Why Is Periodontal Disease More Prevalent and More Severe in People with Down Syndrome?

James Morgan, BA, BDentSc Co. Kildare, Ireland Spec Care Dentist 27(5):197-202, 2007

Reprinted with the permission of Ronald L. Ettinger, BDS, MDS, DDSc, Editor Special Care Dentistry Association

Abstract

Introduction

Down syndrome (DS) is an autosomal chromosomal disorder resulting from trisomy of all or part of chromosome 21.¹ Approximately 95% of people with DS have an extra complete chromosome 21. The remaining 5% result from other chromosomal abnormalities including translocation in 3% of people and mosaicism in 2% of people.^2,3 The incidence of DS is generally cited as being between 1 in 600 to 1 in 1,000 live births.² In Ireland, this condition affects approximately 1 in 580 live births, which is the highest incidence in Europe.⁴

Periodontal disease is defined as "an inflammatory disease of the supporting tissues of the teeth caused by specific microorganisms, resulting in progressive destruction of the periodontal ligament and alveolar bone with pocket formation, recession, or both."⁵

The pathogenesis of periodontal disease is complex. In response to microbial substances released from plaque bacteria in the gingival sulcus, epithelial and connective tissue cells are stimulated to produce inflammatory mediators, leading to infiltration of the connective tissue by numerous defense cells. In the early stages of the immune response, neutrophils predominate. As further microbial substances enter the systemic circulation, committed lymphocytes return to the site of infection, and antibodies specific to bacterial antigens are produced by plasma cells. This essentially protective response is enough to control the infection in people who are not susceptible to periodontitis.⁶

In susceptible individuals, however, the primary host defenses are unable to control the microbial challenge, leading to the epithelium becoming increasingly permeable and ulcerated. There is increased migration of neutrophils into the tissues, which secrete a variety of inflammatory mediators and proteolytic enzymes. Once the concentration of these inflammatory mediators and enzymes becomes pathologically high, histological destruction of the collagen fibers, periodontal ligament, and alveolar bone occurs.⁶ Preshaw et al.⁶ noted that the majority of periodontal destruction is the result of "collateral damage arising from the activation of the host defenses against the presence of bacteria".

In 2005, the World Health Organization provided an overview of periodontal disease worldwide and reported that 10% to 15% of adults suffered from periodontal disease.⁷ Brown et al.⁸ reported that the prevalence of periodontal disease among the general population in the United States ranged from 29% for persons aged 19 to 45 years, to 50% for persons aged 45 years and older. An increased prevalence and severity of periodontal disease has been reported in people with DS compared with age-matched subjects of similar levels of intellectual impairment and compared with the general population.^9-15 Prevalence varies between 58% and 96% for those under 35 years of age.^11,14

The increased prevalence and severity of periodontal disease in persons with Down syndrome may be attributed to a range of local factors associated with the oral cavity, as well as systemic factors associated with the genetic disorder itself.

Prevalence and severity of periodontal disease

Johnson and Young14 examined 70 children with DS (mean age 10.8 ± 3.0 years) and compared them with 40 age-matched subjects who did not have DS but had similar learning disabilities. The presence of periodontal disease was observed in 96% of persons in the group with DS and it was much more severe than in the control group. Bone loss followed a horizontal pattern and was most obvious in the lower anterior segment. Agholme et al.,¹² Cichon et al.,16 and Saxén et al.¹⁷ also observed this pattern of bone loss.

Saxén et al.¹⁷ used orthopantomograms to provide a more objective method for evaluating periodontal disease. Bone loss was measured from the cemento-enamel junction to the alveolar bone margin. A tooth with bone loss of 5mm or more was regarded as affected. It was reported that 69% of subjects with DS aged 9 to 39 years had more than 5mm bone loss compared with 20% of the control group, despite similar levels of plaque and calculus. In a follow-up study carried out five years later, the prevalence of bone loss of 5mm or more had increased to 75% in the subjects with DS.¹⁸

In a longitudinal study carried out by Agholme et al.,¹² periapical and bitewing radiographs were used to aid in the diagnosis of periodontal disease. It was reported that 35% of subjects with DS (mean age 16.6 years) had experienced alveolar bone loss. Seven years later the prevalence of alveolar bone loss had increased to 74%.

