Nijmegen breakage syndrome is the name given to a rare disease that is already congenital. It involves a disorder of the DNA repair mechanism.
What is Nijmegen breakage syndrome?
Nijmegen breakage syndrome (NBS) is an exceedingly rare autosomal recessive disorder. It belongs to the group of chromosomal instability syndromes and is manifested by a variety of different symptoms. Nijmegen breakage syndrome is characterized by a disorder of the DNA repair mechanism that affects all organs and cells. There is a pronounced chromosomal fragility. The disorder in turn results in symptoms such as developmental and growth delays, mental developmental disorders, an undersized head, and immunodeficiencies. In addition, affected children have an increased susceptibility to severe diseases such as lymphoma, malignant tumors and leukemia. The first description of Nijmegen Breakage Syndrome occurred in 1981 in the Dutch city of Nijmegen (Nijmegen), from which the naming of the disease is derived. The exact incidence of Nijmegen breakage syndrome could not be determined. In the literature, 150 affected persons were described. However, significantly more cases of the disease are recorded in patient registries. It is assumed that the hereditary disease occurs all over the world. It is particularly common in Central and Eastern Europe among the Slavic population.
Causes
Nijmegen-Breakage syndrome is one of the hereditary diseases. It is passed from one generation to another in an autosomal recessive manner. The genetic cause is thought to be a mutation of the nibrin gene (NBS-1) on chromosome 8, more specifically in section q21-24. People in whom only one gene is altered usually do not develop the disease. Nijmegen breakage syndrome, on the other hand, manifests itself when affected individuals have two mutated nibrin genes. The nibrin gene encodes a protein called nibrin. The protein belongs to the protein complex involved in repairs of DNA double-strand breaks. If the polypeptide is absent, incorrectly assembled or damaged, this leads to a stop of the complete genetic repair mechanism. By participating in the ATM signaling cascade, nibrin performs another task. This involves the delivery of impaired cells of apoptosis. In the case of Nijmegen breakage syndrome, this process can also no longer be performed.
Symptoms, complaints, and signs
The complaints that occur in the context of Nijmegen breakage syndrome are exceedingly varied. The reason for this is that the hereditary disease affects all cells of the human body. The most important symptom is microcephaly. The head of the affected person is too small. Microcephaly is already present at birth and increases with age. In addition, the patient has a receding chin and a receding forehead. The other facial features can vary from individual to individual. Thus, there are short, but also long and beak-shaped noses, as well as palpebral fissures that run obliquely in the upper direction. Some patients also suffer from choanal atresia or cleft lip and palate. It is not uncommon for mild growth retardation and premature ovarian failure to occur. Approximately 50 percent of all patients have clinodactyly of the little fingers and syndactyly of the second and third toes. In addition, speech development is delayed in children. Between 50 and 70 percent of all affected individuals also have vitiligo spots. The hair of children suffering from Nijmegen-Breakage syndrome usually turns out sparse and thin. With increasing age, however, this finding improves. Furthermore, congenital malformations of the kidneys are not uncommon. Additional possible symptoms include mental retardation, malformations of the brain such as bar hypoplasia, and various diseases of the immune system. In addition, Nijmegen-Breakage syndrome is associated with the occurrence of malignant cancers already in children and adolescents.
Diagnosis and disease progression
Nijmegen breakage syndrome is diagnosed on the basis of clinical symptoms, combined immunodeficiency, increased cell sensitivity to ionizing radiation, and chromosomal instability.In addition, the normally long nibrin is completely absent. Early diagnosis is considered extremely important in NBS in order not to burden the patient with unnecessary radiation or recurrent infections. Analyzing the family medical history also plays a role in the diagnosis. In doing so, the physician pays attention to possible malignant tumors, early deaths of siblings as well as microcephalies. The NBS diagnosis is ultimately confirmed by DNA analysis. Also important are differential diagnoses of Bloom syndrome, NHEJ1 syndrome, Seckel syndrome, Fanconi anemia, and diseases similar to Nijmegen-Breakage syndrome. The course of NBS usually ends poorly. Thus, only a few patients can reach adulthood. In most cases, increased chromosomal fragility occurs during puberty at the latest, which in turn leads to cancers such as lymphoma. Corresponding treatments are very difficult to carry out, because radiation is not possible for the patients due to the brittleness. The use of cytostatic drugs is therefore also considered problematic. X-ray examinations should generally be omitted because the ionizing radiation increases the patients’ risk of cancer.
