Periodontal conditions in Williams Beuren Syndrome: a series of 8 cases.
Williams Beuren syndrome (WBS) bears the name of the authors who first described it 40 years ago [Williams et al., 1961; Beuren et al., 1962]. It is a rare syndrome, and its genetic origin was clearly demonstrated in 1993 by Ewart . These authors studied 5 sporadic cases and 4 familial ones and were able to show a microdeletion involving several genes, especially the elastin gene, of 114 kb, at q11.23 on one of the homologous chromosomes 7. In the years following this pivotal study, several authors described cases of a haploinsufficiency of the gene encoding for elastin within a microdeletion syndrome [Lowery et al., 1995; Hirota et al., 1996; Brondum-Nielsen, 1997].
Other clinical studies sought to define the phenotypic expression of WBS. In addition to the three major features described by Williams and Beuren, namely supravalvular aortic stenosis, mental retardation and facial dysmorphosis, other more or less specific abnormalities during early childhood were also reported: growth retardation with bone abnormalities, phonation and ocular troubles, and altered cognitive function [Bellugi et al., 1990; Oncag, 1995; Perez-Jurado et al., 1996, American Academy of Pediatrics, 2001; Smoot et al., 2005].
Several years ago a qualitative study of the dermal macromolecular organization was conducted in such patients. More specifically, elastic fibers were quantified using image analysis. Our study involved 8 clinically diagnosed patients who all showed major disarray of skin elastic networks with rarefaction and destruction of oxytalan and elaunin fibers with scarcity of mature elastic fibers [Dridi et al., 1999; Ghomrasseni, 2001]. For the first time in a qualitative and quantitative study, it was shown that a hemizygous for the elastin gene affects the elastic component of both major vascular vessels as well as the cutaneous elastic component. Therefore we suggested that a cutaneous morphometric analysis may be used as a reliable investigational method to evaluate alterations of elastic fibers, and could be a means of distinguishing between hereditary and acquired connective tissue diseases with involvement of elastic fibres.
Gogly et al.  have shown that the structure of the human skin elastic fibre network was identical to that of human gingiva. Several studies have also revealed that the gingival macromolecular component is affected by periodontal disease, with pronounced alterations of collagen and elastin [Ejeil et al., 2003]. However, to our knowledge, there have been no up-to-date studies evaluating either the periodontium in WBS patients or the gingiva, which contains a perfectly well structured elastic fibre network under physiological conditions. It seems reasonable to conclude that in WBS patients, the gingival elastic fibres show similar alterations to those described in their skin. Indeed, a genetic anomaly affecting single gene coding for elastin should have consequences in all tissues where this molecule is present. Therefore we wished to verify whether those patients were particularly susceptible to periodontal diseases, as they seem to have a significant incidence of cardiovascular disease [Garcia et al., 2001].
Material and Methods.
Patients. Eight (8) patients (5 to 12 years) with WBS were documented for this report. They were referred by the Necker Hospital for Sick Children (Paris, France) where they were being medically followed on a regular basis. As for their dental needs, they were all treated for more than two years at the Albert Chenevier Hospital Creteil, France. At their first visit they received a thorough dental examination that was repeated every 6 months. All patients had been diagnosed with WBS shortly after birth and fluorescent in situ hybridization (with a biotinylated Oncor WSCR probe) had proven the disease by showing the hemizygosity at the elastin locus at 7q 11-23. All patients had the same profile with characteristic dysmorphic faces, heart abnormalities (typically supravalvular aortic stenosis, SVAS) and mental retardation.
Traditional periodontal and dental examinations of all patients were completed at T0 and T+2 years. The first author (CJ) performed all the examinations, and collected and reviewed the clinical and radiographic data, while the last member (SMD) reviewed the collected data and verified that they met protocol criteria.