Cutress19 reported that persons with DS who were living in institutions had poorer levels of plaque control, increased calculus deposits, and an increased prevalence of periodontal disease when compared to subjects living at home with DS. Swallow²⁰ came to the same conclusions.

Etiology of periodontal disease in Down syndrome

Local factors

• Oral hygiene
  Cohen et al.21 studied a group of 100 subjects with DS and found that oral hygiene was generally poor. This was in agreement with Sakellari et al.¹⁰ who reported that people with DS had poorer oral hygiene than healthy individuals. In another study, Sakellari et al.²² found that the mean plaque score was 100% in a group of subjects with DS who were between the ages of 26 and 37 years. Sakellari22 also found that following oral hygiene instruction, subjects with DS had reduced ability to maintain adequate plaque control. This could possibly be associated with impairment of fine motor function resulting in poor manual dexterity, as reported by Desai.²
  Cohen et al.²¹ reported that calculus deposits were abundant among children with Down syndrome. This was in agreement with a similar study by Johnson and Young.¹⁴ However, a less severe distribution of calculus was reported by Barr-Agholme et al.²³ (20%) and by Sasaki et al.²⁴ (14.8%), respectively.
• Open-mouth breathing
  Persons with Down syndrome exhibit characteristic phenotypical orofacial anomalies including an underdeveloped facial mid-third resulting in a hypoplastic maxilla and mandibular prognathism.¹ The hypoplastic maxilla, combined with an enlarged tonsillar volume, causes upper airway congestion and a tendency for increased mouth-breathing.^1,2 Swallow²⁰ reported that 82.9% of children with DS had their lips habitually apart.
• Tooth morphology
  Several authors have discovered irregularities in the morphology of crowns and roots in persons with DS.
  Desai et al.² reported that clinical crowns were usually shorter and smaller than normal in subjects with DS, and that root length was reduced. Bajic et al.²⁵ reported a significant reduction in root length as well as an increased prevalence of fused molar roots in persons with DS. The prevalence of fused molar roots in the maxilla was 65.1%, and in the mandible it was 40.5%, compared with 40.5% and 21.1%, respectively, in the general population. Cutress¹⁹ also suggested that tooth morphology, including short roots, could influence periodontal disease in persons with Down syndrome.
• Microbiological plaque composition
  Studies^{10,11,22,26-28} detailing the microbiological composition of plaque from subjects with DS vary in reporting different types of organisms involved in the periopathogenic process. Sakellari et al.¹⁰ reported that subjects with DS in all age groups had significantly higher levels of periodontopathic bacteria. In particular, a significantly higher prevalence of P. gingivalis, A. actinomycetemcomitans (A.a.), T. forsythesis, and P. intermedia was observed. These findings suggest that colonization by significant periodontal pathogens occurs frequently in subjects with DS, even in adolescence. Amano et al.²⁶ observed that even in early childhood (age 2 to 4 years) significantly higher levels of P. gingivalis, B. forsythis, and T. denticola were detected in subjects with DS. These are considered to be important pathogens in severe types of adult periodontitis.²⁶ In particular, the occurrence of P. gingivalis was found to increase with age. No significant differences, however, were found in relation to A.a. between subjects with DS and healthy age-matched controls. Morinushi et al.²⁷ measured the serum antibody titer of subjects with DS to various periodontopathic bacteria and found that even in subjects with DS under the age of 6 years, the average antibody titer to A.a., F. nucleatum, and P. intermedia exceeded that of the normal adult reference pool. It was also found that these titers increased significantly with age. These findings suggest that A.a., F. nucleatum, and P. intermedia are probably present in significant numbers in subjects with DS, even in those under the age of 6 years. Hanookai et al.²⁸ investigated the prevalence of herpes virus species in periodontally involved subgingival sites in subjects with DS. It was found that 32% of patients had Epstein-Barr virus-1, 26% human cytomegalovirus, and 16% herpes simplex virus. Herpes virus species may cause periodontal pathology by suppressing the activity of B- and T- lymphocytes as well as up-regulating certain pro-inflammatory mediators such as IL-1 and TNF-alpha.²⁸
• Acute necrotizing ulcerative gingivitis (ANUG)
  Cohen et al.²⁹ reported that of 100 subjects with DS examined, 29% had experienced ANUG. In a later study, Brown et al.³⁰ compared 149 subjects with DS with 657 normal subjects and found that at least 35.6% of patients with DS had experienced at least one episode of ANUG compared with 4.1% of the control group. Of the affected subjects with DS, 49.1% had experienced recurrent episodes. The mean age at the time of the first recorded episode was 9.4 ± 4.4 years, even though ANUG typically affects young adults.³¹ Dissimilarities in the diagnostic criteria for ANUG have led to confusion in the literature as to its prevalence among the general population. These values range from less than 1% to 6.9%.32

