SM1 3periodontology 2000,65th vol

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    Aggressive forms of periodontitissecondary to systemic disorders

    AH M E D KH O C H T & JA S I M M. AL B A N D A R

    A compromised host immune response is an impor-

    tant risk factor in the pathogenesis of severe forms of

    periodontitis (90). Certain systemic disorders may

    compromise the host immune system and these

    disorders are often associated with destructive peri-

    odontal disease (29). Neutrophils are important im-

    mune defense cells that play a significant role in

    controlling the spread of microbial plaque infections

    in the dentogingival region. Neutrophils are the first

    immune cells to arrive at affected gingival sites. They

    exit the blood vessels in the gingival connective tis-

    sues, cross the junctional epithelium, move into the

    gingival sulcus pocket and form a live defense bar-

    rier between the microbial infection and the peri-

    odontal tissues. Individuals with altered neutrophil

    function or counts are unable to mount a successful

    neutrophil defense barrier against microbial plaque

    infections in the dentogingival region and are moresusceptible to periodontal disease. Many systemic

    diseases can alter neutrophil function and or

    counts. Individuals affected with these diseases tend

    to develop acute and aggressive forms of periodon-

    titis that often lead to early tooth loss (29).

    Approximately three decades ago prepubertal

    periodontitis was defined as a unique clinical entity

    with an onset during or immediately after eruption of

    the primary teeth, leading to early exfoliation of some

    or all of the primary teeth (67). Destructive peri-

    odontitis resulting in the early loss of teeth in pre-

    pubertal children is very rare. However, for the af-fected children, the loss of teeth at an early age could

    be devastating and may significantly influence their

    quality of life (109).

    According to the 1999 American Academy of Peri-

    odontologys classification of periodontal diseases,

    aggressive forms of periodontal diseases secondary to

    a systemic condition are termed periodontitis as a

    manifestation of systemic disease (12). More recent

    studies suggest that prepubertal children with severe

    periodontitis are often diagnosed with certain sys-

    temic disorders, usually involving a compromised

    host response to bacterial infections. However, a

    systemic disorder is not invariably ascertained, either

    because it is incipient or for other reasons. Hence, at

    present the classification of prepubertal periodontitis

    is not recommended, and the classification of peri-

    odontitis as a manifestation of systemic disease is

    used instead. This article will review relevant major

    systemic diseases with a focus on disorders that are

    associated with defects in the mineralization of bone

    and dental tissues and with alterations in either

    neutrophil counts (quantitative disorders) or neu-

    trophil function (qualitative disorders).


    Hypophosphatasia is a genetic disorder characterized

    by defective mineralization of bone and teeth and a

    deficiency of tissue-nonspecific alkaline phosphatase

    activity. Tissue-nonspecific alkaline phosphatase is

    involved in collagen and calcium binding and also

    hydrolyzes inorganic pyrophosphate, which is a po-

    tent natural inhibitor of hydroxyapatite crystal

    growth (93). Therefore, a deficiency in tissue-non-

    specific alkaline phosphatase leads to the accumu-

    lation of extracellular pyrophosphate, and this causes

    inhibition of skeletal and dental mineralization (35,

    70, 108).The clinical expression of hypophosphatasia is

    highly variable and ranges widely in severity. In the

    severe form the bone does not mineralize, resulting

    in stillbirth. Early loss of teeth is common to most

    forms of hypophosphatasia. Clinical signs of the

    childhood form include early exfoliation of the pri-

    mary teeth, skeletal deformities, short stature, wad-

    dling gait, bone pain and fractures. The adult form is

    usually recognized in middle age and presents as foot


    Periodontology 2000, Vol. 65, 2014, 134148

    Printed in Singapore. All rights reserved

    2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


  • 8/12/2019 SM1 3periodontology 2000,65th vol


  • 8/12/2019 SM1 3periodontology 2000,65th vol


    and stem cells, and also stimulates the bone marrow

    to release these cells into the bloodstream. In addi-

    tion, granulocyte colony-stimulating factor also

    stimulates the survival, proliferation, differentiation

    and function of neutrophil precursors and mature

    neutrophils (52). As a result, children born with de-

    fects in granulocyte colony-stimulating factor recep-

    tor cannot make neutrophils and are therefore sus-

    ceptible to infections, including periodontal diseases.There are only a few studies describing the oral and

    periodontal status of subjects affected with infantile

    genetic agranulocytosis, and some of the reported

    findings include a generalized gingival inflammation

    characterized by red spongy gingiva, increased

    probing depth, gingival bleeding on probing and se-

    vere alveolar bone loss (11, 23, 30). A case report

    implicates herpes viruses in the pathogenesis of the

    periodontal defects associated with the condition

    (112). It has been suggested that a therapeutic regi-

    men consisting of scaling and root planing, soft-tis-

    sue curettage and the use of selected antimicrobial

    agents could be successful in the resolution of peri-

    odontal infection in subjects inflicted with this syn-

    drome (77).

