Fraser syndrome is a very rare genetic disorder characterized by multiple physical malformations. The expression of the individual malformations is not uniform, so that in addition to cases of stillbirths and children who die immediately after birth, there are also affected individuals with normal life expectancy. Therapy depends on the type of malformation.
What is Fraser syndrome?
Fraser syndrome was first described in 1962 by British human geneticist George R. Fraser. Because of one of its main symptoms, closed palpebral fissures, this condition was initially called cryptophthalmos syndrome. In the following years more cases were diagnosed. In very many cases, in addition to cryptophthalmos, adhesions of adjacent fingers or toes (syndactyly) could be detected. Therefore, the synonymous name cryptophthalmos-syndactyly syndrome was often used. Other synonyms of the disorder include Meyer-Schwickerath’s syndrome, Ullrich-Feichtiger syndrome, or Fraser-François syndrome. The term Fraser syndrome, after the American human geneticist Victor Almon McKusick, has finally become accepted as the main name. In total, there are about 150 case descriptions of this syndrome. It was recognized that there are different manifestations of the individual malformations. Some affected individuals suffer only from cryptophthalmos without any other physical malformations. In other cases, a multitude of dysmorphias occur. The disease presents with various major and minor symptoms, and the life expectancy of individual patients also varies. For example, as many as 25 percent of affected children are stillborn. Another 20 percent of patients die in the first year of life from kidney or laryngeal malformations. Most affected individuals, however, have a normal life expectancy.
Causes
The cause of Fraser syndrome may be an autosomal recessive gene mutation. In the majority of cases, it is a gene defect in the FRAS1 gene, which is located on chromosome 4. Other possible affected genes are GRIP1 on chromosome 12 or FREM2 on chromosome 13. The gene FRAS1 codes for a protein belonging to the extracellular matrix. The absence of certain proteins of the extracellular matrix leads to imbalances in the growth processes during embryogenesis. The mode of inheritance for all affected genes is autosomal recessive. This means that the affected person must be homozygous for two defective genes. If the mutated gene is present only once, the disease does not occur. The syndrome can only be inherited if both parents each have at least one defective gene. Therefore, this syndrome accumulates in offspring of related parents who have this particular genetic defect.
Symptoms, complaints, and signs
Fraser syndrome is characterized by the appearance of various major and minor symptoms. Thus, a confirmed diagnosis can be assumed when either two major symptoms and one minor symptom or one major symptom and four minor symptoms appear. Major symptoms include absence of palpebral fissures (cryptophthalmos), malformations of genitourinary organs such as kidneys or reproductive organs, adhesions of adjacent fingers or toes (syndactyly), and malformed or absent lacrimal ducts. Secondary symptoms include small-headedness (microcephaly), wide interocular distance (hypertelorism), narrowing or absence of the larynx, immature fetal lungs (pulmonary hypoplasia), widening of the pubic symphysis, and skeletal abnormalities. Malformations of the auricles, lips or palate are also observed, as well as displacement of the umbilicus or nipple. In the past, cognitive impairment was thought to be another symptom. However, this has not been confirmed. The prognosis of the disease depends on any malformations of the kidneys, larynx, or lungs. These cause the high rate of stillbirths and infant mortality. Otherwise, life expectancy is not limited.
Diagnosis and course
Diagnosis mainly refers to the combination of major and minor symptoms in addition to the history. Emphasis is placed on examination of the eyes, kidneys, larynx, and lungs. Fraser syndrome can be diagnosed prenatally with the help of ultrasonography.This may reveal echogenic lungs, indicating narrowing or obstruction of the larynx. The constantly forming fluid cannot flow back into the lungs due to the narrowing of the larynx, thus forming a congestion, also known as fetal CHAOS (Congenital High Airway Obstruction Syndrome). “Congenital High Airway Obstruction Syndrome” translates to “narrowing of the upper airway.” This condition can lead to stillbirth and is considered a medical indication for possible termination of pregnancy. Prenatal diagnosis also includes human genetic testing via chorionic villus sampling or amniocentesis.
Complications
Fraser syndrome is due to a genetic defect; therefore, causative, curative treatment is not possible. Because of the rarity of the syndrome and because of the high mortality rate of affected individuals (nearly a quarter of affected individuals die before birth, and another quarter die in the first year of life), therapeutic approaches and complications are poorly described. Survivors are usually treated surgically, depending on the affected condition. The most frequent complications in the treatment of Fraser syndrome are therefore the general risks associated with surgery. These include leg vein thrombosis (blood clots in the legs, occlusion of a pulmonary vessel (pulmonary embolism), injury to nerves, and infection. Postoperatively, there is an increased risk of wound healing disorders and even gangrene. If left untreated, the common symptoms of Fraser syndrome can severely impact the overall living situation of those affected. Untreated microphthalmia (or anophthalmia) results in complete loss of possibly dim vision. If cosmetic correction of the eyes (such as insertion of an ocular prosthesis or correction of severe strabismus) is not performed, the consequences are primarily psychological impairments, up to and including the development of depression. If the syndactyly (fused fingers and / or toes) remains untreated, the motor function is severely impaired – grasping, holding a pen or walking is hardly possible depending on the severity. Renal agenesis, which often accompanies Fraser syndrome, leads to the patient’s death if left untreated.
