T-lymphoblastic leukemia/lymphoma in macedonian patients with Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a relatively rare chromosomal instability disorder with an estimated incidence of less than 1:100,000 live births [1,2]. The disease seems to be more prevalent among Central and Eastern European populations, with Polish patients constituting approximately half of all registered NBS patients worldwide. Nijmegen breakage syndrome is clinically characterized by microcephaly, typical facial appearance, growth and mental retardation, immunodeficiency and a high predisposition to lymphoid malignancies, in particular to lymphoma and leukemia [1,2]. Important additional features are skin abnormalities, particularly café au lait spots and vitiligo, as well as clinodactyly and syndactyly. The laboratory analyses demonstrate immunodeficiency characterized by the involvement of both humoral and cellular immunity. The NBS patients’ cells display chromosome instability and hypersensitivity to the lethal effects of agents, such as ionizing radiation, that induce double-strand breaks in genomic DNA. The disease is caused by mutations in the NBS1 gene that is located on chromosome 8q21 [3-5]. The NBS1 gene encodes nibrin, a member of the Mre11/Rad50/nibrin complex involved in the cellular response to DNA double-strand breaks [6-8]. After identification of the gene, a truncating 5 bp deletion, 657-661delACAAA, was identified as the disease-causing mutation in patients with the NBS [9-11]. Patients with the same genotype may vary in their phenotypic expression. In this report, we describe the clinical features and molecular characterization of two patients with NBS in a Macedonian family. To the best of our knowledge, this is the first family with NBS reported from Macedonia.

Nijmegen breakage syndrome has been reported in different populations, but so far, most of the patients have been of Slavic origin and carry a typical mutation (657 del5) on the NBS1 gene [1,2]. To the best of our knowledge, this is the first family with NBS reported from Macedonia. B-cell lymphomas are the most frequently encountered malignancies in NBS, but cases of precursor T-cell, B-cell leukemia or myeloid leukemia, have also been reported [13,14]. Data from the Nijmegen registry indicate that patients with NBS develop cancer before the age of 21 years [1]. The majority of lymphomas in NBS were diagnosed in patients younger than 15 years of age with lymphomas as the leading cause of death [1,2]. Due to the small number of patients with NBS and NHL, experience related to their treatment is limited [13,14]. The treatment outcome is poor, and drug dose reductions are warranted to reduce serious toxic effects in these patients.

Our patients developed T-NHL and T-ALL at the age of 7 and 9.5 years, respectively. The first patient received more than 80.0% of the recommended doses of chemotherapy. During treatment, no major toxic or infectious complications were observed. He achieved a complete remission that lasted for 21 months. The remission was not achieved in his brother and he died after a very brief and severe episode of a gram-negative sepsis and SIRS. Immunodeficiency in NBS is significant, affecting both the humoral and cellular immunity but it is highly variable, with a tendency to progress over time [14]. In our patients, we found a normal humoral immune system (cellular immunity was not tested). The diagnosis of NBS was established based on the clinical characteristics and molecular analyses of the NBS1 gene. The constitutional karyotypes of the NBS patients were normal. Cultured T cells often show a poor proliferative capacity, making the cytogenetic analysis far from easy. Early diagnosis of NBS is very important in order to avoid severe recurrent infections by employing appropriate prophylaxis in order to avoid unnecessary exposure to radiation for diagnostic purposes and the adverse reactions of the radiotherapy for the treatment of malignant tumors. It is important in cases presenting with malignancy and suggestive clinical features, that the diagnosis is confirmed prior to the initiation of treatment. Diagnosis on a genetic level provides prevention of the disease in families who are at an increased risk for having a sick child with NBS. Establishing an early genetic diagnosis will provide prenatal diagnosis in each successive pregnancy and prevent the recurrence of the disease in the family.