Rodent syndrome is a congenital malformation syndrome belonging to the acrofacial dysostosis group. The symptom complex is based on a mutation in the SF3B4 gene, which codes for components of the splicing mechanism. Therapy is purely symptomatic.
What is rodent syndrome?
Acrofacial dysostoses are a group of diseases in the group of congenital skeletal dysplasias with malformations of the acras and face. Type AFD1 is also known as rodent syndrome and is associated with additional limb malformations in addition to the characteristic acra and facial malformations. Synonymous terms for rodent syndrome include acriofacial dysostosis, preaxial acrodysostosis, mandibulofacial dysostosis with preaxial limb abnormalities, and rodent (de)Reynier syndrome. The rare hereditary disease was first described in the mid-20th century. In addition to the Swiss ENT physician Felix Robert Nager, the French physician Jean Pierre de Reynier is considered the first describer. Both names have entered the multiple designations of the disease. The frequency of the congenital syndrome is not yet known. Since the initial description, case reports include approximately 100 cases. Like all acrofacial dysostoses, Rodent syndrome is hereditary and results from a mutation. Given the mere 100 documented case reports, definitive elucidation of all the relationships related to the malformation syndrome is proving difficult.
Causes
Rodent syndrome is caused by several mutations in the SF3B4 gene. Thus, the gene was affected by alterations in about half of all patients. In humans, this gene is located at gene locus 1q21.2 and encodes the protein SF3B4, which is a component of the splicing mechanism. The mutation causes a defective composition of this protein, which is associated with loss of function of the splicing mechanism. The protein already plays a role in processes in mRNA that are disrupted when it is defective, apparently causing Rodent syndrome. Rodent syndrome appears to occur sporadically in only the rarest cases. A hereditary basis is assumed due to the familial observed accumulation. Inheritance appears to be largely autosomal dominant. However, autosomal recessive inheritance has also been observed in isolated cases. Whether, in addition to genetic factors, external factors such as exposure to toxins or malnutrition during pregnancy promote the mutation has not yet been conclusively determined.
Symptoms, complaints, and signs
Like any syndrome, rodent syndrome causes a full range of clinical symptoms. The most important clinical criteria include multiple facial findings similar to those of Treacher Collins syndrome combined with reduction malformations on the radial ray. In addition to mandibulo-facial dysostosis and atypical palpebral fissures, ptosis is often present in patients with Rodent syndrome. In addition, affected individuals often suffer from a coloboma of the lower eyelid, absent eyelashes, and hypoplasia of the zygomatic bone as well as the maxilla. Furthermore, many patients have choanal atresia or cleft palate. The facial malformations are often associated with hypoplasia, aplasia, or multinodularity of the thumb. Underdevelopment or shortening of the radius, rarely tibial malformations, and rib or vertebral abnormalities may round out the clinical picture. In some cases, radioulnar synostosis is also present. Conductive hearing loss on one side of the body is also characteristic.
Diagnosis and disease course
The initial tentative diagnosis is made on the basis of clinical examination. Diagnostic imaging helps to confirm the diagnosis. Molecular genetic analysis can also test the SF3B4 gene for mutations. If mutations in the gene can be detected, the diagnosis is considered confirmed beyond doubt. However, if no evidence of abnormalities in the corresponding gene can be found, rodent syndrome is not immediately ruled out. Differentially, other forms of mandibulo-facial dysostosis as well as acrofacial dysostoses must be excluded. Additionally, mandibulo-facial dysostosis-microcephaly syndrome and Goldenhar syndrome must be excluded. In most cases, Rodent syndrome is diagnosed immediately after birth.Somewhat less common is a prenatal diagnosis, as can be made by fine ultrasound and molecular genetic analysis. Prognosis is associated with normal life expectancy. Many affected individuals suffer from adverse health effects only in infancy.
Complications
Due to rodent syndrome, affected individuals suffer from many different malformations and deformities that can occur throughout the patient’s body. Unfortunately, causal treatment of this disease is not possible, so those affected are dependent on various therapies that can make everyday life easier. However, it is not uncommon for the patient’s parents and relatives to suffer as well due to Nager syndrome and require psychological treatment. The patients themselves suffer from hearing loss and also from cleft palate. The various deformities sometimes give rise to teasing or bullying by fellow patients, which further diminishes the quality of life of the affected person. There are also significant deformities of the ribs or vertebrae. The patients themselves are in many cases dependent on the help of other people in their lives and cannot easily cope with many things in everyday life. Without therapy, rodent syndrome not infrequently leads to respiratory distress and further to speech disorders. With the therapy usually no complications occur. Also, the life expectancy of the affected person is usually not limited by the syndrome.
When should one go to the doctor?