Systemic factors

• Neutrophil dysfunction
  "Neutrophils are the primary cells involved in the first line of host defense against bacterial infection."³³ "Neutrophils have multiple surface receptors that enable them to bind to and phagocytize bacteria once they reach the site of infection."³⁴ In the different stages of periodontal disease, accumulation of neutrophils in the connective tissue, junctional epithelium, and gingival sulcus are characteristic morphological findings.³⁵
  Izumi et al.³³ reported that neutrophil chemotaxis was significantly impaired in subjects with DS when compared with healthy controls. The authors found that 50% of subjects with DS had defective neutrophil chemotaxis. They also found that the prevalence of bone loss in subjects with DS was inversely proportional to the neutrophil chemotactic index of the patient. These findings are in agreement with Yavuzyilmaz et al.,³⁵ who found a reduction in neutrophil chemotaxis, in neutrophil phagocytosis, and in the mean random migration of neutrophils. The relatively short half-life of neutrophils in people with DS (3.7 hours compared with 6.6 hours in healthy individuals) may account for their neutrophil dysfunction.³⁵
• T-lymphocyte dysfunction
  Cichon et al.¹⁶ reported that peripheral T-lymphocytes in subjects with DS have a diminished ability to recognize and respond to specific antigens. This study demonstrated a quantitative and qualitative deficiency of T-lymphocytes. Clee-Sohoel et al.³⁶ observed that the number of T-cell receptor-bearing lymphocytes in marginal periodontitis in subjects with DS was less than in otherwise healthy individuals. Shaw and Saxby³⁷ stated that the percentage of circulating T-cells is low from birth and suggested that T-cell maturation may be an integral part of Down syndrome. Whittingham et al.³⁸ demonstrated an atypical immunodeficiency of the T-lymphocyte system. The authors reported that the T-cell pattern included hypo-responsiveness to antigenic stimulus, a low mitotic activity, and an increase in immature T-lymphocytes. Björkstén et al.³⁹ reported a link between depressed neutrophil chemotaxis and depressed lymphocyte responsiveness in patients with DS who had low serum zinc levels. Following a two-month course of treatment with zinc phosphate, an increase in serum zinc levels as well as enhanced neutrophil and T-lymphocyte function was observed. Zinc is involved in numerous metabolic pathways and is essential for synthesizing RNA and DNA.⁴⁰
• Inflammatory mediators and proteolytic enzymes
  Komatsu et al.⁴¹ found that tissue destruction related to progressive periodontitis was due to actions of both the host and bacterial-derived proteolytic enzymes. Barr-Agholme et al.⁴² reported that the mean level of Prostaglandin E₂ (PGE₂) in the gingival crevicular fluid (GCF) of subjects with DS was significantly higher than in the healthy controls. This finding was in agreement with a similar study carried out by Tsilingaridis et al.⁴³ PGE₂ was present in inflamed periodontal tissue and was a potent mediator of bone resorption.⁴⁴ Barr-Agholme et al.⁴² also proposed that the enhanced levels of PGE₂ found in the GCF of patients with Down syndrome might be related to the altered composition of the subgingival microflora. This suggestion was based on the fact that lipopolysaccharide from A.a. has been reported to stimulate the production of PGE₂ in monocytes.⁴²
  Komatsu et al.⁴¹ reported that the production of matrix metalloproteinases was significantly higher in subjects with DS than in the control group. These findings were in agreement with Tsilingaridis et al.⁴³ "Matrix metalloproteinases comprise a family of proteolytic enzymes that collectively degrade the extra-cellular matrix in chronic inflammatory diseases such as periodontitis."⁴⁴
• Hyper-innervation of the gingiva Barr-Agholme et al.⁴⁵ observed that the gingivae of subjects with DS display profound inflammatory reactions alongside hyper-innervation of what was assumed to be the sensory part of the innervation of the gingiva. This "hyper-innervation" may not be particular to Down syndrome but may be a reaction brought on by inflammation. Alternatively, chemical transmitters released from these nerves may be responsible for the inflammatory reaction observed.⁴⁵ This phenomenon may explain results obtained from two studies on experimental gingivitis, which showed that despite identical plaque accumulation, the gingivae of subjects with DS had more extensive inflammation when compared to age-matched healthy individuals.^46,47 However, functional defects of neutrophils and lymphocytes have also been proposed as possible explanations for the difference in gingival response to plaque.⁴⁷

