© 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
Introduction
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.
Results
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 symptomsNo 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)
ImmunodeficienceHumoral deficiencies17
Cellular deficiencies17
Total18
IVIG supplementation19
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.
In total number of patient (n=19): crowded teeth were observed in 5 patients, lack of primate spacing in 1 patients, gothic palate in 8 pts. In 3 cases lack in the number of teeth were observed which might reflect hypodontia or arrest of hypodontia or stop of tooth eruption process. One child lacked teeth 22 and 14, and 2 children lacked single tooth 14 and one 21 another (fig. 3). Accessory tooth and reversed position of teeth 21 and 22 were observed in 1 patient.
Fig. 3. Gingivitis and lack of single tooth 21 of 13.5 years-old male NBS patient
In most patients lack of oral cavity hygiene was observed. In 3 patients it was assessed as unsatisfactory in 8 sufficient. 17 patients presented with gingivitis in 3 it was severe and in 4 moderate (tab. 2, fig. 4 a).
Table 2. Hygiene status of the oral cavity, gingivitis and dental caries in patients with NBS.
Number of patients examined19
OHImean1.5
median1.6
number of patientsOHI 0-1.08
OHI>1.0-2.08
OHI>2.0-3.03
GImean0.9
median0.8
number of patientsGI 0-0.12
GI>0.1-1.011
GI>1.0-2.04
GI>2.03
dmftmean/median7.6/6
dtmean/median7.18/4
mtmean/median0.24/0
ftmean/median0.18/0
DMFtmean/median8.3/9
Dtmean/median6.86/6
Mtmean/median0.32/0
Ftmean/median1.12/1
Dental caries treatment indexmean/median0.1/0
Fig. 4. Infectious changes in oral cavity of 4 years-old male NBS patient.
a) Gingivitis and accumulation of dental plaque.
b) Atrophic candidiasis.
Dental caries were detected in 18 out of 19 patients. It was present with high intensity in milk as well as in adult teeth.: dmft- mean 7.6; median 6, DMFt – mean 8.3; median 9, dmft+DMFt – mean 10.4; median 10. Dominate component of indexes were the number of teeth with caries. Low value of caries treatment indexes were disturbing (mean 1; median 0) (tab. 2).
Impaired enamel development characterized by opacities and hypoplasia was observed in 7 patients (opacity – 4, hypoplasia-2, opacity and hypoplasia). In one child it was noted in milk teeth and in the rest of the patients in the permanent teeth.
Mycologic investigations revealed the presence of candida colonies in 8 patients – Candida albicans in 6 and Candida dubliniensis in 2 patients. In 3 patients the density of Candida spp. colonies were> 102 to 103 CFU/ml, in 3>10 to 102 CFU/ml and in 2 patients – up to 10 CFU/ml.
Symptomatic Candida infection was diagnosed in 6 patients (fig. 4 b). Oral cavity candidosis, white coated tongue and RAS minor were the most frequently observed pathologic conditions.
Pathological changes in oral cavity presented in 10 patients. In 6 patient were observed to have more than one pathological conditions in the oral mucosa. Besides yeast like fungi infection these were: coated tongue (n=4), RAS minor (n=3), geographic tongue (n=2), herpes labialis (n=1), leukoplakia (n=1).
Discussion
Literature search revealed that as of today there is no available data on the status of oral cavity in patients with NBS.
Results of our study revealed that patients with NBS present with various pathologic conditions, which amongst others include the oral cavity.
We found that there is an impaired development of the mandibula and maxilla in patients with NBS. Posterocclusion (Angle class II), gothic palate and crowded teeth were most frequently observed. All these conditions were evaluated clinically, no radiological studies were performed, due to hyprsensitivity to ionizing radiation associated with NBS, thus it is difficult to make a final and definite diagnosis. Any patients made orthodontic treatment because in patients with mental retardation, orthodontics therapy may do some complications from the use of an orthodontic appliance. Preventive orthodontic service should be apply, yet.
Impaired development of the enamel in the form of opacity and hypoplasia (7 out of 19 patients) and dental caries of severe intensity were frequently observed. At the same time only in 8 patients presented with satisfactory hygiene status of the oral cavity. Poor oral hygiene in NBS patients very often is a result of mental retardation. It is well known, that dental plaque is important etiologic factor of developing periodontal disease and dental caries. In addition, high frequency of dental caries (18 of 19 patients examined) may be associated with underlying immune defects in these patients. Decrease in the secretion of immunoglobulins may include IgA causing that it´s concentration in the saliva is lower or absent. This problem warrants further analysis and is the subject of our further studies.