    Glycogen storage diseases

    Glycogen is an energy storage molecule. Glycogen

    storage diseases are rare metabolic disorders involving

    glycogen synthesis or storage,and these diseasescause

    the body to either not be able to make enough glucose,

    or not be able to use glucose as a form of energy (42).

    There are 11 known types of glycogen storagediseases. Type 1 glycogen storage disease accounts for

    about 25% of all cases diagnosed in the USA and

    Europe and has an estimated incidence of about

    1 100,000 live births. The two most frequent symp-

    toms of the disease include enlarged liver and hypo-

    glycemia. There are two different subtypes of type 1

    glycogen storage disease: type 1a and type 1b. Gly-

    cogen storage disease type 1b is an autosomal-reces-

    sive disease caused by a deficiency of microsomal

    glucose-6-phosphate translocase. Glucose-6-phosphate

    translocase transports glucose-6-phosphate from the

    cytoplasm to the lumen of the endoplasmic reticulumwhere the enzyme glucose-6-phophatase converts

    glucose-6-phosphate into glucose. The gene that

    codes for glucose-6-phosphate translocase is called

    SLC37A4 and is located on chromosome 11q23.3. In

    glycogen storage disease type 1b the SLC37A4 gene is

    mutated and this results in a deficiency in glucose-6-

    phosphate translocase.

    Patients with glycogen storage disease type 1b have

    neutropenia accompanied by progressive defects of

    neutrophil functions, such as chemotaxis and respi-

    ratory burst. Overexpression of proapoptotic proteins

    may accelerate the apoptosis of neutrophils in

    patients with glycogen storage disease type 1b. The

    underlying cause of neutrophil dysfunction in gly-

    cogen storage disease type 1b is endoplasmic retic-

    ulum stress generated by disruption of endogenous

    glucose production. It has also been suggested

    that glucose-6-phosphate translocase deficiency mayresult in a redox shift toward oxidizing conditions in

    the endoplasmic reticulum lumen of neutrophils in

    glycogen storage disease type 1b. Patients with gly-

    cogen storage disease type 1b are susceptible to a

    variety of infections, including periodontal infections.

    Patients showing aggressive forms of periodontal

    breakdown have been reported in the dental litera-

    ture (18, 71).

    Cohen syndrome

    Cohen syndrome is a rare genetic disorder with an

    autosomal-recessive mode of transmission. The dis-

    ease is characterized by intellectual disability, devel-

    opmental delay and a unique physical appearance

    including narrow hands and feet with long, slender

    fingers (34). Most affected individuals have truncal

    obesity (deposition of fat around the midsection of

    the body) and prominent upper central incisors. The

    etiology of this disease is mutations in the VPS13B

    gene (frequently called the COH1gene). The VPS13B

    gene is located on the long (q) arm of chromosome 8

    at position 22.2. The exact function of the protein

    expressed by this gene is not known, but it is believedto be involved in protein sorting and transportation

    inside the cell. Almost all affected individuals have

    abnormally low counts of white blood cells (granul-

    ocytopenia), and the neutrophil is the cell type par-

    ticularly affected (neutropenia). Because of the low

    white-blood-cell counts, affected individuals are

    susceptible to infections, including periodontitis (5).

    Qualitative neutrophil disorders

    Leukocyte adhesion deficiency syndrome

    Leukocyte adhesion deficiency syndrome is a rare

    immunodeficiency disorder inherited in an autoso-

    mal-recessive trait and characterized by defects in

    adhesion receptors of the white blood cells (33).

    There are three main types of leukocyte adhesion

    deficiency syndrome. Type I involves a deficiency in

    membrane integrins, type II involves a defect in the

    expression of ligands for selectins, and type III

    encompasses other variants of leukocyte adhesion


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    deficiency syndrome and may include platelet

    aggregation abnormalities. Type I is the most com-

    mon form of the disease, whereas types II and III are

    extremely rare.

    Integrins are integral cell-surface proteins com-

    posed of an alpha chain and a beta chain. Integrins

    are involved in cell adhesion as well as in cell-sur-

    face-mediated signaling. In humans, the integrin

    beta-2 gene (ITGB2), on the long arm of chromosome21, encodes integrin beta-2 protein (CD18). Integrin

    beta-2 combines with various alpha-chain partners to

    form various integrins. CD18 paired with CD11a

    forms lymphocyte function-associated antigen-1;

    CD18 paired with CD11b forms macrophage antigen-

    1; and CD18 paired with CD11c forms the p150,95

    protein. Lymphocyte function-associated antigen-1 is

    expressed on the surface of lymphocytes and is in-

    volved in lymphocyte trafficking, antigen presenta-

    tion and cytotoxic T-cell activity. Macrophage

    antigen-1 and p150,95 are expressed on leukocytes

    and are involved in the adhesion of leukocytes to

    endothelial cells (88).

    A mutation in the ITGB2 gene results in a non-

    functioning leukocyte cell-adhesion molecule. The

    affected neutrophils have migration and phagocytic

    abnormalities. Thus, they cannot mount a successful

    defense response against microbial infections.

    Affected individuals are susceptible to infection,

    including periodontal infections.