Barriers to dental services

Kaye et al.⁴⁸ reported that while most adults with DS regularly attended their dentist, little treatment was actually provided. Allison et al.⁴⁹ observed that parents of children with Down syndrome frequently encounter problems with access to oral care for their children. Children with DS were significantly less likely to receive dental treatment than their non-DS siblings. Although some authors^16,18 have reported that preventive programs have little effect on the progression of periodontal disease in patients with Down syndrome, more recent studies^9,24 have shown the effectiveness of frequent preventive care. Yoshihara et al.⁹ demonstrated the usefulness of periodic preventive care in suppressing the severity and progression of periodontal disease in subjects with DS. In their study, patients were divided into two groups: those who had received frequent preventive care, and those who had not been treated professionally in more than a year. Significant reductions were noted in mean pocket depth (2.5mm and 3.1mm, respectively), mean frequency of periodontal pockets (46% and 91% respectively), and frequency of the prevalence of pathological alveolar bone loss (62% and 100% respectively), when the "managed group" was compared to the "interrupted group." Sasaki et al.²⁴ showed the efficacy of monthly preventive care, which consisted of mechanical plaque control and oral hygiene instruction over a period of two and a half years. Significant reduction in gingival inflammation and probing pocket depths were noted at that time (mean pocket depth at baseline was 2.9mm and after 2.5 years was 1.3mm). The use of chlorhexidine mouthwash to compensate for ineffective plaque removal has also been advocated.⁵⁰

Discussion

People with Down syndrome experience more prevalent and severe periodontal disease.^9-15 It has been reported16,37 that the progression of the disease in persons with DS was similar to aggressive periodontal disease. A multi-factorial etiology accounting for this prevalence and severity has been proposed. People with DS have poorer levels of oral hygiene,^2,10,21,22 and increased calculus.^{14,17,21,23,24} However, most authors agree that the amount of plaque and calculus present was not commensurate with the severity of periodontal disease observed.^{16,17,19,21,47,51}

Open-mouth breathing reduces the cleansing action of the saliva and encourages the accumulation of plaque; it also dehydrates the gingival tissues, which may impair the individual's resistance to infection.⁵² Shorter root lengths and an increased prevalence of fused roots may also influence periodontal disease.^2,19,25 It has been suggested that the fused molar roots favor the progression of periodontal disease because occlusal forces have a greater effect on these than on teeth with divergent roots.²⁵

Subgingival plaque in people with DS harbors increased amounts of suspected periodontal pathogens.^10,26-28 Gram-negative bacteria contain lipopolysaccharide in their cell wall. Among other effects, lipopolysaccharide has the potential to activate the complement system, produce inflammation, and stimulate bone resorption.⁵³ Herpes virus can also influence periodontal disease. Hanookai et al.²⁸ suggested that periodontal herpes virus and bacterial co-infections might favor destructive periodontal disease. However, few studies have been carried out on this subject.

ANUG is more prevalent in Down syndrome.^29,30 ANUG can result in the formation of characteristic gingival craters, which encourages plaque stagnation, and can favor the progression of any underlying periodontal disease.³¹

Neutrophils and T-lymphocyte function is impaired in people with DS.^16,33,35,36 Neutrophils play an intimate role in the periodontal disease process because they have the ability to detect and migrate toward infection and phagocytose microorganisms.³⁴ Van Dyke et al.⁵⁴ suggested that because of this close involvement in periodontal disease, a decrease in neutrophil function might result in more severe periodontal breakdown. They also suggested that in diseases where neutrophil function was impaired (for example, neutropenia, Papillon-Lefèvre syndrome, and Down syndrome), an increase in periodontal disease was usually seen.⁵⁴ The immune system can be further compromised by the T-cell dysfunction in Down syndrome. Whittingham et al.³⁸ proposed that the T-cell dysfunction "might be explained by failing immuno-competence due to accelerated ageing". He further proposed that it might even be caused "by a heavy load of infections early in life because of an incapacity to maintain adequate standards of personal hygiene".

