NORD gratefully acknowledges Alex Nguyen, MDCM Candidate, McGill University School of Medicine, and Joel Noutakdie Tochie, MD, Department of Anaesthesiology and Critical Care Medicine, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Cameroon, for assistance in the preparation of this report.
Fraser syndrome (FS) is a rare genetic disorder characterized by several malformations that are present at birth. These include eyes that are completely covered by the skin and usually malformed (cryptophthalmos) causing blindness; fusion of the skin between the fingers and toes (cutaneous syndactyly), a blocked or missing anal opening (imperforate anus); limb anomalies; kidney (renal) abnormalities; external genital malformations; a narrow, blocked and malformed voice box and lower respiratory tract (nostrils, larynx and lungs); skeletal defects; umbilical hernia and intellectual disability. Infants and children with Fraser syndrome may also have additional abnormalities including malformations of the middle and outer ear that may result in hearing impairment. More recently, missing eyes (bilateral anophthalmia) and liver malformations (intrahepatic biliary atresia) have been found in children with FS. Fraser syndrome is inherited in an autosomal recessive pattern. There is currently no cure for FS but surgery is available to correct some malformations associated with this disorder, depending on the severity of the malformations. Fraser syndrome is named after the Canadian geneticist George R. Fraser who first described the syndrome in 1962.
Fraser syndrome is characterized by multiple physical abnormalities.
Failure of the eyelids to form properly (cryptophthalmos) is the most common abnormality, seen in 93% of affected individuals. Other less common forms of cryptophtalmos seen in these individuals are only one eye completely covered by skin, or one or both eyes partially covered. In addition, there are other possible malformations of the eyes such as small eyes (microphthalmia), missing eyes (anophthalmia), absent or malformed lacrimal tear ducts (nasolacriminal ducts) and increased distance between the eyes (hypertelorism). These eye abnormalities lead to vision loss or impairment.
Cutaneous syndactyly is another common abnormality in people with Fraser syndrome. Affected individuals typically have their three middle fingers joined and their three middle toes joined, but the other fingers/toes can also be joined.
Another common sign is kidney abnormalities such as the absence of one or both kidneys (unilateral or bilateral renal agenesis). Other kidney malformations may include improper development (dysplasia) and underdevelopment (hypoplasia).
Genital malformations are common in individuals with FS. In affected males, one or both testes may fail to descend into the scrotum (cryptorchidism), the urinary opening (meatus) may be abnormally placed on the underside of the penis (hypospadias), and/or the penis may be abnormally small (micropenis). Affected females may have malformed fallopian tubes, an abnormally enlarged clitoris (clitoromegaly), an abnormally shaped uterus with two horn-like extensions (bicornate uterus) and/or abnormally closed or absent vagina (vaginal atresia). Some affected individuals’ outer genitals may not have the typical appearance of either a male or female (ambiguous genitalia).
Respiratory tract abnormalities are another common sign in people with FS. There may be malformations of the voice box (larynx) (laryngeal stenosis or atresia), meaning it is more narrow than average or blocked. Malformations of the nose and lungs are also common. This can cause breathing difficulties leading to potentially fatal respiratory insufficiency.
Other possible signs and symptoms are:
Fraser syndrome is caused by changes (mutations) in the FRAS1, FREM1, FREM2 or GRIP1 genes). More specifically, Fraser syndrome 1 (FRASRS1) is caused by mutations in the Fraser extracellular matrix complex subunit 1 (FRAS1) gene. Fraser syndrome 2 (FRASRS2) is caused by mutations in the FRAS1-related extracellular matrix protein 2 (FREM2) gene. Fraser syndrome 3 (FRASRS3) is caused by mutations in the glutamate receptor-interacting protein 1 (GRIP1) gene. FRAS1 gene mutations are the most common cause for Fraser syndrome, representing approximately half of the FS cases; whereas FREM2 gene and GRIP1 gene mutations account for a smaller percentage of cases.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The FRAS1 and FREM2 genes produce proteins (FRAS1 and FREM2 proteins, respectively) that work together as part of the FRAS/FREM complex. One of the FRAS/FREM complex’s functions is to connect the different layers of skin together, one on top of the other, to essentially form the skin. Its function is important during the embryonic period before birth. This group of proteins play a role in the proper development of the skin, internal organs including kidneys and other tissues. Therefore, a mutation in the FRAS1 or FREM2 gene causes its respective protein to be faulty, thus the FRAS/FREM complex cannot function properly and therefore leading to improper development of the skin, internal organs and other tissues. This improper development ultimately causes signs and symptoms such as cryptophthalmos, cutaneous syndactyly and renal agenesis. The GRIP1 gene produces the GRIP1 protein that ensures that FRAS1 and FREM2 proteins get to their correct location within the cell to carry out their function. Mutations in the GRIP1 gene prevent normal function of the FRAS1 and FREM2 proteins, causing an improper development of the skin, internal organs and other tissues.
Fraser syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal/mutated gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Fraser syndrome affects males and females in equal numbers. The age of onset for this disorder is neonatal/antenatal, meaning an affected individual develops this disorder before birth. FS is seen to be more prevalent in gypsy populations (Roma ethnicity) of southern and eastern Europe.
The incidence of FS is 0.43 in 10,000 or 1 in 200,000 newborns and 11.06 in 10,000 babies that die before birth (stillbirths).
Fraser syndrome can be diagnosed before birth by ultrasound at 18 weeks of gestation. Prenatal ultrasonographic diagnosis is usually done when there is family history for the disorder. The diagnosis can be made if two of the following signs are present on ultrasound of the fetus: microphthalmia (one eye being abnormally small), syndactyly, enlarged echogenic lungs, oligohydramnios (deficiency in amniotic fluid during pregnancy).
Fraser syndrome is usually diagnosed at birth based on the signs and symptoms found in the child. IT Thomas and colleagues suggested the following criteria to diagnose FS: the presence of one major criterion and one minor criterion or alternatively the presence of two major criteria and one minor criterion. Major criteria include cutaneous syndactyly, cryptophthalmos, ambiguous external genitalia, anorectal abnormalities and limb anomalies. Minor criteria are ear and nose anomalies, skull bone defects, umbilical hernia, intellectual disability and urinary and respiratory tract anomalies. None of the major criteria are mandatory for diagnosis.
Genetic testing for mutations in the FRAS1, FREM1, FREM2 or GRIP1 genes can confirm the diagnosis of Fraser syndrome.
There is currently no cure for Fraser syndrome. Treatment of FS may include surgery to correct some of the malformations associated with this disorder depending on their severity. Other treatment is symptomatic and supportive. A team of specialists is required to evaluate each patient and determine ways to treat the symptoms. The prognosis without treatment depends on the severity of the specific anomalies in the patient, especially respiratory tract malformations and anal imperforations. Unfortunately, death in the first year of life is common in children with severe anomalies.
Genetic counseling is recommended for families of children with this disorder.
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