Nijmegen Breakage Syndrome (NBS) Italian website

Clinical Phenotype
Cited literature

 

Disease Description



Focus on:

     NBS with neurological abnormalities and without chromosomal instability.

              Seemanova et al. (2006) report the identification of the missense mutation R215W (643C>T) at the compound heterozygous state with the classic 657del5 mutation in two monozygous twin brothers , who presented with a clinically severe form of NBS with neurological abnormalities, and without chromosomal instability nor increased cellular radiosensitivity.




Microcephaly (occipitofrontal circumference [OFC] below the 3rd percentile) is the most consistent symptom of NBS.
Other clinical hallmarks of the disease are: a distinct facial appearance, growth retardation, immunodeficiency accompanied by recurrent respiratory infections, impaired sexual maturation in females due to ovarian dysgenesis and a strong predisposition to lymphoid malignancy. Common additional features are skin pigmentation abnormalities (café-au-lait spots and/or patchy depigmentation of skin) and limbs defects (clinodactyly and sindactyly).


Microcephaly. About 75% of patients have a birth OFC below the 3rd percentile; the remainder develop progressive and severe microcephaly during the first months of life. Microcephaly is usually associated with a normal or only mildly delayed early psychomotor development.


Craniofacial features. All patients have a typical distinctive facial appearance, characterised by a sloping forehead, small and receding mandible and prominent mid face with a relatively long nose and long philtrum. Other features include: upward slanting of the palpebral fissures in most patients, freckles on the cheeks and nose and relatively large and protruding ears with dysplastic helices. Hair can be thin or sparse, and early greying usually appears by adolescence or early adulthood. Subtle scleral telangiectasia has been noted in some patients. Facial characteristics become more obvious with age, as the microcephaly progresses.


Growth. The growth retardation can be of pre- or postnatal onset. Most children with NBS are born at term and birth weight can range from below 2000g to normal. However, growth failure is observed during the first years of life and results in height falling below the 10th percentile in almost all patients. Thereafter, the linear growth rate tends to be normal, but patients remain small for age. The growth retardation is proportionate and weight corresponds to height.
Bone age can be retarded.


Immunological function. In general, disturbances of the immune system in NBS are profound and tend to progress over time. Considerable variability has however been observed among different patients. Both humoral and cellular response are involved.
Humoral Immunity. Humoral immunity defects can range from isolated immunoglobulin G (IgG) subclass deficiency to severe hypogammaglobulinemia/agammaglobulinemia which requires intravenous immunoglobulin [IVIG] therapy.
A combined deficiency of IgG and IgA is frequently observed, while IgM levels tend to be normal or even increased. About 20% of patients have Ig levels in the reference range, however, in more than one third of cases, normal concentrations of total serum IgG mask deficiency of one or more IgG subclasses. A defect in IgG subclasses can be observed in virtually all adequately tested NBS patients, with selective or combined IgG2 and IgG4 deficiency being the commonest defects. A progressive deterioration of the immune system is often observed and may lead to the loss of different Ig isotypes, reaching severe hypogammaglobulinemia/agammaglobulinemia in about 20% of patients.
Absence or very low titres of specific antibodies against vaccinal antigens can be expected.
Cellular Immunity. A tendency toward low B-cell count has been observed, however a normal number of B-lymphocytes (CD19+, CD20+) can be demonstrated in about 25% of patients; no correlation exists with the degree of Ig deficiency.
A mild to moderate lymphopenia, expressed as a low percentage (or reduced absolute number) of CD3+ T-cells, is observed in the great majority of NBS patients. Low CD4+ (helper) cell levels mainly account for the CD3+ cell reduction, while the CD8+ T-cell number can be normal, a decreased CD4+/CD8+ ratio being observed in about 70% of cases. A reduced CD4+CD45RA+ naïve cell/CD4+CD45RO+ memory cell ratio has been reported as well. An increased number of natural killer (NK) cells (CD16+, CD56+) is found in about 60% of patients.
The in vitro proliferative response of T-lymphocytes to mitogens/antigens (e.g. PHA, anti-CD3, anti-TCR) is decreased in nearly all NBS patients and greatly reduced in most.
Thymus aplasia/dysplasia and/or diffuse lymphoid tissue hypoplasia have been reported in some cases.
Bone marrow aplasia has been observed in three NBS patients. In one of them it was associated with EBV infection and B-cell lymphoma.

