Lujan-Fryns syndrome (LFS) is an X-linked inherited disorder that causes a decrease in intelligence with a concomitant marfanoid growth. To date, the disease is not considered curable.
What is Lujan-Fryns syndrome?
Another name for Lujan-Fryns syndrome is: X-linked mental retardation with Lujan syndrome concurrent with marfanoid habitus. It was first observed in 1984 by the American pediatrician J. Enrique Lujan in four male patients. In 1987, human geneticist Jean-Pierre Frans described two cases with the same symptomatology. The very rare disorder was named after these scientists. Lujan-Fryns syndrome causes mild to moderate intelligence impairment with concomitant marfanoid growth, facial dysmorphia and behavioral abnormalities. It can also cause malformations that affect the heart and brain. According to the ICD-10 diagnostic classification system, Lujan-Fryns syndrome is classified as a mild decrease in intelligence with marked behavioral disturbance; observation is advised.
Causes
Mutations in the MED12 gene are responsible for Lujan-Fryns syndrome. MED12 is a subunit of a multiprotein complex that regulates transcription, a mediator. The cases studied had a point mutation, or more precisely a substitution. This is when one base of DNA is exchanged for another. The category of substitution present in Lujan-Fryns syndrome is a missense mutation of type p.N1007S. This means that the amino acid asparagine, which should normally be at position 1007 along the MED12 sequence, has been incorrectly replaced by serine. The mutation causes incorrect expression of the protein being encoded, leading to the disorder. The affected gene can be localized on the X chromosome; its gene locus is 13.1, but the exact etiology is still unclear.
Symptoms, complaints, and signs
Typical symptoms include mild to moderate intelligence impairment, but isolated cases of severe mental retardation have also been reported. In addition to the mental limitation associated with marfanoid habitus, people affected by Lujan-Fryns syndrome usually have a facial physiognomy typical of the disease. Marfanoid habitus refers to a group of physical features that are typical of Marfan syndrome. These include a high forehead, a long face with narrow features, and a large nose with a high nasal root often hypoplasia of the upper jaw, a short, deep philtrum, and a high palate. Also typical are long hyperextensible limbs, fingers and toes. The big toe is relatively short, and the second toe is too long. A brain abnormality often associated with the syndrome is agenesis, i.e., the lack of attachment and development, of the corpus callosum, also called the brain bar. This tissue, consisting of about 250 million nerve fibers, connects the two brain hemispheres. Among the most common abnormalities in the behavior of affected individuals is a disorder similar to that seen in individuals on the autism spectrum. Other mental disorders that may be associated with Lujan-Fryns syndrome include psychotic behavior, schizophrenia, hyperactivity and attention deficit disorder, oppositional defiant disorder, obsessive-compulsive disorder, low frustration tolerance, lack of impulse control, learning disabilities, short-term memory deficits, and loss of appetite and even malnutrition. However, in isolated cases, Lujan-Fryns syndrome occurs without mental impairment.
Diagnosis and course of the disease
Lujan-Fryns syndrome primarily affects men, which is probably genetic. However, exact prevalence figures are not known. Until 2007, only a clinical diagnosis of the syndrome was possible; since the corresponding gene has been identified, diagnosis can be made by DNA analysis. Diagnosis based on symptoms involves not only physical findings but also the psychopathological behavioral patterns of the patients. Lujan-Fryns syndrome differs from other forms of X-linked mental retardation by the accompanying marfanoid habitus. However, the marfanoid habitus can often only be recognized during puberty, since the physical structures of the patients are not yet appropriately developed before that time. For the DNA diagnosis, the blood of the patient as well as that of other family members is examined.Sequencing is used to analyze exon 22 of the MED12 gene including the intron/exon splice sites and the flanking intronic regions. In the differential diagnosis, there is another disorder that shares some similarities with Lujan-Fryns syndrome and is also due to a mutation of the MED12 gene, Opitz-Kaveggia syndrome. DNA analysis allows us to determine that it is a missend mutation p.R961W.
Complications
First and foremost, Lujan-Fryns syndrome leads to a severe reduction in the patient’s intelligence. As a result, it is not uncommon for affected individuals to be dependent on the help of others for the rest of their lives and unable to manage their daily lives alone. For this reason, the relatives and parents of the children are also severely affected by Lujan-Fryns syndrome and not infrequently suffer from psychological limitations or depression. The affected persons are hyperactive and not infrequently schizophrenic. Obsessive-compulsive disorders or defiant behavior occur, which can have a very negative effect on the social environment. Especially at a young age, Lujan-Fryns syndrome can lead to bullying or teasing of the patient. Furthermore, the syndrome can also lead to malnutrition or loss of appetite, significantly reducing the quality of life. Various learning disabilities may also occur in the process. In some cases, the syndrome causes heart problems or epileptic seizures. Therefore, treatment is only symptomatic and aims to reduce the symptoms. However, a complete cure is not possible, so patients are usually permanently dependent on care. However, the life expectancy of those affected is not reduced by the syndrome.
