Nijmegen breakage syndrome (NBS) is a rare autosomal recessive condition of chromosomal instability that is clinically characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity, and a strong predisposition to lymphoid malignancy. Mutations in the NBS1 gene located in band 8q21 are responsible for NBS. NBS is identified as entries 251260 in and 602667 in Online Mendelian Inheritance in Man. In 1981, Weemaes et al1 first delineated the syndrome in 2 siblings with microcephaly, short stature, skin pigmentation abnormalities, mental retardation, immunologic defects, and a high prevalence of chromosome 7 and/or chromosome 14 rearrangements in cultured lymphocytes. In 1985, Seemanova et al2 described a group of patients with an apparently new genetic disorder characterized by microcephaly with normal intelligence, cellular and humoral immune defects, and a striking predisposition to lymphoreticular malignancies. These cases were subsequently studied and found to fit into the category of NBS. Further investigations revealed that in vitro cells derived from patients with NBS display characteristic abnormalities similar to those observed in ataxia-telangiectasia (A-T), including spontaneous chromosomal instability, sensitivity to ionizing radiation (IR), and radioresistant DNA synthesis (RDS). However, aside from immune deficiency and a predisposition for malignancies (particularly those of lymphoid origin), the clinical manifestations are distinct. Consequently, NBS has long been considered a variant of A-T. In 1998, on the basis of cellular phenotypes and the results of somatic cell complementation studies suggesting genetic heterogeneity, Jaspers et al proposed the term A-T variants for diseases in this group of patients. The 2 distinct groups were designated as A-T variant 1 (V1) for NBS and A-T variant 2 (V2) for Berlin breakage syndrome. Linkage studies allowed the exclusion of the gene responsible for NBS from the A-T locus on band 11q23 and from the translocation breakpoints in a Polish patient. When 2 independent groups of researchers finally mapped the gene to band 8q21 and isolated it in 1998, mutations in the single NBS1 gene were found to account for both A-T complementation groups V1 and V2.
History * The patient history may reveal clues to the diagnosis, such as the following: o Course of pregnancy and delivery: Most children with NBS are born at term, in vertical presentation. o Early somatic development: Birth weight, length, and head circumference are usually significantly lower in comparison with sex-matched controls; a slow growth rate and poor weight gain is observed in infancy and early childhood. o Psychomotor development: Usually, no gross delay of milestones is observed during the first year of life; toddlers and preschool children are frequently hyperactive; speech delay is common. o Mild complications after vaccinations (ie, against polio or measles) or in the course of childhood infectious diseases (eg, varicella) are reported in some patients. o Recurring infections: These are mainly of the respiratory tract, urinary tract, and gastrointestinal system, and they become a problem in approximately two thirds of patients. * The following information from the family history is also particularly important: o Occurrence of microcephaly or hydrocephaly in patient's siblings o Death of patient's siblings due to malignancy or severe infection o Malignancies among other family members Physical The main clinical manifestations of NBS include progressive microcephaly with characteristic facies, growth retardation, and impaired sexual maturation in females; recurrent infections due to a combined immune deficiency; and a strongly increased risk of developing cancer, in particular leukemia and lymphoma. Other frequently observed manifestations include skin pigmentation defects (café au lait and/or vitiligo spots) and minor limb abnormalities. * Microcephaly o Microcephaly (ie, head circumference below the third percentile) is the most striking and consistent symptom of NBS. In the great majority of children, it is observed at birth; in individuals who were born with a head circumference within the reference range, progressive and severe microcephaly develops during the first months of life. However, despite severe and progressive microcephaly, neuromotor development is not disturbed; epileptic seizures are not characteristic of the disease. o Among the 58 patients of Polish descent whom Chrzanowska observed, the deficiency of occipitofrontal circumference ranged from -4.4 to -9 standard deviation, but the proportions among the diminished head measurements (length and breadth) were retained. * Craniofacial characteristics o A sloping forehead and receding mandible, a prominent midface with a relatively long nose, upward slanting of the palpebral fissures (in most), and relatively large and dysplastic ears (in some) characterize the facial appearance in NBS, which is similar among all patients. o The craniofacial characteristics of NBS become more obvious with patient age, probably because of progressive microcephaly. * Growth retardation o Children with NBS, in spite of being born at term, are characterized by a significantly lower birth weight and head circumference in comparison with sex-matched controls, as well as lower birth length and chest circumference. o The range of birth weight of Polish neonates was 1900-3600 g for females and 2170-3950 g for males. o After approximately a 2-year period of distinct postnatal growth retardation, a slight improvement in the growth rate (including those of body height and weight but not head circumference) is usually observed. o Most patients' growth is around the third percentile for height and weight; in some teenage patients, growth