Aplastic anemia associated with a homozygous I171V mutation in the NBS1 gene.

Shimada et al. (2004) reported the case of an 11-year-old Japanese girl diagnosed with idiopathic severe aplastic anemia at the age of 9. The girl had neither other clinical signs of disease nor features of NBS. After immunosuppressive therapy, her blood analysis was normal apart from mild thrombocytopenia.
Cytogenetic analysis on metaphase spreads obtained from Lymphoblastoid Cell Lines showed a remarkable increase in the frequency of spontaneous chromosomal aberrations (polyploidy, chromosome and chromatid breaks, quadri-radial configurations, telomeric end-to-end fusions).
On the basis of pyrosequencing results, the Authors concluded that the majority of patient's blood cells are homozygous for the mutation I171V in the NBS1 gene, and the minority are heterozygous for the same mutation. The analysis of blood cells from the healthy parents demonstrated that the father and the mother are heterozygous for the I171V mutation and homozygous for the wild-type allele, respectively. The Authors therefore postulated that the patient inherited the germline I171V mutation from her father and the wild-type allele from her mother, and that the second I171V hit occurred on the the wild-type allele early in embryonic development. The patient's wild-type allelic frequency was estimated to be less than 5%.

Infections. Recurrent infections of the respiratory tract, sinusitis, mastoiditis and otitis media are very common in NBS. They are followed by urinary tract infections, gastrointestinal infections with chronic or recurrent diarrhea and skin infections. On the contrary, opportunistic infections are rare.


Sexual maturation. Poor development of secondary sex characteristics (genital organs, breasts, pubic and axillary hair) and primary amenorrhoea can be expected in most female patients who reach pubertal age. This is due to ovarian dysgenesis leading to hypergonadotropic hypogonadism. Ultrasound examination reveals small homoechoic ovaries that resemble streaks.
In male patients a slight delay in onset of puberty has been observed, while no data are available about fertility.


Malignant disease. Malignancy is the most common cause of death in patients with NBS. Most malignancies (85-90%) are of lymphoid origin and develop in patients younger than 20 years (about 50% of patients develop a tumour at a mean age of 9 years). The commonest types are B-cell non-Hodgkin lymphomas (NHL), T-cell NHL, acute lymphoblastic leukemia (ALL, with both precursor B cells and T cells), Hodgkin disease and acute myeloblastic leukemia (AML). A wide morphological spectrum of NHL is observed, with clonal rearrangements involving Ig and T-cell receptor (TCR) genes. The youngest patient recorded to have had ALL was a 1-year-old girl.
Different solid tumours have been reported sporadically: Ewing sarcoma, gonadoblastoma, neuroblastoma, glioma, meningioma and papillary thyroid carcinoma. Three patients had a medulloblastoma.

Association between perineal region rhabdomyosarcoma and NBS.

Recently, Meyer et al. (2004) reported the third case of association between NBS and perineal region rhabdomyosarcoma (RMS), in a 7-year-old girl who is homozygous for the 698del4 mutation. Perineal region RMS had been previously described in two NBS patients, one of them was homozygous for the 657del5 mutation, the other one was a compound heterozygous for the 657del5/1142delC mutations of the NBS1 gene.
Meyer et al. point to the fact that perineal RMS is extremely uncommon, and that, therefore, the identification of three cases in as many NBS patients suggests a strong association with NBS. An indirect confirmation of an important association between perineal region RMS and NBS might come from the inferior prognostic outlook in children with RMS arising perianally compared with other anatomical sites. This could suggest that some patients treated for perineal RMS might in fact have been patients with NBS.
Therefore, the Authors stress the importance of considering the diagnosis of NBS when confronted with a perineal RMS, as this also carries important clinical implications in terms of potential need for therapy modification and follow up investigations.
They also underlie the absence of alveolar RMS specific fusion genes involving the PAX and FKHR genes in their patient with perianal alveolar RMS and NBS.