Complications
Nijmegen breakage syndrome is associated with significant complications. It is a hereditary disorder characterized by increased chromosomal fragility. Therefore, a cure for Nijmegen-Breakage syndrome is not possible. The onset of complications can only be delayed by symptomatic treatment. It is the chromosome fragility that leads to malignant cancers such as leukemia, lymphoma or other malignant tumors. Due to the disturbed repair system of the DNA, the usual treatments of the cancer such as radiation or the use of cytostatic drugs are associated with further dangers in the case of chromosome breaks. Although the existing cancer can be treated in this way. However, chromosome breaks that occur due to radiation or drug therapy can be poorly repaired. As a result, new malignant tumors develop. For this reason alone, only a few affected individuals reach adulthood. X-ray and CT examinations should also be avoided because they are associated with very high risks due to chromosomal instability. Another serious symptom of the Nijmegen-Breakage syndrome is also the pronounced immune deficiency. This leads to numerous infectious diseases that require constant treatment. Due to these infections, the life expectancy of the patients is also very limited. Furthermore, the child’s mental development can be very disturbed due to the malformations of the brain, so in addition to fighting infectious diseases and cancer, constant psychological and psychotherapeutic treatment is also necessary.
When should you go to the doctor?
Nijmegen-Breakage syndrome is a congenital disorder that is diagnosed immediately after birth. Because of the various malformations and other complications, close medical attention is necessary in all cases. Parents of affected children should inform the pediatrician if unusual symptoms or complaints occur. If the child’s health suddenly deteriorates, medical advice is also required. Serious complaints, such as tumors or immunodeficiencies, must be treated as an inpatient in a hospital or a specialist clinic for genetic diseases. If there are already cases of the disease in the family, a genetic test should be carried out in the event of pregnancy. The result will indicate whether the child also suffers from Nijmegen-Breakage syndrome, thus enabling early treatment. The disease can be diagnosed by a specialist. The individual symptoms are examined and treated by the respective doctors in charge. For example, growth disorders must be presented to an orthopedist, among others, while lymphomas and leukemias must be treated by a dermatologist.
Treatment and therapy
It is not possible to treat the cause of Nijmegen-Breakage syndrome. For this reason, treatment is limited to the symptoms. It includes physiotherapeutic applications, fighting infections, and psychological care. If cancer breaks out, the usual treatment measures of cancer therapy are carried out as far as possible.Multidisciplinary treatments and long-term follow-up examinations are also important.
Outlook and prognosis
Nijmegen breakage syndrome has an unfavorable prognosis. Patients experience health problems of the organs as well as the cells. Numerous symptoms in various areas occur, leading to severe distress for the affected person as well as the relatives. In most cases, independent living is unthinkable. The disease is not curable with the current legal and medical possibilities. There is a genetic defect that cannot be repaired. Medical doctors are not allowed to change human genetics due to the legal situation. The treating physician therefore concentrates on the individually pronounced symptoms and draws up an appropriate treatment plan, which is regularly adjusted over the course of a person’s life. The aim of therapy is to improve the general quality of life and alleviate existing symptoms. Recovery from this syndrome can be ruled out to this day. Due to the multitude of different complaints, strong emotional overstrain can occur. Often, therefore, psychological care is necessary to prevent the development of secondary diseases that have a negative influence on further physical processes. Since the risk for the onset of cancer is increased in the patient, control examinations are necessary at regular intervals. Nevertheless, even with early detection of the malignant tissue changes and intensive medical care, premature death of the affected person is often the result due to the unfavorable course of the disease.
Prevention
Unfortunately, prevention of Nijmegen-Breakage syndrome is not possible. Thus, it is counted among the already congenital diseases.
Aftercare
In most cases, no special or direct measures of aftercare are available to those affected by Nijmegen breakage syndrome. Because it is a congenital disease, there may also be no complete cure. If the patient wishes to have children, genetic testing and counseling is recommended to prevent recurrence of Nijmegen-Breakage Syndrome in offspring. Most of the affected persons depend on various surgical interventions that can alleviate the symptoms and deformities. Bed rest should always be observed after such interventions, and the affected person should also take it easy in any case. Exertion or other physical activities should be avoided. In many cases, it is also necessary to take various medications. The correct dosage and regular intake must always be observed. If there are any uncertainties or questions, a doctor should always be consulted first. Those affected are often dependent on the help and care of relatives and their own family in their daily lives. In this case, psychological support also has a very positive effect on the further course of the symptoms. Possibly, due to the Nijmegen-Breakage syndrome, the life expectancy of the affected person is also reduced.
What you can do yourself
Because Nijmegen-Breakage syndrome is a genetic disorder, there is currently no possibility for causal treatment. Therapies can only be symptomatic. It is important to individually address the disease state of each patient. In addition to medical therapies, other alternative therapy methods can be used to improve the quality of life of the affected person. Parents and relatives can help sick children to exercise functions restricted by the disease through various types of stimulation. Small individual successes can boost patients’ self-esteem. Doctors and physiotherapists can also provide guidance on light training methods that are designed to maintain the physical capacity of individuals. In addition to appropriately challenging mental as well as physical exercises, there are also various relaxation methods that can be learned by parents of affected children and used at home. These include, among other things, different types of meditation. Also, for example, singing bowls or dance therapy can help to challenge and promote different senses of the children. It is important to apply these measures continuously. Only in this way can, at best, an increase in performance in various areas of life be achieved.In addition to centering the individual, it can be extremely important for affected children as well as family caregivers to involve the social environment in non-medical measures. An intact social network helps to cope better with the stresses.
