© Borgis - Nowa Stomatologia 1-2/2009, s. 3-8
*Dorota Olczak-Kowalczyk1, 2, Bożena Dembowska-Bagińska3, Hanna Gregorek4, Anna Wakulińska3, Barbara Pietrucha5, Krystyna H. Chrzanowska6
Dental Aspect of Nijmegen Breakage Syndrome
Zespół Nijmegen w aspekcie stomatologicznym
1Department of Oral Pathology, The Children´s Memorial Health Institute of Warsaw
Head: Dorota Olczak-Kowalczyk, PhD, MD.
2Pediatric Dentistry Department, Medical University of Warsaw
Head: Aleksander Remiszewski, PhD, MD.
3Department of Oncology The Children´s Memorial Health Institute of Warsaw
Head: Danuta Perek, PhD, MD.
4Department of Clinical Microbiology and Immunology, The Children´s Memorial Health Institute of Warsaw
Head: Danuta Dzierżanowska PhD, MD.
5Immunology Outpatient Clinic, The Children´s Memorial Health Institute of Warsaw
Head: Ewa Bernatowska PhD, MD.
6Department of Medical Genetics, The Children´s Memorial Health Institute of Warsaw
Head: Małgorzata Krajewska-Walsek, PhD, MD
Nijmegen Breakage Syndrome (Nijmegen breakage syndrome; NBS) is a rare, multisystem disease inherited in an autosomal recessive manner. Chromosomal breaks and rearrangements are one cellular characteristics of NBS, however constitutional karyotypes of these patients are generally normal (1, 2). NBS is caused by biallelic mutations in the NBN (formerly called NBS1) gene located on the long arm of chromosome 8. It encodes protein called nibrin (NBN), which forms a multi-metric complex with two other proteins, hMre11 and hRad50 (3). Nibrin plays crucial role in recognizing and repairing DNA damage and its deficiency can lead to cell death or it´s uncontrolled divisions and malignant transformation. Chromosome breakage can be spontaneous. Exposure to X-ray lead to increase risk of DNA strand breaks.
NBS occurs worldwide with increased prevalence in Eastern and Central Europe, especially in Poland and Czech Republic (3, 4).
Patients with NBS present with very characteristic features like severe microcephaly, with receding forehead and retracted chin and low set ears. Skin abnormalities in the form of café au lait and vitiligo spots are also observed. Most patients are of short stature and underweight (5, 6). A mild to moderate mental retardation, impaired sexual maturation in girls and immunodeficiency are also frequently observed (7). Defective immunological status is characterized by dysgammaglobulinemia with or without decrease in IgG, IgA, IgE, and rarely IgM (8). Decrease in T lymphocytes expressed as CD3+ cells, low proportion of CD4+ (helper) T cells is also frequently observed (9).
Clinical features of these unique patients suggest that pathologic changes in the status of oral cavity can be present. Such features like frequently observed microgenia, growth retardation and weight deficiency can be associated with developmental impairments of structural elements of oral cavity. Immune defects contribute to development of pathologic changes in the oral cavity, caused by infections and autoimmune processes. NBS patients are predisposed to malignancies so one should be aware of pathologic changes, which may occur in these patients as a result of malignant disease or as an effect of anticancer treatment.
To our best knowledge there is no data in the literature on the status of oral cavity in these patients. Due to this and the fact that our center admits most of children diagnosed with NBS in Poland we began a prospective follow-up study of the oral cavity of these patients.
Aim of study
The aim of our study was assessment and characterize the type and frequency of pathologic conditions of the oral cavity in patients with NBS.
Material and methods
Eighteen patients with a diagnosis of NBS, aged from 1.7 to 20 years (mean 10.8±4.65) underwent dental examination. There were 5 patients with deciduous dentition, 6 – with mixed dentition and 8 – with permanent dentition. All patients are under medical care of Oral Cavity Pathology, Department of Immunology, Oncology, and Genetics of The Children´s Memorial Health Institute.
Study included analysis of patients´ characteristics, dental examination and mycological laboratory diagnostics.
The information about phenotype features was collected on the basis of data from hospital documentation.
