Fraser Syndrome is a rare, complex genetic disorder that affects development in multiple body systems, beginning before birth. It is classified as a multisystem congenital malformation syndrome, involving structural anomalies in several parts of the body. The condition is infrequently encountered, with an estimated prevalence of about one in 500,000 live births in Europe. Severity varies widely; while some individuals experience mild manifestations, the condition can be life-limiting in its most severe forms.
Defining the Major Physical Features
The characteristics of Fraser Syndrome are defined by a specific set of physical features, with three primary anomalies frequently present. The most common eye abnormality is cryptophthalmos, where the eyelids are partially or completely fused, causing the skin to cover the eyeball. The underlying eye structure is often malformed, such as being abnormally small (microphthalmia) or entirely absent (anophthalmia), typically resulting in severe vision impairment or blindness.
Another major feature is syndactyly, which involves the fusion or webbing of the skin between the fingers and toes. This cutaneous syndactyly most often affects the middle three digits on both the hands and feet. The third main group of anomalies involves the genitourinary tract, which can present with issues like ambiguous external genitalia or undescended testes in males.
The most serious genitourinary problem is often renal agenesis, the failure of one or both kidneys to develop, occurring in a significant percentage of cases. Affected individuals may also have malformations of the ear, leading to hearing loss, or defects in the respiratory tract like laryngeal stenosis. Other associated features include skeletal abnormalities, umbilical hernias, and cleft lip or palate.
Genetic Cause and Inheritance
Fraser Syndrome arises from mutations within specific genes that disrupt early embryonic development. The condition follows an autosomal recessive inheritance pattern, meaning an individual must inherit a mutated copy of the gene from each parent to be affected. Parents who carry one mutated copy are generally healthy carriers and do not show symptoms.
The genes implicated are FRAS1, FREM2, and GRIP1, all involved in forming the FRAS/FREM protein complex. This complex is normally situated in the basement membrane, anchoring the top layer of skin to the layer beneath it during development. Mutations prevent the complex from forming or localizing correctly, impairing adhesion between the skin layers. The resulting detachment leads to blistering during the embryonic period, which interferes with the proper formation of structures, including the eyes and digits. While FRAS1 mutations account for the majority of cases, mutations in FREM2 and GRIP1 are also identified in smaller percentages.
Methods of Identification
Diagnosis of Fraser Syndrome relies on a combination of clinical, imaging, and molecular findings, occurring both before and after birth. Postnatal identification is based on a thorough clinical examination, looking for the characteristic triad of cryptophthalmos, syndactyly, and genitourinary abnormalities. Imaging studies, particularly ultrasound, are frequently used to assess internal organ structure, especially the kidneys and urogenital tract, which often show malformations like renal agenesis.
For high-risk pregnancies, prenatal diagnosis is possible. Fetal ultrasound may detect features like microphthalmia, syndactyly, or renal anomalies as early as the second trimester.
Definitive confirmation is achieved through genetic testing, which analyzes the DNA to identify pathogenic mutations in the FRAS1, FREM2, or GRIP1 genes. This confirmation is valuable for carrier testing, family planning, and confirming a diagnosis when clinical features are less pronounced. Invasive prenatal procedures, like amniocentesis or chorionic villus sampling, can also be performed to analyze fetal DNA if a familial mutation is known.
Supportive Treatment and Long-Term Care
There is currently no direct cure for Fraser Syndrome, so management focuses on symptomatic and supportive care to improve function and quality of life. Treatment requires a coordinated effort from a multidisciplinary team, including surgeons, ophthalmologists, urologists, and nephrologists. Corrective procedures include separating fused digits (syndactyly release), oculoplastic surgery to separate fused eyelids, and surgical reconstruction for genitourinary tract malformations. Vision restoration is often limited due to underlying eyeball malformation.
Long-term care focuses heavily on managing renal function, especially in cases of kidney malformation or agenesis, which may require dialysis or a kidney transplant. Supportive therapies, such as visual aids or hearing devices, address sensory deficits. Physical, occupational, and speech therapy help maximize developmental potential and independence. Genetic counseling is also routinely offered to affected families to explain the inheritance pattern and recurrence risk.