When should you see a doctor?
Physical abnormalities that deviate from the norm should always be clarified by a physician. The human body has a basic structure, the deviation of which is an indication of a disease. Adhesions, malformations or growths are considered unusual and should be examined by a doctor. If there are changes in the skeletal system of the human body, a visit to the doctor is necessary, even if there are no other symptoms. Malformations, ossifications, or limitations of movement must be evaluated by a physician. If the toes and fingers cannot be moved individually, if they are altered due to a deviating shape or if the affected person has webbed hands and feet, it is advisable to consult a doctor. If the distance between the eyes is unusual, if the larynx is missing or if there are constrictions in the neck, a doctor is needed. Deformities of the face, especially the ears, eyes, nose or lips should be medically examined. If there are changes in the palate, a doctor is also needed because there may be problems with feeding. If the belly button or nipples are in altered positions on the body, these features should be presented to a physician. Deviations in possible joint movements or visual changes in the joints are considered unusual and should be examined by a medical professional. If there are dysfunctions of individual systems due to existing deformities, a physician is needed.
Treatment and therapy
The renal and laryngeal deformities are the main causes of death in Fraser syndrome. Therefore, if there is any laryngeal malformation after birth, a procedure called a tracheostomy must be performed immediately. Tracheotomy involves creating surgical access to the trachea to ensure the patient is ventilated. In later years, depending on the existing situation, a revision of the restoration of function may be performed. Unfortunately, the absence of both kidneys is incompatible with life. In this case, treatment is no longer possible. However, in the case of unilateral renal agenesis, the function of one kidney is preserved. Furthermore, surgical opening of the palpebral fissures is attempted. However, this operation is useful only if the eyeballs are present.
Outlook and prognosis
Fraser syndrome is an extremely rarely diagnosed disorder worldwide to date. There are barely more than 150 documented cases in which the diagnosis has been given. Most patients to date have a short life expectancy. Due to the severe malformations, they die in the womb, immediately at birth or shortly after delivery. These children suffered from severe malformations of the larynx or kidneys. Since the physical malformations occur individually, there are also sufferers in whom there is no significant shortening of life expectancy. Many mutations can be optimized in surgical interventions after birth, so that an improvement of the quality of life is possible. In the case of malformations of the palpebral fissure, the lacrimal ducts or in the case of adhesions of fingers and toes, the patient has a good prognosis. Already within the process of growth and development, corrective measures can be taken in the first years of life. Desired changes are made at the latest with the completion of physical growth. A complete cure is not possible for the gene disease. The DNA of the human being cannot and must not be changed. Nevertheless, the symptoms can be well and sufficiently taken care of with the available therapy and treatment options. In case of malformations of the sexual organs or organs of the urogenital tract, secondary diseases may occur. In some cases, the patient is dependent on donor organs.
Prevention
Fraser syndrome is genetic and commonly occurs in marriages of relatives. In cases of familial clustering, human genetic counseling and, if necessary, DNA testing should be sought if the patient has an existing desire to have children. Furthermore, prenatal examination methods are available by which Fraser syndrome can be diagnosed prenatally.
Follow-up
As a rule, no special follow-up options are available to the affected person with Fraser syndrome, since it is a genetic disease. The patient is therefore dependent on purely symptomatic treatment of this disease to prevent further complications and to avoid a reduced life expectancy. Self-cure is not expected in Fraser syndrome. Symptomatic treatment can usually maintain an ordinary life expectancy. In most cases, the treatment of this complaint is remedied by surgical intervention. No particular complications occur and ventilation can be ensured again. After this complex operation, the affected person must rest and take care of the body. No more strenuous activities or stressful activities should be performed. Bed rest should be strictly observed. Since Fraser syndrome can also damage the kidneys, regular examinations by an internist are very useful to prevent this damage. The eyes should also be examined and treated regularly. Since Fraser syndrome can also have a negative effect on the psyche of the affected person, support and help from friends and through family is very useful to prevent complications.
What you can do yourself
The shortened life expectancy often associated with Fraser syndrome is particularly challenging for sufferers and their families. Because the psychological burden of this prognosis is very high, a way to cope well with the stress should be found independently in everyday life in addition to conventional medical support. Open communication with family members and friends helps to clarify mutual concerns and fears. In many cases, therapeutic support should be sought to prevent further illnesses from developing as a result of the psychological pressure. The exchange of information in self-help groups or forums can help to get hints and tips on how to deal with the disease in everyday life. Experiences and adventures are discussed with other sufferers. This helps in processing what has happened and strengthens the psyche. In addition, relaxation techniques can be used to establish inner balance. With Qi Gong, autogenic training, meditation and yoga, stress reduction can be achieved and mental strength is strengthened. The individual deformities lead to the patient being dependent on daily assistance.This results in restructuring, which has an impact other family members. However, a positive attitude should be maintained and the time spent together should be used for enjoyable activities.