    Patients with leukocyte adhesion deficiency syn-

    drome often show severe gingival inflammation and

    rapidly progressive periodontal destruction aroundthe primary and permanent teeth, usually resulting in

    the early loss of the affected teeth (26). Other oral

    manifestations may include acute gingival lesions,

    gingival enlargement, recession, tooth mobility and

    pathologic migration. The management of the

    aggressive periodontal disease associated with leu-

    kocyte adhesion deficiency syndrome is very chal-

    lenging and is often unsuccessful in arresting the

    progression of periodontal tissue loss (19).

    ChediakHigashi syndrome

    ChediakHigashi syndrome is a rare autosomal-recessive genetic disorder of granule morphology and

    function affecting multiple organ systems (105). It is

    clinically characterized by partial albinism, frequent

    infections and an accelerated lymphohistiocytic

    phase (14). The pathological hallmark of Chediak

    Higashi syndrome is the presence, in all white blood

    cells and in certain other cell types, of massive lyso-

    somal inclusions in the cytoplasm of the cells. The

    defect is secondary to a mutation of a lysosomal

    trafficking regulator protein (105). Clinical reports

    have identified mutations throughout the

    CHS1 LYST gene, and the nature of these mutations

    can be a predictor of the severity of the disease (45).

    These mutations result in the impaired function

    of multiple body cells and systems. Subjects with

    ChediakHigashi syndrome have immune-system

    abnormalities, recurrent infections, bleeding abnor-

    malities and muscle weakness. Progressive damage tothe peripheral nervous system, partial albinism and

    sensitivity to light are associated with the disease. In

    addition, subjects with ChediakHigashi syndrome

    tend to have slight cognitive deficits. The disease is

    lethal, and life expectancy is usually short, with the

    majority of patients dying in childhood. Fatality is

    associated with infections and lymphoproliferative

    disorders in multiple organs (43). Treatment with

    bone marrow transplantation may be helpful in cor-

    recting neutrophil dysfunction in some patients (1,


    ChediakHigashi syndrome is associated with sig-

    nificant periodontal symptoms, including profound

    gingival inflammation, deep probing depth general-

    ized to most of the dentition (Fig. 1) and severe

    alveolar bone loss (13, 46) (Fig. 2). The management

    of the periodontal component of the disease is very

    challenging, and both successful (13) and unsuc-

    cessful (31, 83) results have been reported in the lit-

    erature. The response to treatment may be related to

    the severity of the ChediakHigashi syndrome. Early

    reports did not specifically address recommended

    periodontal management and possible bleedingcomplications. In a recent study, Khocht et al. (46)

    described a severe case of ChediakHigashi

    Fig. 1. Clinical photograph of a 13-year-old African-

    American boy with ChediakHigashi syndrome. Patholog-

    ical tooth migration, heavy accumulations of deposits on

    teeth and severe gingival inflammation is shown (Adapted

    from Khocht et al. (46). Reproduced with permission from

    the International Academy of Periodontology).


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    syndrome and recommended the extraction of peri-

    odontally compromised teeth and the fabrication of

    dentures to avoid significant oral infections that may

    impact on the systemic health of these patients.

    PapillonLefe`vre syndrome

    PapillonLefevre syndrome is a rare genetic disorder

    characterized by hyperkeratosis of the palms, the

    soles of the feet, the elbows, the knees and other

    organs (Fig. 3), and, in addition, shows a rapidly

    progressive, severe periodontitis that leads to early

    loss of the primary and permanent teeth (6, 28)

    (Fig. 4). The disease is inherited as an autosomal-

    recessive trait. A loss-of-function mutation affecting

    the cathepsin-C gene (CTSC) on chromosome

    11q14.1-q14.3 has been associated with the disease.

    Cathepsin-C is expressed by epithelial cells and

    immune cells, such as leukocytes and macrophages.

    Cathepsin-C functions as a key enzyme in the acti-

    vation of granule serine proteases (e.g. elastase), the

    activation of granzymes and the regulation of epi-

    thelial morphogenesis. The prevalence of the syn-

    drome in the general population is 13 per million,

    with no sex or race preference. The skin symptoms

    vary greatly. In some affected individuals the hyper-

    keratotic skin lesions are dramatic, whereas in others

    they are hardly visible or almost missing.

    The periodontal manifestations include gingival

    inflammation, increased probing depth and ad-

    vanced radiographic alveolar bone loss (Fig. 5). Typ-

    ically, the affected individuals lose their teeth early inlife and eventually become edentulous with significant

    ridge resorption. Immunohistological examination of

    the gingival tissues shows a massive inflammatory

    infiltrate dominated by plasma cells (47). Lundgren

    et al. (57) reported impaired salivary secretions and

    somewhat altered salivary gland function in children

    and young adults affected with PapillonLefevre


    Several studies have investigated the pathogenesis

    of periodontitis in individuals affected with Papillon

    Lefevre syndrome. Impaired neutrophil functions,

    including chemotaxis, phagocytosis and bacterialkilling, were reported by some authors (53, 102). Se-

    verely depressed natural killer cell cytotoxicity has

    also been reported in affected individuals (54). There

    arealso reports of increased levels of interleukin-1beta

    Fig. 2. Panoramic radiograph of the patient with Chediak

    Higashi syndrome shown in Fig. 1; severe alveolar bone

    loss, affecting all permanent teeth, is apparent (Adapted

    from Khocht et al. (46). Reproduced with permission from

    the International Academy of Periodontology).