Dental examination included analysis of face profile, status of oral cavity and other examinations. Assessment of oral cavity included the occlusion, hygiene status (OHI acc. to Greena i Vermilliona), teeth status with evaluation of dental caries (dental status with assessment of caries intensity with dmfs/DMFs), status of marginal gingiva (Gingival Index acc. to Loë and Silnesa) and mucosa including pathologic changes.
Dental hygiene status assessment with use of Oral Hygiene Index (OHI-S) acc Green and Vermillion. Dental plaque examined on buccal/labial and palate/lingual surfaces of six teeth; 55(16), 53(13), 51(11), 75(36), 73(13),71(31) after coloration with eozyne. In case of tooth lack, examined neighbor tooth. The average value of OHI-S index as basis dental hygiene status defined as:
good- value 0-1.0
sufficient – value>1.0-2.0
poor – value>2.0-3.0.
The dental examination included presence of caries foci, fillings, development abnormalities of mineralized tissues of teeth (discolorations, opacities and hypoplasia of enamel) and loss of teeth. Intensity of caries was occur (dmft/DMFt). DMFt index apply to permanent teeth, and dmft – milk teeth. Value of index consist of sum dt/Dt- teeth with caries, mt/Mt- missing teeth, ft/Ft- filling teeth. Occur the caries tread index – quotient of average number of filling teeth and sum of average number of filling teeth and teeth with caries: ft+Ft: [(ft+Ft)+(dt+Dt).
The presence and degree of gingivitis define with use of Gingival Index (GI) acc Löe and Sillness (10). In examinations excluded teeth during eruption. Value of index was average of sum of values for individual tooth. Gingivitis occur as:
mild – GI value 0.1-1.0
moderate – GI value>1.0-2.0
severe – GI value>2.0
Material for mycological analysis was obtained from the mucosa of oral cavity (recess of oral vestibule, buccal mucosa and dorsum of the tongue) and placed directly in sterile tube. The material was then cultured on Sabouraud plate and incubated in temperature of 37°C. Type of Candida species were identified on the basis of biochemical features of the fungi using test ID 32°C (bioMerieux).
No x-ray examinations were performed due to inherited hypersensitivity to irradiation in NBS.
All 19 patients presented with microcephaly, 18 (95%) were immunodeficient, 17 (85%) were of short stature (below the 3rd percentile), and 15 had deficits in body weight (fig. 1a). Mental retardation, mild to moderate, was observed in 17 patients (apart from the three youngest patients – aged below 4 yr), and abnormalities in skin pigmentation noted in 8 patients (fig. 2). Six patients were diagnosed with malignancies: B-cell non Hodgkin lymphoma (3 patients), T-cell origin non Hodgkin lymphoma or acute lymphoblastic leukemia (3 patients) (tab. 1).
Fig. 1. Facial features in a 13.5 years-old male with NBS.
a) Front presenting microcephaly, low and narrow forehead, prominent phlitrum and large ears.
b) Lateral view presenting microcephaly and receding mandible.
Fig. 2. Irregular skin pigmentation menifested as hyperpigmented spots („cafe-au-lait”) of 13.5 years-old male NBS patient.
Table 1. Phenotype features in the examined group of patients with NBS.
|Clinical symptoms||No of patients|
|Microcephaly (OFC < 3rd centile)||19|
|Short stature (height Ł 3rd centile)||17|
|Malnutrition (weight Ł 3rd centile)||15|
|Mental retardation (mild to moderate)||17|
|Skin pigmentation ("cafe au lait" spots)||8|
|Lymphoblastic lymphoma or leukemia (B- or T-cell origin)||6 (3 + 3)|
Retracted chin was observed in 12/19 patients (tab. 1, fig. 1b). Six of them presented with features of posteroclusion (in 1 case – with protrusion of upper incisors and in 3 it was accompanied by defect of palate – (gothic palate), in 1 gothic palate and crowded teeth, in 1 – gothic palatinum and no primate spacing and in 1-protrusion of upper incisors, crowding of teeth and gothic palate. In two observed only gothic palate, in 1 with retracted chin there were no occlusal abnormalities in intraoral examination. Among the remaining 8 patients with retracted chin, 6 had crowded teeth. Eighteen patients presented features suggesting impaired development of the mandibula and maxilla.
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