Preshaw et al.⁶ highlighted the important role played by both inflammatory mediators and proteolytic enzymes in the pathogenesis of periodontal disease. Both PGE₂ and matrix metalloproteinases have been shown to be present in significantly higher levels in people with DS.^41-43 PGE₂ is a vasodilator, which is "involved in the increased vascular permeability occurring at sites of inflammation, and a mediator of bone demineralization".⁴⁴ Matrix metalloproteinases can degrade type I-V collagens, laminin, gelatin, fibronectin, and elastin.⁴⁴

Institutionalization has been shown^19,20 to be associated with an increased prevalence and severity of periodontal disease. Swallow20 proposed that this may be a reflection of the quality of oral hygiene practiced, whereby aid given to non-institutionalized children by their parents may slow the disease's process. Cutress¹⁹ suggested that fecal-oral transmission of contagious microorganisms in institutionalized patients may account for the increased prevalence of periodontal disease.

Recent studies^9,22,24 have reported the effectiveness of frequent preventive care in slowing the progression and reducing the severity of periodontal disease. Therefore, any barriers that hinder the access of people with DS to dental services could have detrimental effects on their oral health. Fiske and Shafik³ recommended the development and instigation of a realistic preventive program that would include regular scaling and root planing, and advice regarding anti-microbial agents. The results obtained by Yoshihara et al.⁹ suggest that to combat the severity and progression of periodontal disease in persons with DS, a more frequent treatment interval than the six months suggested by Hennequin et al.¹ should be employed. In their study, the mean interval between dental visits in the managed group was 3.7 (± 1.3 months). Sakellari et al.²¹ also recommended a three-month treatment interval. It has been suggested that an oral hygiene regime that includes chlorhexidine — as a mouthwash, a gel, or as a professionally applied varnish — may be beneficial in reducing oral plaque, and may help compensate for inadequate tooth-brushing.⁵⁰

Conclusions

The increased prevalence and severity of periodontal disease in persons with Down syndrome is due partly to an inability to adequately maintain oral hygiene. Other contributing factors include an earlier and more extensive colonization with known periodontal pathogens along with other local factors such as open-mouth breathing, tooth morphology, altered microbial plaque composition, and acute necrotizing ulcerative gingivitis. Increasing evidence, however, supports the theory that an impaired immunity due to a reduction in neutrophil chemotaxis, neutrophil phagocytosis, and T-lymphocyte function, as well as an increased production of inflammatory mediators and proteolytic enzymes, may contribute most to the prevalence and severity of periodontal disease in persons with Down syndrome.

Down syndrome is the most commonly diagnosed intellectual disability in Ireland.⁴ In recent years, trends toward de-institutionalizing people with Down syndrome and placing them in community settings have emerged.¹⁵ Therefore, it is increasingly likely that most dental practitioners will encounter a patient with Down syndrome. Every effort must be made to encourage the implementation of frequent preventive care in order to decrease the severity and progression of periodontal disease in their patients.