All patients received motivation and instructions in oral hygiene techniques. Dental and periodontal care that could cause bleeding was completed during antibiotic prophylaxis according to the protocol of the French medical authorities  (amount flash and single, amoxicillin 75 mg/kg 1 hour before the treatment; no allergy to amoxicillin was reported). Fluoridated mouthwash containing chlorhexidine was also prescribed for 3 weeks from the beginning of therapy. Patients were re-examined every 3 to 6 months for periodontal maintenance. The particularly anxious, very distressed, phobic or very backward patients were treated under conscious sedation (nitrous oxide, Kalinox[R]).
Dental examination. This recorded the physiological stages of the patients' teeth, the patients' dental age, the forms of their arches and alveolar process, the relation of the arches and the status of each tooth (malposition, malformation, and anomaly of number). Their oral functions (breathing, swallowing) were also recorded. DMF or dmf index was scored in order to measure the patient's lifetime experience of dental caries.
Periodontal examination. The gingival phenotype according to the classification of Maynard and Wilson.  was used. This classification allowed the clinicians to observe the different gingival tissues in terms of morphology, height and width, and to group them by types:
* Type I: thick bone with palpation, thick and wide gingiva (3 to 5 mm),
* Type II: thick bone, fine gingiva and medium wide (< 2mm),
* Type III: thin bone with palpation, the dental roots can be palpated, thick and extended gingival,
* Type IV: thin bone, fine gingiva and medium wide.
The plaque control record of O'Leary et al. (or plaque index, PI)  was used. The examination was carried out on the interproximal, vestibular and lingual sites of teeth. The index was expressed as a percentage by dividing the number of dental areas with plaque by the total number of examined sites or areas:
* Score -: absence of plaque in the marginal gingival area,
* Score +: presence of plaque detectable by the probe or visible after staining.
The gingival condition was scored using the index of Loe and Silness (GI) . The severity of gingival inflammation was evaluated at the vestibular, interproximal and lingual sites of teeth. Only the average measurement was taken into account:
* 0 = normal gingival,
* 1 = mild inflammation, slight colour change, slight oedema, no bleeding on probing,
* 2 = moderate inflammation, redness, oedema, glazing, bleeding on probing,
* 3 = severe inflammation, obvious redness and hypertrophy, ulceration, tendency to spontaneous bleeding.
The bone quality was evaluated on an orthopantomogram.
Of the 8 patients assessed, 1 was in full primary dentition, 4 were in the initial stage of mixed dentition, 2 were in mixed dentition and 1 was in early adult dentition. All patients presented parafunction (infantile swallowing persistent and/or tongue thrust), as well as anomalies of dental number and malocclusions. Half of them showed eruption delays of approximately 1 to 2 years and anomalies of dental structures (tables 1 and 2). DMF indices varied from 0 (for the majority of the patients) to 4 (for the first 6 year old patient).
Concerning the periodontal status, average gingival height and width were greater than normal. The phenotype was classified as type I (Maynard and Wilson); the gingival tissue obviously covered the vestibular and lingual faces of the posterior teeth. Plaque index (PI) was always very high from 52% to 99%, except for one child (patient 3) who presented a PI (37.5%), which was quite acceptable. It should be specified that the parents of patient 3 were very attentive and brushed their child's teeth 3 times a day. Gingival inflammation was observed in all cases, it was generalized but the severity was not related to the quantity of clinically visible bacterial deposits (table 3). The gingival index (GI) varied from 1 to 2 maximum. No attachment loss was recorded. No bone loss was visible on the radiographs.
These clinical and radiographic data allowed us to diagnose gingivitis or periodontitis in all patients. The therapeutic regimen stabilized the periodontal condition of all children. At the two-year follow-up, no periodontal tissue loss was observed. Gingivitis did not worsen in periodontitis. However, plaque index, despite a notable improvement, remained high. During that time, carious lesions appeared in patients 3 and 4.
Periodontal diseases are part of the clinical picture of some acquired or hereditary connective tissue diseases. Ehlers-Danlos type VIII and IV syndromes are perfect examples of such manifestations [Perez et al., 2002]. These diseases, which are transmitted according to an autosomal dominant mode, are differentiated from other clinical types in this large group of syndromes by an increased susceptibility to periodontitis [Hartsfield and Kousseff, 1990; Page and Beck, 1997; Nualart-Grollmus et al., 2007].