    Fig. 3. Hyperkeratosis lesions on the knees and dorsal

    surface of the palms of a 7-year-old white male child with

    PapillonLefevre syndrome (Adapted from Albandar et al.

    (6). Reproduced with permission from the American

    Academy of Periodontology).

    Fig. 4. Clinical photograph of the boy with Papillon

    Lefevre syndrome shown in Fig. 3. Note the premature

    loss of the deciduous teeth (Adapted from Albandar et al.

    (6). Reproduced with permission from the American

    Academy of Periodontology).

    Fig. 5. Panoramic radiograph of the boy with Papillon

    Lefevre syndrome shown in Fig. 3. Note the severe alveolar

    bone loss and the premature loss of the deciduous teeth

    (Adapted from Albandar et al. (6). Reproduced with per-

    mission from the American Academy of Periodontology).


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    and matrix metalloproteinase-8 in gingival crevicular

    fluid (98), and atypical activity of the plasminogen

    activating system with a disturbed epithelial function

    in the gingival tissues of affected individuals (99). It

    has been suggested that the periodontal destruction

    seen in individuals with PapillonLefevre syndrome

    might be attributed to a defect in the epithelial barrier

    defense system.

    The subgingival microbial profile of subjects withPapillonLefevre syndrome has been investigated.

    Studies using bacterial culture or DNA probes

    showed that the subgingival microbial profile in

    individuals with PapillonLefevre syndrome closely

    resembled a profile characteristic of deep pockets in

    patients with chronic periodontitis (47, 56, 75, 103).

    On the other hand, Albandar et al. (6) conducted a

    comprehensive analysis of the subgingival microbi-

    ota in subjects with PapillonLefevre syndrome using

    16S ribosomal RNA clonal analysis and the 16S

    ribosomal RNA-based Human Oral Microbe Identi-

    fication Microarray and concluded that the subgin-

    gival microbiota in these patients is diverse and

    comprises periodontal pathogens commonly associ-

    ated with chronic and aggressive periodontitis as

    well as opportunistic pathogens, the most prevalent

    of which included Gemella morbillorum, G. haemol-

    ysans, Granulicatella adiacens, Lachnospiracease,

    Parvimonas micra, Selenomonas noxia and Veillo-

    nella parvula. Velazco et al. (103) reported the pres-

    ence of cytomegalovirus and EpsteinBarr virus type

    1 in the subgingival sample of a patient with Papil-

    lonLefevre syndrome and hypothesized that viruses,in concert with subgingival periodontopathic bacte-

    ria, may contribute to the development of peri-

    odontitis in PapillonLefevre syndrome-affected


    The treatment of periodontitis and the control of

    periodontal tissue loss in PapillonLefevre syndrome

    are difficult, and most previous studies have consis-

    tently shown that the early loss of primary and per-

    manent teeth is inevitable. However, some recent

    reports suggest that it is possible to control peri-

    odontal disease in individuals with PapillonLefevre

    syndrome by combining antibiotic therapy withconventional periodontal therapy, including

    mechanical debridement and surgical pocket reduc-

    tion (3, 55, 66). A long-term follow-up case report

    showed a successful outcome following a multidis-

    ciplinary treatment approach consisting of extraction

    of periodontally involved teeth, rehabilitation of the

    edentulous region with temporary dentures, a guided

    bone-regenerative procedure to augment lost alveo-

    lar bone and construction of dental implants,

    together with a meticulous oral hygiene regimen by

    the patient (95). Also, full-mouth rehabilitation of the

    missing dentition in a patient with PapillonLefevre

    syndrome using fixed prostheses supported by

    osseointegrated dental implants has been reported (2).

    Down syndrome

    Down syndrome is more common than other genetic

    disorders, with an incidence of about 1 per 8001,000births (82, 84). The disease is characterized by the

    presence of an extra copy of chromosome 21. The

    most common manifestations of the syndrome in-

    clude a characteristic physical appearance and varied

    mental and physical disorders (59), including con-

    genital heart disease, thyroid dysfunction, Alzheimer

    disease and alteration of the immune system,

    including granulocyte monocyte cell dysfunction

    (21, 50, 59).

    Periodontal disease is a common manifestation

    among subjects with Down syndrome, with an esti-

    mated prevalence of 5896% in patients under

    35 years of age, and periodontitis is more severe in

    these subjects than in persons who do not have Down

    syndrome (60). The disease starts early in life, pro-

    gresses with age and eventually leads to tooth loss (37,

    100). Periodontal disease adversely impacts on the

    quality of life of subjects with Down syndrome (9).

    The factors contributing to the increased preva-

    lence and severity of periodontitis in individuals with

    Down syndrome have been studied extensively.