Acknowledgements

References

1. Hennequin M, Faulks D, Veyrune JL, Bourdiol P. Significance of oral health in persons with Down syndrome: a literature review. Dev Med Child Neurol 1999; 41:275 83.
2. Desai S. Down syndrome: A review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 84:279-85.
3. Fiske J, Shafik H. Down's syndrome and Oral Care. Dent Update 2001; 28:148-56.
4. Bradley C, McAlister T. The oral health of children with Down syndrome in Ireland. Spec Care Dentist 2004; 24:55-60.
5. Newman MG, Takei H, Carranza FA. Carranza's Clinical Periodontology. 9th ed. Philadelphia: Saunders; 1996: 67.
6. Preshaw PM, Seymour RA, Heasman PA. Current concepts in periodontal pathogenesis. Dent Update 2004; 31:570-8.
7. Peterson PE, Ogawa H. Strengthening the prevention of periodontal disease: the WHO approach. J Periodontol 2005; 76:2187-93.
8. Brown LJ, Oliver RC, Loe H. Periodontal Diseases in the U.S. in 1981: Prevalence, severity, extent, and role in tooth mortality. J Periodontol 1989; 60:363-80.
9. Yoshihara T, Morinushi T, Kinjyo S, Yamasaki Y. Effect of periodic preventative care on the progression of periodontal disease in young adults with Down's syndrome. J Clin Periodontol 2005; 32:556-60.
10. Sakellari D, Arapostathis KN, Konstantinidis A. Periodontal conditions and subgingival microflora in Down syndrome patients. A case control study. J Clin Periodontol 2005; 32:684-90.
11. Amano A, Kishima T, Akiyama S, Nakagawa I, Hamada S, Morisaki I. Relationship of periodontopathic bacteria with early-onset periodontitis in Down's syndrome. J Periodontol 2001; 72:368-73.
12. Agholme MB, Dahllof G, Modeer T. Changes of periodontal status in patients with Down syndrome during a 7-year period. Eur J Oral Sci 1999; 107:82-8.
13. Orner G. Periodontal disease among children with Down's syndrome and their siblings. J Dent Res 1976; 55:778-82.
14. Johnson NP, Young MA. Periodontal disease in mongols. J Periodontol 1963; 34:41-7.
15. Barnett M, Press K, Friedman D, Sonnenberg E. The prevalence of periodontitis and dental caries in a Down's syndrome population. J Periodontol 1986; 57:288-93.
16. Cichon P, Crawford L, Grimm WD. Early-onset periodontitis associated with Down's syndrome—clinical interventional study. Ann Periodontol 1998; 3:370-80.
17. Saxén L, Aula S, Westermarak T. Periodontal disease associated with Down's syndrome: an orthopantomographic evaluation. J Periodontol 1977; 48:337-41.
18. Saxén L, Aula S. Periodontal bone loss in patients with Down's syndrome: a follow-up study. J Periodontol 1982; 53:158-62.
19. Cutress TW. Periodontal disease and oral hygiene in trisomy 21. Arch Oral Biol 1971; 16:1345-55.
20. Swallow JN. Dental disease in children with Down's syndrome. J Ment Defic Res 1964; 53 Suppl:102-18.
21. Cohen M, Winer RA, Shklar G. Periodontal disease in a group of mentally subnormal children. J Dent Res 1960; 39:745.
22. Sakellari D, Belibasakis G, Chadjipadelis T, Arapostathis K, Konstantinidis A. Supragingival and subgingival microbiota of adult patients with Down's syndrome. Changes after periodontal treatment. Oral Microbiol Immunol 2001; 16:376-82.
23. Barr-Agholme M, Dahllof G, Modéer T, Engström P, Engström G. Periodontal conditions and salivary immunoglobulins in individuals with Down syndrome. J Periontol 1998; 69:1119-23.
24. Sasaki Y, Sumi Y, Miyazaki Y, Hamachi T, Nakata M. Periodontal management of an adolescent with Down's syndrome-a case report. Int J Paediatr Dent 2004; 14:127-35.
25. Bagic I, Verzak Z, Cukovic-Cavka S, Brkic H, Susic M. Periodontal conditions in individuals with Down's syndrome. Coll Antropol 2003; 27 Suppl 2:75-82.
26. Amano A, Kishima T, Kimura S, et al. Periodontopathic bacteria in children with Down syndrome. J Periodontol 2000; 71:249 55.
27. Morinushi T, Lopatin D, Van Poperin N. The relationship between gingivitis and the serum antibodies to the microbiota associated with periodontal disease in children with Down's syndrome. J Periodontol 1997; 68:626-31.