For type VIII or "periodontal" syndrome, symptoms are characterized by an aggressive, generalized, and resistant periodontitis affecting both the primary and permanent dentition. This can cause early-onset tooth loss [McKusik, 1975; Nelson and King, 1981; Biesecker et al., 1991, Perez-Jurado et al., 1996;]. Patients with type IV or "vascular" syndrome often suffer from generalized, aggressive periodontitis, although it is of a more moderate intensity [Hartsfield and Koussef, 1990]. Moreover, histologic studies reveal dermal matrix disorders for type IV, with a significant decrease in collagen type III in the extracellular matrix essentially, and an abundance of elastic fibres that appear to be large, irregular and fragmented [Holbrook and Byers, 1989; Berteretche et al., 1995]. Compared with the latter disease, whose genetic origin is linked to type III collagen and is reflected in the elastic component, our WBS patients did not seem to be susceptible to periodontitis in spite of the presence of abundant calculus and bacterial biofilms both on teeth and gingiva. The gingiva was slightly or moderately inflamed in all our patients, and the gingival index did not correlate with the plaque index.
In the general population, the prevalence of periodontal disease is low in healthy children, but not in disabled children, who have a higher rate of gingivitis and periodontitis [Vigild M, 1985]. Moreover, for most of these patients, most authors find a positive relationship between the severity of gingival inflammation and the quantity of clinically visible (high PI and high GI) bacterial and calcific deposits. All 8 WBS children described here present backwardness mentally and gingivitis, but this relationship was not found (high PI and low GI). Inefficient self-cleaning lingual movements, dental malpositions and the patients' delayed mental development, all of which make it difficult or impossible to use toothbrushes, can explain the extent of the bacterial deposits. The greater the degree of retardation, the higher the plaque index, except for patient 3 whose dental hygiene was strictly controlled.
The lack of relationship between the degree of gingival inflammation and the plaque index can be explained by the type I phenotype (thick bone with palpation, thick and wide gingiva), which we observed in all of the patients. Benoit and Genon  found this phenotype in only 40% of patients in good health. Compared with a fine gingival phenotype (types III and IV), type I resists bacterial aggression better and is more compatible with favourable periodontal healing.
Our previous studies provide some explanations. In 1999, we observed in 10 skin biopsies from WBS patients a very significant decrease in volume fractions occupied by preelastic and mature elastic fibres as compared with patients with healthy skin. We also saw in WBS skin that elastic fibres were especially thin, fragmented and dispersed [Dridi et al., 1999] These results are in concordance with the in vitro findings of Urban et al.  which revealed a significant decrease in elastin production by smooth muscle cells (SMC) and dermal fibroblasts of patients with WBS.
Dridi et al.  reported major disorganization of the arterial elastic network after microscopic analysis of fragments of aortas collected during surgical intervention in SWB patients. Evidence of obstructive thickening was observed. The aorta wall was also thickened in the media, and elastic lamellae appeared highly fragmented and thinner than normal elastic lamellae. The relative surface of elastic lamellae decreased consistently in WBS patients. Moreover, SMC had lost their original position, were numerous and appeared as multiple clusters surrounded by thin and dispersed elastic components in the stenotic region. This had already been reported by various authors [Perou, 1961; O'Connor et al., 1985; Urban et al., 2002], who have also demonstrated that the expression of some metalloproteinases (MMP2, MMP9 and MMP7) was significantly increased compared with the aorta controls, whereas no inflammatory cells were to be observed in the tissue samples. It was also noted altered MMP9/TIMP1 balance in favour of matrix degradation that could facilitate SMC migration and neointimal hyperplasia. Therefore, we may assume that an adaptive process intended to standardize the parietal constraint probably existed at the arterial level. As proposed by Urban et al.  "inadequate deposition of insoluble elastin may be pathophysiologically connected to SMC hyperplasia during development of vascular thickening in WBS".