    Studies show that individuals with Down syndrome

    have difficulty maintaining adequate oral hygieneand thus tend to harbor high levels of supragingival

    dental plaque (25, 46, 78). In addition, following oral

    hygiene instructions, individuals with Down syn-

    drome continue to show reduced ability to achieve

    adequate plaque control (79) (Fig. 6). It has often

    been surmised that mental disability associated with

    Down syndrome is an important factor in the re-

    duced ability of patients to maintain adequate oral

    hygiene and leads to an increased susceptibility to

    periodontitis (32, 60). Khocht et al. (46) recently used

    a multivariate model that included assessment of

    mental disability and traditional risk factors of peri-odontitis, and showed that loss of periodontal

    attachment in individuals with Down syndrome was

    not associated with mental disability.

    It is well documented that Down syndrome is

    associated with immune deficiencies and host re-

    sponse impairment (50, 72, 73). Infections, and

    respiratory infections in particular, are an important

    cause of mortality in Down syndrome (20, 94). The

    most likely reason for this increased susceptibility to


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    infection and reduced immunity in individuals with

    Down syndrome is the increased dosage of protein

    products encoded by chromosome 21, which are

    likely to result from an increased amount of proteinproducts encoded by chromosome 21 (there are

    three copies of this chromosome in subjects with

    Down syndrome), which are likely to result from the

    increased transcription of one or more of the approxi-

    mately 310 genes present on this chromosome, and a

    complex genetic interplay caused by increased copies

    of many of these genes leading to the diverse Down

    syndrome phenotypes (51). Several proteins impor-

    tant in immune function are encoded by genes

    present on chromosome 21 (38), including superox-

    ide dismutase, nicotinamide adenine dinucleotide

    phosphate (NADPH)-dependent carbonyl reductase

    and integrin beta-2 (CD18). Increased production of

    superoxide dismutase and of NADPH are associated

    with increased oxidative stress and tissue injury (4,

    89). Aberrant expression of CD18 integrin on im-

    mune-cell surfaces in Down syndrome may be

    associated with altered lymphocyte function (50, 91,

    92). The interleukin-10 receptor beta subunit com-ponent of the interleukin-10 receptor (involved in the

    resolution of inflammation) is encoded by chromo-

    some 21, and its function may be altered in Down

    syndrome (40). In addition, it seems that interleukin-

    1 is up-regulated indirectly by some chromosome 21-

    based genes (64). Interleukin-1 is an important

    inflammatory mediator, and its increased production

    may be associated with brain tissue damage (64).

    Periodontitis is initiated by bacterial infection, and

    the impaired immune response to infections in

    individuals with Down syndrome may be the primary

    contributing factor to the increased susceptibility of

    these individuals to periodontal destruction. It is

    likely that the compromised host response makes it

    easier for virulent periodontopathic microbial species

    to colonize the subgingival sites, and consequently if

    these bacteria remain unchallenged an intense

    inflammatory reaction could be induced within the

    periodontal tissues. The increased periodontal

    inflammation would lead to elevated production of

    degrading enzymes and alter bone remodeling. The

    end result of these inflammatory-induced changes

    would be the loss and destruction of the periodon-tium, and eventually tooth loss (Fig. 7). Several

    studies have investigated the microbiological, host

    response and inflammatory aspects in Down syn-

    drome. These are discussed below.

    Microbiological findings

    Barr-Agholme et al. (15) reported increased fre-

    quency of detectingAggregatibacter actinomycetem-

    comitans, Capnocytophaga and Porphyromonas

    gingivalis in the subgingival plaque of adolescents

    Fig. 6. Clinical photograph of a 55-year-old African-

    American woman with Down syndrome showing multiple

    missing teeth, poor oral hygiene, heavy accumulations of

    dental plaque and calculus on the remaining teeth, and

    significant attachment loss, gingival inflammation and

    gingival recession.

    Fig. 7. Peri-apical radiographs of the woman with Down syndrome shown in Fig. 6. Note the dental calculus on the teeth

    and significant alveolar bone loss.


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    with Down syndrome.A. actinomycetemcomitanswas

    detected in 35% of subjects with Down syndrome

    compared with 5% of healthy, age- and sex-matched

    controls. The authors suggested that this increased

    frequency ofA. actinomycetemcomitansindicated an

    altered microbial composition in the subgingival

    plaque of subjects with Down syndrome compared

    with healthy controls.

    Amano et al. (8) detected various periodontal dis-ease-causing bacteria in very young subjects with

    Down syndrome and suggested that periodonto-

    pathic bacteria could colonize the teeth of these

    patients at a very early age. Periodontal pathogens in

    the subgingival plaque of subjects with Down syn-

    drome were detected with far greater frequency than

    in age-matched controls, and this may explain the

    intense gingival inflammation in these individuals.

    The authors concluded that certain periodontal

    pathogens, particularlyP. gingivalis, play a key role in

    the initiation of gingival inflammation.

