Nijmegen Breakage Syndrome Clinical Presentation
- Author: Krystyna H Chrzanowska, MD, PhD; Chief Editor: William D James, MD more...
The patient history may reveal clues to the diagnosis, such as the following:
Course of pregnancy and delivery: Most children with Nijmegen breakage syndrome are born at term, in vertical presentation.
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.
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.
Mild complications after vaccinations (ie, against polio or measles) or in the course of childhood infectious diseases (eg, varicella) are reported in some patients.
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:
Occurrence of microcephaly or hydrocephaly in patient's siblings
Death of patient's siblings due to malignancy or severe infection
Malignancies among other family members
The main clinical manifestations of Nijmegen breakage syndrome 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.[23, 39, 41]
Microcephaly (ie, head circumference below the third percentile) is the most striking and consistent symptom of Nijmegen breakage syndrome. 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.
Among the 77 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.
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 Nijmegen breakage syndrome, which is similar among all patients. The craniofacial characteristics of Nijmegen breakage syndrome become more obvious with patient age, probably because of progressive microcephaly. Note the images below.
Children with Nijmegen breakage syndrome, 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.
The range of birth weight of Polish neonates was 1900-3600 g for females and 2170-3950 g for males.
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 (Polish data).
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 Nijmegen breakage syndrome can reach a height of approximately 165 cm (ie, approximately 50th percentile for females and less than third percentile for males; Polish data).
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 Nijmegen breakage syndrome who reached pubertal age.
Endocrinologic evaluation indicates ovarian failure (see Lab Studies). Affected female patients fail to reach sexual maturity because of hypergonadotropic hypogonadism.[42, 43]
Immune deficiency and recurring infections
Because of defective humoral and cellular immunity, Nijmegen breakage syndrome patients are prone to developing infections. A considerable variability in immune deficiency is observed among different patients.
The most common infections are respiratory tract infections (pneumonia, bronchitis) and sinusitis. Recurrent bronchopneumonia may result in bronchiectasis. Urinary and/or gastrointestinal tract infections and otitis media are also relatively common. Opportunistic infections are rare, as they are in patients with A-T.
Immunodeficiency in Nijmegen breakage syndrome is caused by reduced numbers of peripheral B and T lymphocytes, which can be explained as a precursor B-cell and, probably, also T-cell differentiation problem, due to a dysfunction of a truncated nibrin molecule. A defect in humoral immunity in Nijmegen breakage syndrome patients is caused by reduced numbers of peripheral B lymphocytes and, simultaneously, by failure of their maturation, which results in an ineffective class-switch recombination.
Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.
The prevalence of lymphoid malignancies in individuals with Nijmegen breakage syndrome 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 Nijmegen breakage syndrome 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 (two morphological subtypes predominate: diffuse large B-cell lymphoma, DLBCL, and T-cell lymphoblastic lymphoma, T-LBL), lymphoblastic leukemia (acute lymphoblastic leukemia, with both precursor B cells and T cells), and Hodgkin disease.[47, 48, 49, 50] Two cases of acute myeloblastic leukemia (Chrzanowska, unpublished data), a single case of T-cell prolymphocytic leukemia, and a single case of acute monocytic leukemia were also reported.
Among solid tumors, 2 were observed relatively frequently: medulloblastoma in 5 patients[9, 53, 54] (further 2 cases unpublished) and rhabdomyosarcoma of the perianal region in 3 others.[55, 56, 57] The latter, rhabdomyosarcoma arising perianally, is extremely uncommon in children; therefore, taking into account the number of Nijmegen breakage syndrome patients with this type of cancer, a strong association with Nijmegen breakage syndrome is suggested.
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
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.[23, 38, 39] In 3 Polish patients, vitiligo was observed by the time they became adolescents, with progression as they aged. Less frequently, sun sensitivity of the eyelids is observed, and, occasionally, cutaneous telangiectasia (particularly on the back) is seen. Multiple pigmented nevi and cavernous or flat hemangiomas can also occur.
Cutaneous, sarcoidlike granulomas were observed in two female Nijmegen breakage syndrome patients with accompanying ocular manifestations in one of them. (Chrzanowska, unpublished data). Primary cutaneous tuberculosis and necrobiotic cutaneous granulomas were reported, respectively.[59, 60]
Usually, the hair is thin in infants and toddlers, but later, improvement is observed. Early graying of hair may be observed by adolescence.
Note the images below.
Other developmental anomalies
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).[55, 61, 62]
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. Note the image below.
Urogenital defects noted in several patients with Nijmegen breakage syndrome have included kidney pathology (eg, agenesis or hypoplasia, ectopic single kidney or dystopic kidneys), hydronephrosis, hypospadias, and cryptorchidism.
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.
Two pediatric patients were reported to suffer from juvenile rheumatoid arthritis–like arthritis and chronic polyarthritis, respectively.[63, 64]
Nijmegen breakage syndrome is a disease with an autosomal recessive pattern of inheritance. Note the following:
Consanguineous matings have been reported.
The gene responsible for Nijmegen breakage syndrome, designated NBN ( 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 (c.657_661del5) in exon 6 of the NBN gene. 
The remaining patients tested to date are either heterozygous for c.657_661del5 and a second unique mutation (compound heterozygosity) or homozygous for a unique mutation. Ten unique mutations have been detected in various ethnic groups [11, 13, 14, 40, 65, 66] ; see the Table in Lab Studies.
The recent finding of the homozygous mutation c. 1089C>A in Pakistani Nijmegen breakage syndrome 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. [67, 68]
Single case of Nijmegen breakage syndrome due to maternal isodisomy of chromosome 8 was reported. 
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|Mutation||Exon||Mutation Type||Change in Protein||Number of Families and Origin||Allelic Status|
protein (233 aa)
protein (229 aa)
protein (236 aa)
protein (251 aa)
protein (279 aa)
protein (283 aa)
protein (305 aa)
protein (402 aa)
|*He - Heterozygous (compound with 657del5).
†Monozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.
‡Ho - Homozygous.
§Three nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).[67, 68]