These previous notions appear logical. In fact in the extracellular matrix, the different components interact with one another, and any change in one component can lead to disorganized extracellular matrix [Christiano and Uitto, 1994] and consequently can disturb the interactions between matrix and cells. On the other hand, our results agree with the findings of several studies indicating that, in certain acquired and hereditary conditions, the amount of elastin in the skin and the loss of integrity of elastin fibres reflect similar changes in major vessels [Bouissou et al., 1976; Biesecker et al., 1991; Gogly et al., 1998].
We can reasonably extend this analysis to the gingival tissue as it has a macromolecular structure similar to that of cutaneous tissue. As a consequence, if the alteration of the gingival elastic fibres in our WBS patients is identical to that described in the dermis, the gingival fibroblasts could compensate for the decreased elastic component by secreting more collagen in order to respond to daily constraints. It could be an adaptive process. This hypothesis can explain gingival hyperplasia. Unfortunately, we could not obtain a gingival biopsy for histological analysis (according to French law, a biopsy can only be carried out for diagnostic and therapeutic purposes).
Our study population was too small to allow definitive conclusions to be drawn, and we are aware that all our hypotheses require verification. We are currently working on this. In addition, other clinical observations are necessary in order to confirm or reject the finding that WBS patients, irrespective of age, are not really susceptible to periodontitis. This syndrome is unfortunately progressive and periodontal condition could change with time. Regular monitoring is thus essential for SWB patients.
Because there is no evidence to the contrary, we suggest that the hemizygous elastin gene does not result in periodontal disease, whereas genetic disorders affecting fibrillar collagens do. We also suggest the existence of a possible correlation between the elastin gene haploinsufficiency and the periodontal type I phenotype.
This report was conducted after institutional review board approval of both the protocol and the informed consent.
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C. Joseph, M. M. Landru, F. Bdeoui, B. Gogly, S. M. Dridi. Dept. Dentistry, Albert Chenevier-Henri Mondor Hospital, Paris 5 Rene Descartes University, France.
Postal address: Dr. C Joseph, 11 rue de Capri, Paris, France, 75012.
[TABLE 1 OMITTED]
Table 2. Results of dental examination of patients with Williams Beuren Syndrome at first consultation. Occlusion Number anomaly * Patient Parafunction & malposition (agenesis) 1 * Persistent * None The behaviour of infantile the child made it swallowing impossible to take any radiographs * Persistent 2 tongue thrust * Cross-bite left * 35 3 * Anterior over- * 15, 25, 35, 45 bite (4mm) * Total crossbite 4 * Cross-bite left * 25 * Underhung jaw 5 * Anterior * 35, 45 open-bite 6 * Class III, * 12 bis & 52 bis multiple dental (surpernumerary malpositions, teeth) specially in anterior * Anterior open-bite 7 * Mandibular * 15, 25 protrusion * Multiple dental malposition 8 * DMD ** * 55, 65, 42 * Posterior crossbite Patient Dental DmF hypoplasia index 1 None 0 2 54, 64, 74, 84 4 3 None 0 4 31 0 5 36, 46 0 6 None 0 7 0 8 3 * using International Classification of the Dentition; ** DMD: Dento-Maxillary Disharmony Table 3. Results of periodontal examination of subjects with Williams Beuren Syndrome at first consultation. Patients Gingival Phenotype Plaque Gingival index index 1 I 66% 1 2 I (+ slight maxillary tori) 52% 1 3 I (+ maxillary tori) 37.5% 1 4 I 70% 1 5 I (+ slight mandibulary tori) 61% 1 6 I 88% 1 7 I 62% 1 8 I 99% 2 Patients Attachment Cicatrization Pathology loss 1 none normal slight 2 gingivitis 3 4 5 6 7 moderate 8 gingivitis
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|Author:||Joseph, C.; Landru, M.M.; Bdeoui, F.; Gogly, B.; Dridi, S.M.|
|Publication:||European Archives of Paediatric Dentistry|
|Date:||Sep 1, 2008|
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