28. Hanookai D, Nowzari H, Contreras A, Morrison J, Slots J. Herpesvirus and periodontopathic bacteria in Trisomy 21 periodontitis. J Periodontol 2000; 71:376-84.
29. Cohen M, Winer RA, Schwartz S, Shklar G. Oral aspects of mongolism. Part 1. Periodontal disease in mongolism. Oral Surg Oral Med Oral Pathol 1961; 14:92-107.
30. Brown RH. Necrotizing ulcerative gingivitis in mongoloid and non-mongoloid retarded individuals. J Periodontal Res 1973; 8:290-5.
31. Eley BM, Manson JD. Periodontics. 5th ed. Chapter 25. Acute necrotizing ulcerative gingivitis. Wright; 2004: 354-7.
32. Falkler WA, Martin SA, Vincent JW, Tall BD, Nauman RK, Suzuki JB. A clinical, demographic and microbiologic study of ANUG patients in an urban dental school. J Clin Periodontol 1987; 14:307-14.
33. Izumi Y, Sugiyama S, Shinozuka O, Yamazaki T, Ohyama T, Ishikawa I. Defective neutrophil chemotaxis in Down's syndrome patients and its relationship to periodontal destruction. J Periodontol 1989; 60:238-42.
34. Deas DE, Mackey SA, McDonnell HT. Systemic disease and periodontitis: manifestations of neutrophil dysfunction. Periodontol 2000 2003; 32:82-104.
35. Yavuzyilmaz E, Ersoy F, Sanal O, Tezcan I, Ercal D. Neutrophil chemotaxis and periodontal status in Down's syndrome patients. J Nihon Univ Sch Dent 1993; 35:91-5.
36. Sohoel DC, Jonsson R, Johannessen AC, Nilsen R. Gamma/delta T lymphocytes in marginal periodontitis in patients with Down's syndrome. Adv Exp Med Biol 1995; 371B:1135-6.
37. Shaw L, Saxby MS. Periodontal destruction in Down's syndrome and in juvenile periodontitis. How close a similarity? J Periodontol 1986; 57:709-15.
38. Whittingham S, Pitt DB, Sharma DL, Mackay IR. Stress deficiency of the T-lymphocyte system exemplified by Down syndrome. Lancet 1977; 1:163-6.
39. Björkstén B, Bäck O, Gustavson KH, Hallmans G, Hägglöf B, Tärnvik A. Zinc and immune function in Down's syndrome. Acta Paediatr Scand 1980; 69:183-7.
40. Kumar P, Clark M. Clinical Medicine. 6th ed. Edinburgh: Elsevier Ltd; 2005:249.
41. Komatsu T, Kubota E, Sakai N. Enhancement of matrix metalloproteinase (MMP)-2 activity in gingival tissue and cultured fibroblasts from Down's syndrome patients. Oral Dis 2001; 7:47-55.
42. Barr-Agholme M, Krekmanova L, Yucel- Lindberg T, Shinoda K, Modeer T. Prostaglandin E2 level in gingival crevicular fluid from patients with Down syndrome. Acta Odontol Scand 1997; 55:101-5.
43. Tsilingardis G, Yucel-Lindberg T, Modéer T. Enhanced levels of prostaglandin E₂, leukotriene B₄, and matrix metalloproteinase-9 in gingival crevicular fluid from patients with Down Syndrome. Acta Odontol Scand 2003; 61:154-8.
44. Page RC. The role of inflammatory mediators in the pathogenesis of periodontal disease. J Periodont Res 1991; 26:230-42.
45. Barr-Agholme M, Modéer T, Luthman J. Immunohistological study of neuronal markers in inflamed gingiva obtained from children with Down's syndrome. Periodontol 1991; 18:624-33.
46. Reuland-Bosma W, Liem RS, Jansen HW, van Dijk LJ, van der Weele LT. Morphological aspects of the gingiva in children with Down's syndrome during experimental gingivitis. J Clin Periodontol 1988; 15:293-302.
47. Reuland-Bosma W, van Dijk LJ, van der Weele L. Experimental gingivitis around deciduous teeth in children with Down's syndrome. J Clin Periodontol 1986; 13:294-300.
48. Kaye PL, Fiske J, Bower EJ, Newton JT, Fenlon M. Views and experiences of parents and siblings of adults with Down syndrome regarding oral healthcare: A qualitative and quantitative study. Br Dent J 2005; 198:571-8.
49. Allison PJ, Hennequin M, Faulks D. Dental care access among individuals with Down syndrome in France. Spec Care Dentist 2000; 20:28-34.
50. Nunn J. Disability and Oral Care. London: FDI World Dental Press; 2000:33.
51. Reuland-Bosma W, van Dijk LJ. Periodontal disease in Down's syndrome: A review. J Clin Periodontol 1986; 13:64-73.
52. Eley BM, Manson JD. Periodontics. 5th ed. Edinburgh: Elsevier Ltd; 2004: 43.
53. Eley BM, Manson JD. Periodontics. 5th ed. Edinburgh: Elsevier Ltd; 2004: 66.
54. Van Dyke TE, Levine MJ, Genco RJ. Neutrophil function and oral disease. J Oral Pathol 1985; 14:95-120.