Download - SM1 3periodontology 2000,65th vol
-
8/12/2019 SM1 3periodontology 2000,65th vol
1/15
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
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
134
Periodontology 2000, Vol. 65, 2014, 134148
Printed in Singapore. All rights reserved
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PERIODONTOLOGY 2000
-
8/12/2019 SM1 3periodontology 2000,65th vol
2/15
-
8/12/2019 SM1 3periodontology 2000,65th vol
3/15
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
136
Khocht & Albandar
-
8/12/2019 SM1 3periodontology 2000,65th vol
4/15
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,
96).
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).
137
Syndromic aggressive periodontal disease
-
8/12/2019 SM1 3periodontology 2000,65th vol
5/15
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
syndrome.
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).
138
Khocht & Albandar
-
8/12/2019 SM1 3periodontology 2000,65th vol
6/15
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
individuals.
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
139
Syndromic aggressive periodontal disease
-
8/12/2019 SM1 3periodontology 2000,65th vol
7/15
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.
140
Khocht & Albandar
-
8/12/2019 SM1 3periodontology 2000,65th vol
8/15
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
141
Syndromic aggressive periodontal disease
-
8/12/2019 SM1 3periodontology 2000,65th vol
9/15
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
-
8/12/2019 SM1 3periodontology 2000,65th vol
10/15
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
loss.
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
143
Syndromic aggressive periodontal disease
-
8/12/2019 SM1 3periodontology 2000,65th vol
11/15
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
microorganisms.
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.
References
1. Abdulsalam AH, Sabeeh N, Bain BJ. Bone marrow aspirate
in ChediakHigashi syndrome.Am J Hematol2012: 87: 100.2. Ahmadian L, Monzavi A, Arbabi R, Hashemi HM. Full-
mouth rehabilitation of an edentulous patient with
PapillonLefevre syndrome using dental implants: a clin-
ical report.J Prosthodont2011: 20: 643648.
3. Ahuja V, Shin RH, Mudgil A, Nanda V, Schoor R. Papillon
Lefevre syndrome: a successful outcome. J Periodontol
2005: 76: 19962001.
4. Akinci O, Mihci E, Tacoy S, Kardelen F, Keser I, Aslan M.
Neutrophil oxidative metabolism in Down syndrome pa-
tients with congenital heart defects. Environ Mol Mutagen
2010: 51: 5763.
144
Khocht & Albandar
-
8/12/2019 SM1 3periodontology 2000,65th vol
12/15
5. Alaluusua S, Kivitie-Kallio S, Wolf J, Haavio ML, Asikainen
S, Pirinen S. Periodontal findings in Cohen syndrome with
chronic neutropenia.J Periodontol1997: 68: 473478.
6. Albandar JM, Khattab R, Monem F, Barbuto SM, Paster BJ.
The subgingival microbiota of PapillonLefevre syndrome.
J Periodontol2012: 83: 902908.
7. Amano A, Kishima T, Akiyama S, Nakagawa I, Hamada S,
Morisaki I. Relationship of periodontopathic bacteria with
early-onset periodontitis in Downs syndrome. J Period-
ontol2001: 72: 368373.
8. Amano A, Kishima T, Kimura S, Takiguchi M, Ooshima T,
Hamada S, Morisaki I. Periodontopathic bacteria in chil-
dren withDown syndrome.J Periodontol2000: 71: 249255.
9. Amaral Loureiro AC, Oliveira Costa F, Eustaquio da Costa
J. The impact of periodontal disease on the quality of life
of individuals with Down syndrome. Downs Syndr Res
Pract2007: 12: 5054.
10. Ancliff PJ, Gale RE, Linch DC. Neutrophil elastase muta-
tions in congenital neutropenia.Hematology2003:8: 165
171.
11. Antonio AG, Alcantara PC, Ramos ME, de Souza IP. The
importance of dental care for a child with severe con-
genital neutropenia: a case report.Spec Care Dentist2010:
30: 261265.
12. Armitage GC. Development of a classification system for
periodontal diseases and conditions. Ann Periodontol
1999: 4: 16.
13. Bailleul-Forestier I, Monod-Broca J, Benkerrou M, Mora F,
Picard B. Generalized periodontitis associated with Che-
diakHigashi syndrome. J Periodontol 2008: 79: 1263
1270.
14. Barak Y, Nir E. ChediakHigashi syndrome.Am J Pediatr
Hematol Oncol1987: 9: 4255.
15. Barr-Agholme M, Dahllof G, Linder L, Modeer T.Actino-
bacillus actinomycetemcomitans, Capnocytophaga and
Porphyromonas gingivalis in subgingival plaque of ado-
lescents with Downs syndrome.Oral Microbiol Immunol
1992: 7: 244248.16. Barr-Agholme M, Dahllof G, Modeer T, Engstrom PE,
Engstrom GN. Periodontal conditions and salivary
immunoglobulins in individuals with Down syndrome.