    Sakellari et al. (78) assessed clinical periodontal

    parameters in 70 subjects with Down syndrome and

    in 121 age-matched healthy controls, collected sub-

    gingival plaque samples from the Ramfjord teeth and

    assessed the presence of 14 bacterial species using

    checkerboard DNADNA hybridization. The study

    reported that important periodontal pathogens col-

    onize subjects with Down syndrome earlier, and at

    higher levels, compared with age-matched healthy

    individuals. Reuland-Bosma et al. (74) compared

    the subgingival microflora in adult subjects with

    Down syndrome with that in other individuals withintellectual disabilities. Despite advanced periodontitis

    in subjects with Down syndrome, no differences in

    the prevalence of distinct suspected periodonto-

    pathic bacteria were established, and the authors

    conclude that host factors are the most likely expla-

    nation for the advanced periodontal disease associ-

    ated with subjects with Down syndrome.

    Amano et al. (7) sampled subgingival plaque from

    67 young adults with Down syndrome and 41

    age-matched systemically healthy individuals with

    mental disabilities. The prevalence of A. actinomy-

    cetemcomitans, P. gingivalis, Tannerella forsythia(previously known as Bacteroides forsythus), Trepo-

    nema denticola, Prevotella intermedia, P. nigrescens,

    Capnocytophaga ochracea,C. sputigena,Campylobacter

    rectus and Eikenella corrodens were investigated

    in subgingival plaque samples using the PCR.

    The authors found no significant differences in the

    bacterial profiles between the groups.

    The cited microbiological studies indicate early

    colonization of important periodontal pathogens in

    children and adolescents with Down syndrome.

    However, the microbial subgingival profile of adults

    with Down syndrome is not different from that of

    matched non-Down-syndrome individuals. Despite

    the lack of differences in microbial profiles, adults

    with Down syndrome still show greater loss of peri-

    odontal attachment than do adults who do not have

    Down syndrome (7, 74). This suggests that the host

    response to the same bacteria is different betweenindividuals with Down syndrome and those who do

    not have Down syndrome.

    Immune response

    Significant evidence exists suggesting that subjects

    with Down syndrome have an impaired immune

    response to infection (50). Studies investigated the

    hypotheses that the immune inflammatory re-

    sponse in Down syndrome is either defective or more

    intense, resulting in greater periodontal tissue

    damage. Various studies investigated different com-

    ponents of the immune system in relation to peri-

    odontitis in subjects with Down syndrome, with

    more focus on neutrophil function, the gingival im-

    mune cellular response and antibody production

    against periodontopathic bacteria.

    Neutrophil function. Studies uncovered a defective

    neutrophil chemotaxis in subjects with Down syn-

    drome, leading to a significantly lower chemotaxis

    compared with healthy controls (44). As neutrophils

    are the main cells involved in the first line of host

    defense against invasion with bacteria, defectiveneutrophil chemotaxis can lead to significant tissue

    loss and to the progression of periodontitis. Addi-

    tionally, it has been found that significant correla-

    tions exist between the amount of bone loss and the

    age and chemotactic index, suggesting that the rate of

    periodontal destruction in these subjects is depen-

    dent on the degree of the chemotaxis defect. A study

    assessed the clinical periodontal parameters, che-

    motaxis and random migration of neutrophils in 15

    subjects with Down syndrome and in 15 healthy

    subjects and found more severe gingival inflamma-

    tion, and a significantly decreased random migrationand chemotaxis of neutrophils, in the subjects

    with Down syndrome compared with the control

    group (111).

    A study of the effectiveness of surgical and non-

    surgical periodontal therapies, and the neutrophil

    chemotaxis status and functions in relation to treat-

    ment, were investigated in a group of 14 subjects

    with Down syndrome, 1430 years of age (113).

    Surgical and nonsurgical periodontal therapies were


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    compared in a split-mouth design, and clinical

    periodontal parameters were recorded at baseline,

    and 6 months, and 1 year post-treatment. Neutrophil

    chemotaxis, phagocytic activity and production of

    superoxide anion were compared between the 14

    subjects with Down syndrome and nine healthy

    controls, 2428 years of age. The results showed that

    both surgical and nonsurgical therapies contributed

    to a significant improvement in all clinical parame-ters compared with baseline values. Furthermore,

    neutrophil chemotaxis, phagocytic activity and pro-

    duction of superoxide anion decreased significantly

    following treatment in the subjects with Down syn-

    drome, suggesting that neutrophil impairment may

    not affect the clinical response to therapy (113).

    These studies suggest that deficient neutrophil

    chemotaxis is a common finding in subjects with

    Down syndrome and that this defect may be sec-

    ondary to increased oxidative stress associated with

    trisomy of chromosome 21 (4). The oxidative stress

    may impair internal cell functions and disrupt che-

    motaxis. It has been shown that reduced chemotaxis

    is positively correlated with the severity of peri-

    odontitis (44). Moreover, there is some evidence that,

    despite the reduced neutrophil chemotaxis, peri-

    odontal therapy aiming to reduce plaque and correct

    periodontal architecture may improve the periodon-

    tal health in subjects with Down syndrome (113).