In group of examined patients noted high intensity of caries and low levels of caries treatment indexes. Treatment and hygienic negligence are correlated with mild and moderate mental handicap, which was observed in 17 out 19 patients. This is very essential problem, because in patients with NBS, for reason of accompanying immunity defect, the prophylaxis and early treatment of caries are very important. The complications of caries are often cause arise dental infection foci and pathological changes in periapical tissues of teeth, and in patients with immunodeficiency, infection foci prevention in oral cavity is necessary. In these patients is no exist possibility of X-ray examinations, because ionizing radiation, X- or γ-rays, enhances chromosomal instability in cells (11). In NBS patients, very important is effective prevention and treatment of dental caries andperiodontal disease. The methods of prevention must include education (instruction of oral hygiene and nutrition) and motivation of children, their parents and medical care staff and regular dental visit (application of fluoride, professional scaling).
Immunodeficiences in NBS patients are probably predisposing factors in the incidence of infectious changes in the oral cavity, too. In examined group of patients different kind of infections were observed. Candidiasis and gingivitis were most frequently found. Nowadays it is a well-known fact, that primary immunodeficiences (neutrophil abnormalities, B-cell and T-cell deficiences) are predisposing factors in the incidence of bacterial, fungal and viral infections (12-16). Immunodeficiencies in NBS patients are usually a combination of T- and B cell defects. Authors of this work began investigations of type of immunodeficiency in NBS patients group and correlations with infection changes in oral mucosa and gingival.
Dentists should be aware of oral manifestations and of important role of dental care in NBS patients. Infectious changes in oral cavity in NBS patients may be a source of bacteriemia or fungemia and can so become the cause of grave systemic disorders. Immundeficincy is supporting fast generalizing oneself of infection. This problem should be studied especially when we consider that most of these patients will finally succumb to cancer requiring intensive chemotherapy (17). Then all pathologic changes as gingivitis, dental caries, candidiasis will complicate treatment and aggravate to the treatment related complications. Pathological changes in oral cavity may be the first clinical symptoms of virus infections or neoplasia, too. Besides all that, infectious changes of oral mucosa can be the reason of pain and malnutrition.
Conclusion
Our results suggest that there is a predisposition to pathological conditions in the oral cavity of NBS patients. Therefore, often oral examination and treatment should be an integral part of the multi-disciplinary treatment of NBS patients.
Piśmiennictwo
1. Weemaes CMR et al.: A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Peadiatr Scand 1981; 70(6 Suppl): 557-64. 2. Chrzanowska KH et al.: Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: The Nijmegen breakage syndrome. Am J Med Genet 1995; 57(3): 462-71. 3. Varon R et al.: Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 1998; 93(3): 467-76. 4. Varon R et al.: Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet 2000; 8(11): 900-2. 5. Chrzanowska KH: Microcephaly with chromosomal instability and immunodeficiency - Nijmegen syndrome. Pediatr Pol 1996; 71(3): 223 [In Polish]. 6. Van der Burgt I et al.: Nijmegen breakage syndrome. J Med Genet 1996; 33(2): 153. 7. Chrzanowska KH et al.: Atypical clinical picture of the Nijmegen breakage syndrome associated with development abnormalities of the brain. J Med Genet 2001; 38(1): E3. 8. Gregorek H et al.: Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clin Exp Immunol 2002; 130(2): 319- 24. 9. Michalkiewicz J et al.: Abnormalities in the T and NK lymphocyte phenotype in patients with Nijmegen breakage syndrome. Clin Exp Immunol 2003; 134 (3): 482-490. 10. Löe H: The Gingival Index, the Plaque Index. J. Periodontal 1967; 38: 610-16. 11. Digweed M, Sperling K: Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair 2004; 3: 1207-17. 12. Atkinson JC et al.: Oral manifestations of primary immunological diseases. J Am Dent Assoc 2000; 131(3): 345-56. 13. Boxer L A: Neutrophil abnormalities. Pediatr Rev 2003; 24(2): 52-62. 14. Olczak-Kowalczyk D, Przybylska J, Żukowski P: Pathological changes of the oral cavity in children with congenital neutropenia. Przegl Stom Wieku Rozw 2001; 3/4(35-36): 55-9 [In Polish]. 15. Olczak-Kowalczyk D et al.: Prevalence of oral lesions in children with chronic granulomatous disease. Dent Med Probl 2007; 44(3): 323-30. 16. Sollectio TP et al.: Systemic conditions associated with periodontitis in childhood and adolescence. Med Oral Patol Oral Cir Bucal 2005; 10: 142-50. 17. Duker ND: Chromosome breakage syndromes and cancer. Am J Med Genet 2002; 115(3): 125-29.
otrzymano: 2009-02-20
zaakceptowano do druku: 2009-03-16

Adres do korespondencji:
*Dorota Olczak-Kowalczyk
Zakład Patologii Jamy Ustnej IP CZD
Al. Dzieci Polskich 20, 04-730 Warszawa
tel.: 0(22) 815 13 15, 815 16 32
e-mail: d.olczak-kowalczyk@czd.pl

Nowa Stomatologia 1-2/2009
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