is between the 10th and 25th percentiles for height and weight. Young adult individuals with NBS can reach a height of approximately 165 cm (ie, approximately 50th percentile for females and less than third percentile for males; Polish data). * Sexual maturation o Results of long-term follow-up in a large group of Polish patients drew attention to the poor development of secondary sex characteristics (ie, lack of development of genital organs and breasts, primary amenorrhea) in female patients with NBS who reached pubertal age. o Endocrinologic evaluation indicates ovarian failure (see Lab Studies). o Affected female patients fail to reach sexual maturity because of hypergonadotropic hypogonadism. * Immune deficiency and recurring infections o Because of defective humoral and cellular immunity, NBS patients are prone to developing infections. A considerable variability in immune deficiency is observed among different patients. o The most common infections are respiratory tract infections (pneumonia, bronchitis) and sinusitis. o Recurrent bronchopneumonia may result in bronchiectasis. o Urinary and/or gastrointestinal tract infections and otitis media are also relatively common. o Opportunistic infections are rare, as they are in patients with A-T. * Malignancies o Malignancy is the most common cause of death in patients with NBS. o The prevalence of lymphoid malignancies in individuals with NBS is unprecedentedly high compared with healthy individuals and persons with other cancer-predisposing diseases such as A-T, Bloom syndrome, and FA. To date, 40-50% of NBS patients have developed a malignancy by age 20 years, of which 85-90% are leukemias or lymphomas. The most common of these are non-Hodgkin lymphomas (the B-cell type predominates over the T-cell type), lymphoblastic leukemia (acute lymphoblastic leukemia, with both precursor B cells and T cells), and Hodgkin disease. Two cases of acute myeloblastic leukemia and a single case of T-cell prolymphocytic leukemia were also noted. o Among solid tumors, 2 were observed relatively frequently: medulloblastoma in 4 patients and rhabdomyosarcoma of the perianal region in 3 others. The latter, rhabdomyosarcoma arising perianally, is extremely uncommon in children; therefore, taking into account the number of NBS patients with this type of cancer, a strong association with NBS is suggested. o Other malignancies were present in single patients only. These included papillary thyroid carcinoma, gonadoblastoma, glioma, meningioma, neuroblastoma, and Ewing sarcoma. * Cutaneous manifestations and hair characteristics o Skin pigmentation abnormalities include café au lait spots (usually 2-5 spots, irregular in shape) and/or depigmented spots, which are present in approximately half the patients. o In 3 Polish patients, vitiligo was observed by the time they became adolescents, with progression as they aged. o Less frequently, sun sensitivity of the eyelids is observed, and, occasionally, cutaneous telangiectasia (particularly on the back) is seen. o Multiple pigmented nevi and cavernous or flat hemangiomas can also occur. o One case of childhood sarcoidosis with cutaneous and ocular manifestations was observed. o Usually, the hair is thin in infants and toddlers, but later, improvement is observed. Early graying of hair may be observed by adolescence. * Other developmental anomalies o CNS malformations are observed relatively frequently and may be more common than expected. Small frontal lobes and narrow frontal horns of the lateral ventricles were documented in all patients who underwent cranial MRI. Small brain size may be associated with other CNS developmental abnormalities, including partial agenesis of the corpus callosum, hydrocephaly, arachnoid cysts, and neuronal migration disorder (in the form of schizencephaly or pachygyria). o Minor skeletal anomalies, such as clinodactyly of the fifth fingers and/or partial syndactyly of the second and third toes, are encountered in approximately half the patients. Hip dysplasia, preaxial polydactyly, and sacral agenesis are less common. o Urogenital defects noted in several patients with NBS have included kidney pathology (eg, agenesis or hypoplasia, ectopic single kidney or dystopic kidneys), hydronephrosis, hypospadias, and cryptorchidisms. o Among other abnormalities, tracheal hypoplasia, cleft lip and/or palate, choanal atresia, anal atresia/stenosis, and cardiovascular defects (patent ductus arteriosus, ventricular septal defect) are reported. Polysplenia, a peculiarity with no clinical significance, is relatively frequently detected by ultrasonography.
NBS is a disease with an autosomal recessive pattern of inheritance. * Consanguineous matings have been reported. * The gene responsible for NBS, designated NBS1, is located on band 8q21. * The entire gene consists of 16 exons and spans a DNA region of more than 50 kilobases. * All disease-causing mutations identified to date have been found within exons 6-10 in the NBS1 gene and resulted in the production of a truncated protein. * More than 90% of all patients tested are homozygous for the common mutation of Slavic origin, a 5 base-pair deletion (657del5) in exon 6 of the NBS1 gene. * The remaining patients tested to date are either heterozygous for 657del5 and a second unique mutation (compound heterozygosity) or homozygous for a unique mutation. Ten unique mutations have been detected in various ethnic groups; see the Table in Lab Studies. * The recent finding of the homozygous mutation 1089C>A in Pakistani NBS patients, initially diagnosed as having FA, has drawn attention to the clinical (microcephaly and congenital anomalies) and biological (increased sensitivity to both DNA cross-linking agents and IR) overlap of these 2 diseases