When should you see a doctor?
If children and adolescents show significant delays within their developmental process in direct comparison to peers, the observations should be presented to a physician. If there are learning disabilities, memory problems, interruptions in the ability to remember, or if a mental abnormality is perceived, a visit to the doctor should be made. Visual abnormalities in the child’s face are another sign of an existing irregularity. A particularly high forehead, a long narrow face or an altered nose shape should be clarified by a doctor. If the fingers or toes can be hyperextended without problems, this is unusual. Although there is no pain, the movement possibilities indicate a disease that needs to be examined by a doctor. Disturbances of attention, compulsive actions, a reduction in speech or behavioral abnormalities should be examined by a physician. If the affected person shows an aggressive demeanor, has a low frustration threshold or impulsive actions cannot be controlled, a visit to the doctor is necessary. If the behavior is judged to be off the norm by people in the social environment, a doctor’s evaluation should be sought. The affected person often needs medical help to avoid self-destructive actions. A decrease in body weight, loss of appetite, or change in posture should be discussed with a physician. Hyperactivity, psychopathic behavior, or hallucinations should be evaluated by a physician as soon as possible.
Treatment and therapy
Due to the genetic origins of the syndrome, there is as yet no specific cause treatment for patients suffering from Lujan-Fryns syndrome. The disease is considered incurable. Nevertheless, there are corrective procedures, preventive interventions, and various therapies for dealing with the craniofacial, orthopedic, and psychiatric problems of patients. Irregularities with the heart, as well as any epilepsy, should be checked regularly and treated with medication if necessary. Orthopedic deformities can sometimes be improved with physical therapy. Psychological care for ill persons is also useful. The focus of treatment is on promoting mental development on the one hand and early detection of any psychoses and schizophrenia on the other. Impulse control, avoiding outbursts of anger and socially incompatible behavior can be learned with special educational and psychological care. The disorder is inherited dominantly via the X chromosome.This means that even one defective gene inherited from an affected parent is sufficient to pass on the disease.
Outlook and prognosis
Lujan-Fryns syndrome has an unfavorable prognosis. The cause of the syndrome is based on a genetic defect. Because human genetics cannot be altered due to the current legal situation, there is no way to correct the cause of the condition. Therefore, physicians and scientists focus on the development and application of therapies for symptomatic treatment. The disease is associated with severe mental retardation. For this reason, those affected cannot manage their entire lives without help from other people. It is not possible for them to lead an independent life. They are completely dependent on the support of caregivers or relatives. The disease poses a particular challenge in managing their symptoms. The risk of additional mental illness is therefore increased, especially among the patient’s relatives. In a medical care, the disturbance of the cardiac activity should be minimized. Lifelong medical treatment must be initiated to avoid risks and complications. Special educational and psychological therapies are used to improve the quality of life. Early intervention programs also support disease progression and show improved cognitive performance. Nevertheless, the disease remains incurable. Likewise, despite all efforts, the state of independent living is not achieved.
Prevention
Since Lujan-Fryns syndrome is a genetic disease, there is no way for the individual affected to protect themselves from contracting the disease. For the same reason, there is no risk of infection to the environment, so no prophylaxis is necessary.
Aftercare
In the case of an intellectual disability, care and aftercare can go a long way. Aftercare can include both psychosocial and physical therapy. Depending on the age of the mentally disabled person, fuller participation in the lives of others can be gained with speech and language support or motor skill development. In addition, genetic causes may include physical limitations such as short stature or club feet. These also require medical or orthopedic follow-up and monitoring. Aftercare for mentally retarded people includes comprehensive measures that vary according to the family situation and the degree of disability. Mentally disabled people can live a conducive everyday life in a special workplace. They need offers for assisted living. Given the options available today, many people with mental disabilities can live an independent life without major problems.
Here’s what you can do yourself
There are no special self-help options available to the affected person with Lujan-Fryns syndrome. As a rule, the symptoms of this syndrome cannot be treated directly, so there is no cure. Only a certain reduction of the symptoms through intensive care and therapy can occur. The reduced intelligence can be treated by different exercises. Here, especially the parents and relatives of the patient are needed, as they have to support and encourage the affected person. In this way, further complications in adulthood can be avoided. The occurrence of mental illnesses should also be diagnosed at an early stage in order to avoid psychological disorders. Especially outbursts of rage or psychoses must be taken into account. In this context, conversations with one’s own friends and with the family also have a positive effect on the disease. The symptoms of the heart can only be alleviated by surgical intervention, and regular examinations are highly advisable. Frequently, contact with other affected persons and their parents can also prove very useful, as this can lead to an exchange of information, which can make everyday life easier.