Rodent syndrome is a congenital disorder, which is diagnosed during pregnancy or at the latest after birth. Whether and to what extent medical treatment is necessary depends on the severity of the malformations. Mild rodent syndrome does not necessarily require treatment, as the malformations often do not result in any limitations. In severe cases, surgical interventions are necessary, which usually take place immediately after the birth of the child. Parents should talk to a specialist early on so that appropriate measures can be taken quickly. If one of the parents suffers from the disease themselves, a genetic test is recommended to determine whether the child also has Nager syndrome. Treatment is surgical, and physiotherapeutic measures are always necessary as well. In the case of severe deformities, a therapist must also be consulted in order to counteract any psychological symptoms at an early stage. Furthermore, drug treatment of the pain is necessary, which is why close consultation with the pediatrician is always indicated.
Treatment and therapy
Causal therapies are not yet available for patients with rodent syndrome. Accordingly, the disease is considered incurable to date. Gene therapies are an area of research but have not reached the clinical stage to date. Therefore, the treatment of rodent syndrome is purely symptomatic and aims mainly at resolving neonatal respiratory distress or tracheostoma and resolving feeding problems. The gastrostoma can be brought to resolution endoscopically, reducing feeding problems. The breathing problems are often resolved by percutaneous puncture or dilatation tracheostomy. In addition to these surgical and microsurgical therapeutic steps, some of the facial malformations can also be corrected by surgical intervention, such as cleft palate. Surgical interventions can also correct symptoms such as severe micrognathia or resolve temporo-mandibular joint dysfunction. Hearing aids can be used to combat patients’ hearing loss. If speech disorders or phonological problems occur, speech therapy in the sense of logopedic treatment is also indicated. The parents of affected children also receive genetic counseling. In the course of this consultation, it is first clarified whether the disorder has a familial origin or has occurred spontaneously. Even mildly affected parents are 50 percent likely to pass the defect on to offspring. The recurrence risk for subsequent offspring is 25 percent after a child with the disease even if the parents appear genetically normal.
Outlook and prognosis
Patients who have Nager syndrome have a normal life expectancy. Health problems occur primarily in the respiratory tract and joints.If the symptoms are treated and the doctor’s instructions regarding the intake of the necessary medication are followed, the prognosis is good. The prerequisite for a positive course is an early diagnosis, at best immediately after the birth of the child. Many affected individuals do not suffer from any health impairments or, at most, show abnormalities in infancy that require treatment. However, if complications such as hearing loss, a cleft palate or various other malformations occur, physical complaints may be added. The quality of life and well-being are often reduced. The cause of the low quality of life is not only the physical complaints, but also psychological consequences, which often occur due to bullying and low self-esteem. Patients often need the help of other people in their lives. Life expectancy is limited by Nager syndrome only when severe malformations of the lungs are present. Impaired lung function can lead to respiratory distress and consequent death of the patient. Thus, the prognosis of Rodent syndrome is based on various factors. It is determined by the specialist in charge.
Prevention
To date, Nager syndrome can only be prevented by thorough family planning counseling. For example, affected parents may decide against having a child of their own if the condition is known to run in their family.
Follow-up
In many cases, affected individuals do not have any special or direct measures or options for aftercare when it comes to Nager syndrome. Because this disease is hereditary, it is not completely curable. Therefore, affected individuals should ideally contact a physician at the first signs and symptoms to prevent further worsening of symptoms. Since Nager syndrome is hereditary, affected individuals should undergo genetic testing and counseling if they wish to have children in order to prevent the recurrence of the syndrome. Affected children depend on comprehensive and intensive support from their parents. Intensive support is also necessary at school to compensate for the deficits. In the case of speech difficulties, appropriate therapy can also alleviate the symptoms, whereby many of the exercises can be repeated at home. Malformations can be corrected in the process, although the patient should in any case take it easy and rest after an operation. As a rule, Nager syndrome does not reduce the life expectancy of the affected person. However, the further course depends very much on the time of diagnosis and also on the severity of the individual complaints.
What you can do yourself
Patients with Nager syndrome were and are usually treated from an early age often surgically to correct various defects. In this case, it is important to observe the closed seasons after these operations and to take good care of the surgical wounds to avoid unwanted infection and/or complications. The affected patients are also dependent on various therapies that are based on their findings and are intended to make everyday life easier for them. In particular, it is important to remedy possible shortness of breath, hearing loss and/or problems with nutrition. Therapy instructions should be followed as well as possible additional therapies, such as speech therapy. Children with rodent syndrome are often teased or even bullied in kindergarten and at school. Therefore, they should be accompanied by psychotherapy. This also applies to the parents – who are usually also affected by Nager syndrome – and other relatives. Genetic counseling for the parents and their siblings is also indicated. Because the disease is relatively rare, there is no self-help group in Germany that patients can join. However, the family of a rodent patient has created a platform with the homepage www.nager-syndrom.de, where affected patients can also register and make contact. The feeling of not being alone with this visible and stressful disease is extremely helpful for most patients.
