one or both kidneys. Individuals may also present with abnormalities of the external genitalia, such as undescended testes in males or an enlarged clitoris and malformed reproductive structures in females.
Fraser syndrome can affect the respiratory system, with laryngeal or tracheal abnormalities that can cause severe breathing difficulties shortly after birth. Other less frequent but reported features include defects of the ears, nose, and skeleton, as well as an imperforate anus.
Underlying Genetic Factors
Fraser syndrome is classified as an autosomal recessive congenital disorder, meaning an individual must inherit a mutated gene from both parents to be affected. This inheritance pattern results in a 25% chance of an affected child in each pregnancy when both parents are carriers. The syndrome is linked to mutations in one of three known genes: FRAS1, FREM2, or GRIP1.
Mutations in the FRAS1 gene are the most frequent cause, accounting for over half of all diagnosed cases. These genes code for proteins involved in the formation of the FRAS/FREM complex. This complex is a component of the extracellular matrix, which acts as a structural scaffold that helps anchor the outer layer of the skin (epidermis) to the underlying connective tissue (dermis) during embryonic development.
The FRAS1 and FREM2 genes produce proteins that form the core of this complex, while the GRIP1 gene produces a protein that helps ensure proper assembly. When a mutation occurs in any of these genes, the FRAS/FREM complex fails to form correctly, which disrupts the normal adhesion between tissue layers. This lack of proper adhesion is thought to cause blistering and detachment of the skin layers during early development, subsequently impairing the formation of the eyes and digits, leading to cryptophthalmos and syndactyly.
Identification and Prenatal Screening
The identification of Fraser syndrome can begin before birth through prenatal screening, especially when there is a known family history of the disorder. Ultrasound examination is the primary tool used to detect characteristic structural anomalies in the developing fetus. Features such as renal agenesis (the absence of a kidney) or severe renal abnormalities are often detectable, as are abnormalities in the volume of amniotic fluid (oligohydramnios or polyhydramnios).
Direct visualization of cryptophthalmos can also be a key indicator on a prenatal ultrasound, although it can be difficult to confirm early in gestation. The presence of echogenic lungs, which appear unusually bright on the scan, along with other structural defects, can further raise suspicion of Fraser syndrome. Detecting these structural anomalies early allows health professionals and families to prepare for potential complications at delivery.
A definitive diagnosis is confirmed through genetic testing, performed by sequencing the FRAS1, FREM2, and GRIP1 genes to identify pathogenic mutations. Postnatally, a clinical diagnosis is made based on a specific combination of major and minor criteria established by medical experts. Major criteria include cryptophthalmos, syndactyly, genitourinary abnormalities, laryngeal and tracheal anomalies, and a family history of the disorder.
The presence of either three major criteria, or two major and two minor criteria, or one major and four minor criteria is typically required for a clinical diagnosis. Once a diagnosis is confirmed, genetic counseling is recommended for the parents to understand the autosomal recessive inheritance pattern and the 25% recurrence risk for future pregnancies.
Medical Management and Long-Term Outlook
Since there is currently no cure for Fraser syndrome, treatment is focused on symptomatic and supportive management, requiring a coordinated approach from multiple medical specialties. Immediate interventions often prioritize addressing life-threatening malformations, particularly those affecting the kidneys and the airway. Severe laryngeal or tracheal anomalies can necessitate emergency surgery to establish a secure airway and prevent respiratory failure.
Management of the genitourinary defects is a major focus, as renal failure is a primary cause of early mortality. Individuals with bilateral renal agenesis (both kidneys absent) have a very poor prognosis. Those with less severe renal defects may require ongoing nephrological care, including potential dialysis or a kidney transplant.
Surgical corrections are frequently undertaken for eye abnormalities, with procedures aimed at separating the fused eyelids and reconstructing the ocular structures to maximize any remaining visual potential. Surgical correction is also used to address cutaneous syndactyly to separate the fused digits and improve hand and foot function. Abnormalities of the genitalia are often managed through reconstructive surgery. Non-surgical supportive care includes physical and occupational therapy to improve motor skills, and the use of visual or hearing aids.
The long-term outlook for individuals with Fraser syndrome is highly variable and depends directly on the severity of the malformations. Cases involving severe renal or respiratory anomalies carry a high risk of death within the first year of life. Individuals with milder manifestations can survive into childhood and adulthood, though they require lifelong, multidisciplinary medical care.