Due to their increased radiosensitivity, patients with NBS have high risk of severe toxic complications and second tumours after conventional chemo- and radiotherapic treatment.


Psychomotor development. Despite severe microcephaly, developmental milestones are usually achieved at the expected times during the first year of life. A shift toward a lower level of the cognitive function can be observed with age and speech delay is common. In general, at the time of first evaluation, about 40% of patients have normal development, 50% have borderline to mild retardation and 10% are moderately retarded. Severe developmental delay has been reported in one Pakistani patient, aged 20 months, who is homozygous for the 1089C>A mutation. Psychomotor hyperactivity is common, but social interactions are good.


Central nervous system developmental abnormalities. MRI examinations in a group of NBS patients revealed the presence of small brain frontal lobes with narrow frontal horns of the lateral ventricles in all tested subjects. Another common abnormality seems to be the agenesis of the posterior part of the corpus callosum with colpocephaly (widening of trigones and occipital horns) and lateral ventricles’ temporal horn dilatation.
Hydrocephaly, abnormal dimensions and/or communication of cerebrospinal fluid spaces and a simplified gyral pattern have been observed in some patients. Among major structural malformations, schizencephaly has been reported once and cerebellar abnormalities have been detected in two patients.
Seizures/EEG abnormalities have been reported in some cases.

NBS with neurological abnormalities and without chromosomal instability. up

The missense mutation R215W (643C>T) has been found at the compound heterozygous state with the classic 657del5 mutation in two monozygous twin brothers (Seemanova et al., 2006), who presented with a clinically severe form of NBS with neurological abnormalities. The Authors propose that the compound heterozygosity, 657del5/643C>T(R215W), is the primary cause of the clinical phenotype.
The two patients presented with a similar clinical phenotype which included: oligohydramnion, growth retardation with prenatal onset, severe congenital microcephaly, craniosynostosis and facial dysmorphisms, i.e. large auricles and micrognathia. Imaging study of the brain demonstrated partial lissencephaly, enlarged, mild asymmetric lateral ventricles, and enlarged subarachnoidal spaces. Psychomotor development was severely delayed and the children developed epileptic seizures aggravating to status epilepticus, with progressive respiratory and feeding difficulties. One of the children also showed bilateral hydrocele and diastasis m. recti abdominis.
The patients didn’t show chromosomal instability nor increased cellular radiosensitivity. Full length nibrin was detected in their lymphoblastoid cell lines, but with reduced expression when compared with controls (see also Cytogenetics and Cellular Phenotype and Molecular Biology ).



Cutaneous manifestations. Skin pigmentation abnormalities are observed in more than 50% of NBS patients and include café-au-lait spots and/or depigmented patches. Progressive vitiligo has been reported in some cases. Less frequently sun sensitivity of the eyelids has been described and cutaneous telangiectasia is seen occasionally. Cavernous or flat hemangiomas have also been reported.


Minor skeletal anomalies. Clinodactyly of the 5th finger and partial syndactyly of the II-III toes are observed in about 50% of the patients; congenital hip dysplasia (about 15% of the patients), preaxial polydactyly of hands and sacral agenesis are less common.


Urogenital pathology. Hydronephrosis, kidney malformations (agenesis, hypoplasia, horseshoe kidney), hypospadias, cryptorchidism and ovarian dysgenesis have been noted in several patients.


Other congenital malformations. Polysplenia has been detected by ultrasonographic examination in about 20% of NBS patients and anal stenosis/atresia has been reported in some. Cardiovascular defects include PDA and VSD, each reported once; cleft lip and/or palate, choanal atresia, tracheal hypoplasia and agenesis of phalanges have been occasionally seen.


Page last updated on: 18th May 2007