    Gingival cellular immune response. Assessment of

    the composition of mononuclear cells in the gingival

    inflammatory infiltrate in chronic periodontitisshowed that, compared with non-Down syndrome

    controls, subjects with Down syndrome had a higher

    number of cellular infiltrate, increased numbers of

    CD22+ cells (B lymphocytes), CD3+ cells, CD4+ cells,

    CD8+ cells and CD11+ cells (macrophages), and a

    significantly higher CD4+CD8+ cell ratio (85). This

    indicates that subjects with Down syndrome may

    have a more pronounced and altered gingival cellular

    immune response when compared with controls, and

    this immune profile may be associated with the in-

    creased tissue destruction in Down syndrome.

    Variations in the expression of HLA class II anti-gens on antigen-presenting cells seem to play an

    important role in immune regulation. It has been

    shown that there is an increased frequency of HLA

    class II antigens in the gingival tissues of subjects

    with Down syndrome and chronic periodontitis

    compared with periodontitis patients who do not

    have Down syndrome, and there were also signifi-

    cantly higher numbers of CD1a+ cells, ratios of HLA-

    DR+ CD1a+ cells, and HLA-DP+CD1a+ cells (86).

    The authors concluded that there is a highly activated

    immune response in subjects with Down syndrome.

    Further analysis to characterize the distribution of

    T-cell-receptor gamma delta-expressing lympho-

    cytes in gingival tissues of individuals with Down

    syndrome showed that the percentage of these cells is

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    studies that the humoral immune response against

    periodontopathic bacteria is not impaired in individu-

    als with Down syndrome.

    Barr-Agholme et al. (16) investigated the clinical

    periodontal conditions and salivary immunoglobulins

    in Down syndrome and found an altered distribution

    of IgG subclasses in saliva, with an increased amount

    of IgG1 compared with controls. This is in agreement

    with other studies showing increased salivary IgG1 insubjects with Down syndrome (50). In contrast, the

    proportion of salivary IgG2, IgG3 and IgG4 subclasses

    is notincreased in Down syndrome.It is also noted that

    the level of secretory IgA is increased in subjects with

    Down syndrome who have alveolar bone loss com-

    pared with those without bone loss.

    Chaushu et al. (24) assessed age-related changes in

    the salivary-specific humoral immune response in a

    young group (mean age = 23 years) and an older

    group (mean age = 52 years) of individuals with

    Down syndrome and compared these with the same

    changes in two age-matched groups of healthy con-

    trols. The levels of total IgA and of specific antibodies

    to three common oral pathogens P. gingivalis,

    A. actinomycetemcomitansand Streptococcus mutans

    were analyzed. Compared with young controls, the

    median secretion rates of the specific antibodies of

    young individuals with Down syndrome were 70

    77% lower in whole saliva and 3460% lower in

    parotid saliva. In the older age group the secretion

    rates of subjects with Down syndrome were 77100%

    lower in whole saliva and 7588% lower in parotid

    saliva.Hence, these studies show inconsistent antibody

    responses in saliva and serum in individuals with

    Down syndrome. While the salivary antibody re-

    sponse was low, the serum antibody response to

    several periodontopathic bacteria was elevated. The

    low salivary antibody response to bacteria is associ-

    ated with decreased salivary flow in individuals with

    Down syndrome, and this may facilitate the coloni-

    zation of periodontal pathogens. The elevated serum

    antibody titers corroborate the increased gingival

    immune cellular activity described previously in

    subjects with Down syndrome. It demonstrates thatDown syndrome individuals, despite known immune

    deficiencies, are capable of mounting a specific hu-

    moral immune response. Such antibodies would find

    their way into the gingival tissues and gingival fluid

    and help to contain the microbial damage. Increased

    antibody levels in gingival tissues may also accentu-

    ate the gingival inflammatory response through

    complement activation and thus contribute to tissue


    Inflammatory response

    Inflammatory response studies focused on inflam-

    matory mediators and degrading enzymes in the

    gingival crevicular fluid of subjects with Down syn-

    drome. One study found that the mean level of

    prostaglandin E2 in gingival crevicular fluid was sig-

    nificantly higher in subjects with Down syndrome

    compared with controls (17), suggesting an alterationin arachidonic acid metabolism in subjects with

    Down syndrome. However, the mean level of inter-

    leukin-1beta in the gingival crevicular fluid was not

    significantly elevated in subjects with Down syn-

    drome, although gingival inflammation was more

    severe in the Down syndrome group than in the

    controls. It has been reported that prostaglandin E2down-regulates the production of interleukin-1beta

    (49), and this may explain the lack of difference in the

    level of interleukin-1beta between the groups. This

    issue has not been thoroughly studied and therefore

    further investigation is warranted.Another study assessed the levels of prostaglandin

    E2, leukotriene B4 and matrix metalloproteinase-9 in

    gingival crevicular fluid in 18 subjects with Down

    syndrome and in 14 controls, matched for age and

    degree of gingival inflammation (97). The results

    showed that the mean levels of prostaglandin E2,

    leukotriene B4 and matrix metalloproteinase-9 were

    statistically significantly higher in the gingival cre-

    vicular fluid from subjects with Down syndrome

    compared with that from controls. Furthermore, the

    correlation coefficients for leukotriene B4 to bleeding

    on probing, and to probing depth, respectively, as

    well as for matrix metalloproteinase-9 to bleeding on

    probing, differed significantly between the Down

    syndrome group and the control group. These results

    may indicate an altered host response in periodontal

    tissue in Down syndrome.

