Nijmegen breakage syndrome is an extremely rare monogenic disease with an autosomal recessive type of inheritance, which is characterized by primary immunodeficiency, multiple anomalies. Pathology is associated with a mutation of the NBN gene. The main signs of Nijmegen breakage syndrome are: deformity of the facial skeleton in the form of a “bird” face, frequent recurrent bacterial infections, microcephaly, lagging children in physical development. Diagnostics includes immunological and genetic studies. The basis of treatment of the syndrome is lifelong replacement therapy with immunoglobulins, and the option of infusion of hematopoietic stem cells is also being considered.
Q87.8 Other specified syndromes of congenital anomalies, not classified elsewhere
The syndrome is named after the Dutch city of Nijmegen, where the clinical picture of the disease was first described in 1981. The genetic disorders underlying the disease were mapped in 1998. About 150 cases of the syndrome have been described in the medical literature. However, according to data from national registers (Czech, Polish), its true prevalence is much higher. Basically, the Nijmegen breakage syndrome occurs on the territory of Eastern Europe, which is due to the frequent carrier of the mutation among the healthy Slavic population (the “founder effect”). Among non-Slavs, the prevalence of pathology is 1:3-5 million inhabitants.
Pathology occurs when the NBN gene (NBS1 — Nijmegen breakage syndrome 1) is defective, located on the long arm of the 8th chromosome. It encodes the formation of the nibrin protein involved in the operation of the three-dimensional MRN protein complex, which, in addition to nibrin, includes the proteins MRE11 and RAD50.
Nijmegen breakage syndrome has an autosomal recessive nature of inheritance: in the presence of a specific gene defect in both parents, the risk of having a sick child is 25%. In couples where only the father or mother is the carrier of the mutated gene, sick children are not born, but half of the offspring in the karyotype have a defective gene.
The MRE11/RAD50/NBN complex, whose functioning is disrupted in children suffering from Nijmegen’s disease, is responsible for DNA repair. Proteins regulate the restoration of the normal double-stranded structure of genetic material after damage by ionizing radiation, meiosis and V(D) processesG-recombinations that occur at an early stage of immune cell formation.
Up to 90% of sick children of Slavic origin are homozygous for the hypomorphic mutation 657del5, that is, they have a deletion of 5 base pairs in the sixth exon of the NBN gene. In this case, two abnormal truncated proteins are synthesized — p26-nibrin, p70-nibrin, which are unable to ensure the normal functioning of the protein.
Patients from non-Slavic countries (Great Britain, Germany, Holland, Italy, Canada, Mexico) revealed 11 more damage variants localized not only in exon 6, but also in other regions of the mutated gene. Scientists have proved an inverse relationship between the expression of the p70 protein and the development of hematological diseases in the framework of the Nijmegen breakage syndrome.
With Nijmegen’s disease, characteristic features of the appearance of a “bird” face are noted from birth. Children have a narrow face with a high forehead, a large nose, and a small lower jaw. Also, from the moment of birth, signs of microcephaly are noticeable (reduced size of the skull), cleft palate, deformities of the auricles, mongoloid incision of the eyes in combination with hypertelorism are often detected.
Malformations of the skeleton include clinodactyly, partial syndactyly, polydactyly, hip dysplasia. Dermatological manifestations of the syndrome are detected in 50-70% of children: coffee with milk spots, areas of vitiligo, progressive depigmentation throughout the body.
The pathognomonic feature of the syndrome is a congenital deficiency of cellular (T—lymphocytes) and humoral (antibodies) links of immunity. Because of this, from the first months of life, children have recurrent respiratory tract infections (bronchitis, pneumonia, sinusitis), inflammatory ear diseases (otitis media, mastoiditis), bacterial lesions of the gastrointestinal tract and genitourinary system. Viral infections (cytomegalovirus, Epstein-Barr virus) are less common.
Typical anomalies of the genitourinary organs, which include hypoplasia / aplasia of the kidneys, ectopic kidneys, urethro-anal fistula, boys are often diagnosed with cryptorchidism, hypospadias. Arachnoid cysts are present in the brain tissue, there may be a partial or complete absence of a corpus callosum. Physical development slows down in children, the level of intelligence is normal or moderately reduced.
The most prognostically unfavorable consequence of Nijmegen breakage syndrome are malignant tumors, which are diagnosed in 40% of children. Lymphoid tissue is most often affected: T- and B-cell non-Hodgkin’s lymphomas, Hodgkin’s lymphoma, acute lymphoblastic leukemias appear. Among the solid neoplasias there are medulloblastoma, rhabdomyosarcoma, Ewing’s sarcoma. Oncopathology is the main cause of death in young patients (under 20 years of age).
Recurrent infections are particularly dangerous for Nijmegen breakage syndrome, which usually quickly turn into generalized forms against the background of immunodeficiency. Death can occur from septic complications. Some children develop amyloidosis due to prolonged infections, which causes chronic renal failure and ends in death.
The presence of Nijmegen breakage syndrome may be indicated by specific phenotypic features (a reduced skull, a “bird” face), which are combined with signs of immunodeficiency. A pediatrician is engaged in the examination of children, an immunologist-allergist, a geneticist, an orthopedic traumatologist are involved for a comprehensive diagnosis. To confirm the syndrome , the following diagnostic measures are prescribed:
- Immunological tests. In the extended immunogram, leukopenia and lymphopenia are expressed in children with a decrease in the absolute number of CD3, CD4, a change in the CD4/CD8 ratio. The absolute number of B cells is reduced in 72% of patients, IgG, IgA, IgM deficiency is also observed.
- Genetic testing. To verify the syndrome, a molecular genetic study is necessarily performed, with the help of which mutations in exons 6-10 of the NBN gene are determined.
- Instrumental visualization. Taking into account the increased sensitivity of children with Nijmegen syndrome to radiation, ultrasound diagnostics, endoscopy, magnetic resonance imaging are performed to detect defects of internal organs.
There are no standardized therapy protocols for children with the Nijmegen syndrome clinic, since etiotropic treatment has not been developed at the current stage of medical development. The main task of doctors is to control the patient’s immune status, prevent complications, and improve the quality of life. For this purpose , several treatment directions are used:
- Substitution therapy. Regular administration of immunoglobulins G is necessary to maintain immune protection, reduce the risk of severe infections in children. Subcutaneous injections are recognized as an effective, safe and convenient way to correct immunodeficiency. The IgG level of less than 2.5–3.0 g/l is a marker for the start of replacement therapy.
- Antibiotic therapy. It is carried out in periodic or permanent courses with often recurrent or chronic infections of the respiratory organs.
- Hematopoietic cell transplantation. This is a more modern treatment option for the syndrome, which successfully corrects the immunological defect and can be used in the treatment of oncohematological diseases.
- Polychemotherapy. Cytostatics are recommended for the treatment of lymphoid and solid tumors. Patients are prescribed reduced doses of drugs. As a rule, they are combined with monoclonal antibodies for targeted therapy.
Prognosis and prevention
Nijmegen breakage syndrome often ends with the death of patients at a young age from oncopathology, septic processes. However, thanks to intensive replacement therapy with immunoglobulins, conducting HSCT is possible to prolong the life of patients. Prevention of the syndrome in children includes medical and genetic counseling of couples with burdened heredity at the stage of conception planning, during pregnancy.