    Among studies investigating tissue-degrading en-

    zymes, Halinen et al. (41) characterized the peri-

    odontal status of nine children with Down syndrome,

    917 years of age, relative to their age-matched sys-

    temically and periodontally healthy controls. They

    assessed clinical periodontal parameters and thecollagenase and gelatinase activities in gingival cre-

    vicular fluid and saliva samples. Compared with

    controls, the endogenously active collagenase and

    total collagenase activities were slightly higher, and

    salivary collagenase was high, in children with Down

    syndrome but of the same matrix metalloproteinase-

    8 type as in the saliva of the controls.

    Komatsu et al. (48) examined the level and the

    enzyme activity of matrix metalloproteinase-2 in the


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    gingival tissues and reported a significantly higher

    production of matrix metalloproteinase-2 in cultured

    gingival fibroblasts of subjects with Down syndrome

    compared with controls. In addition, markedly dif-

    ferent levels of expression of membrane-type I matrix

    metalloproteinases and matrix metalloproteinase-2

    mRNAs were observed in cultured fibroblasts from

    subjects with Down syndrome compared with cul-

    tured fibroblasts from controls. This may indicatethat the increased amount of active matrix metallo-

    proteinase-2 produced in Down syndrome could be

    linked to the simultaneous expression of membrane-

    type I matrix metalloproteinases, which could also be

    a marker of periodontal disease that is seen in a

    majority of subjects with Down syndrome.

    Yamazaki-Kubota et al. (110) investigated the

    levels of matrix metalloproteinase-2 and matrix

    metalloproteinase-8 in gingival crevicular fluid and

    the detection of periodontopathic bacteria in sub-

    gingival plaque. The concentrations of the matrix

    metalloproteinases were evaluated using ELISAs,

    and the periodontopathic bacteria were detected

    using the PCR. The levels of matrix metallopro-

    teinase-2 and matrix metalloproteinase-8 were

    higher in subjects with Down syndrome than in

    healthy controls, and increases in the matrix me-

    talloproteinase levels were observed in the gingival

    crevicular fluid from patients with good oral hy-

    giene and absence of bleeding on probing. Also, the

    numbers of periodontopathic bacteria detected in

    subjects with Down syndrome were higher than the

    numbers of such bacteria in healthy controls. Sur-prisingly, the matrix metalloproteinase-2 levels in

    sites harboring P. gingivalis or A. actinomycetem-

    comitans were lower than in sites without these


    The cited studies indicate increased matrix metal-

    loproteinase activity in the gingival tissues of indi-

    viduals with Down syndrome. The presence of matrix

    metalloproteinase-8 suggests that neutrophils, in

    their frustration to reach their target pathogens, re-

    lease their enzymes extracellularly. Matrix metallo-

    proteinases are involved in the breakdown of the

    extracellular matrix, and their increased activity inthe gingival tissues of individuals with Down syn-

    drome explains the gingival tissue loss and associated

    clinical parameters, such as increased probing depth

    and loss of attachment. In addition, the increased

    level of prostaglandin E2, in combination with the

    increased activity of matrix metalloproteinase-9,

    suggests a higher level of osteoclastic activity and

    explains the increased alveolar bone loss seen in

    individuals with Down syndrome.

    In reviewing the presented evidence, it seems that

    a combination of factors, including early microbial

    colonization, altered immune functions and in-

    creased gingival inflammation, contribute to the in-

    creased susceptibility to periodontitis in individuals

    with Down syndrome.

    Summary and concluding remarksThis report reviewed a selected group of systemic

    disorders involving the mineralization of bone and

    dental tissues, or affecting neutrophil counts or

    function and their impact on the periodontium.

    Aggressive forms of periodontitis almost always

    accompany these systemic diseases. When dealing

    with or suspecting these disorders, it is recom-

    mended to establish a differential diagnosis and at-

    tempt to identify the underlying causal factors.

    Proper diagnosis is a prerequisite for proper man-

    agement of the periodontal problem. To establish a

    diagnosis it is important to review the medical his-

    tory, family history, laboratory findings of neutrophil

    counts and functions, and total serum alkaline

    phosphatase activity, and to consult with other

    medical specialists. In certain cases molecular ge-

    netic testing may be indicated and may help validate

    a clinical diagnosis. In most of these diseases con-

    trolling the progression of periodontal disease is very

    challenging. Controlling the supragingival dental

    plaque and combining antimicrobial therapy with

    conventional periodontal therapy may help in somesituations. Future advances in research, including

    gene targeting and the resolution of enzyme defi-

    ciencies, may bring about remedies of the underlying

    genetic defects, and such treatments may signifi-

    cantly improve the outcome of periodontal treatment

    in these patients.


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