J Periodontol1998: 69: 11191123.
17. Barr-Agholme M, Krekmanova L, Yucel-Lindberg T, Shi-
noda K, Modeer T. Prostaglandin E2 level in gingival cre-
vicular fluid from patients with Down syndrome. Acta
Odontol Scand1997:55: 101105.
18. Barrett AP, Buckley DJ, Katelaris CH. Oral complications
in type 1B glycogen storage disease. Oral Surg Oral Med
Oral Pathol1990: 69: 174176.
19. Bimstein E, McIlwain M, Katz J, Jerrell G, Primosch R.
Aggressive periodontitis of the primary dentition associ-
ated with idiopathic immune deficiency: case report andtreatment considerations.J Clin Pediatr Dent2004:29: 27
31.
20. Bloemers BL, Broers CJ, Bont L, Weijerman ME, Gemke RJ,
van Furth AM. Increased risk of respiratory tract infections
in children with Down syndrome: the consequence of an
altered immune system.Microbes Infect2010:12: 799808.
21. Bloemers BL, van Bleek GM, Kimpen JL, Bont L. Distinct
abnormalities in the innate immune system of children
with Down syndrome. J Pediatr 2010: 156: 804809, 809
e801809 e805.
22. Brittain JM, Oldenburg TR, Burkes EJ Jr. Odontohypo-
phosphatasia: report of two cases.ASDC J Dent Child1976:
43: 106111.
23. Carlsson G, Fasth A. Infantile genetic agranulocytosis,
morbus Kostmann: presentation of six cases from the
original Kostmann family and a review. Acta Paediatr
2001: 90: 757764.
24. Chaushu S, Chaushu G, Zigmond M, Yefenof E, Stabholz
A, Shapira J, Merrick J, Bachrach G. Age-dependent defi-
ciency in saliva and salivary antibodies secretion in
Downs syndrome.Arch Oral Biol2007:52: 10881096.
25. Cohen MM, Winer RA, Schwartz S, Shklar G. Oral aspects
of mongolism. I. Periodontal disease in mongolism. Oral
Surg Oral Med Oral Pathol1961: 14: 92107.
26. Dababneh R, Al-Wahadneh AM, Hamadneh S, Khouri A,
Bissada NF. Periodontal manifestation of leukocyte
adhesion deficiency type I. J Periodontol 2008: 79: 764
768.
27. Dale DC, Hammond WPt. Cyclic neutropenia: a clinical
review.Blood Rev1988: 2: 178185.
28. Dalgic B, Bukulmez A, Sari S. Eponym: PapillonLefevre
syndrome.Eur J Pediatr2011: 170: 689691.
29. Deas DE, Mackey SA, McDonnell HT. Systemic disease
and periodontitis: manifestations of neutrophil dysfunc-
tion.Periodontol 20002003: 32: 82104.
30. Defraia E, Marinelli A. Oral manifestations of congenital
neutropenia or Kostmann syndrome. J Clin Pediatr Dent
2001: 26: 99102.
31. Delcourt-Debruyne EM, Boutigny HR, Hildebrand HF.
Features of severe periodontal disease in a teenager with
ChediakHigashi syndrome. J Periodontol 2000: 71: 816
824.
32. Desai SS. Down syndrome: a review of the literature.Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 1997: 84:
279285.
33. Etzioni A. Defects in the leukocyte adhesion cascade.Clin
Rev Allergy Immunol2010:38: 5460.
34. Falk MJ, Wang H, Traboulsi EI. Cohen syndrome. In:Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews. Seattle, WA: University of Washington,
Seattle; 1993-. Available from: http://www.ncbi.nlm.nih.
gov/books/NBK1116/.
35. Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM,
Weinstein RS, Waymire K, Narisawa S, Millan JL, MacGr-
egor GR, Whyte MP. Alkaline phosphatase knock-out mice
recapitulate the metabolic and skeletal defects of infantile
hypophosphatasia. J Bone Miner Res1999: 14: 20152026.
36. Fraser D. Hypophosphatasia.Am J Med1957:22: 730746.
37. Gabre P, Martinsson T, Gahnberg L. Longitudinal study of
dental caries, tooth mortality and interproximal bone loss
in adults with intellectual disability. Eur J Oral Sci 2001:
109: 2026.38. Gardiner K, Slavov D, Bechtel L, Davisson M. Annotation
of human chromosome 21 for relevance to Down syn-
drome: gene structure and expression analysis.Genomics
2002: 79: 833843.
39. Germeshausen M, Skokowa J, Ballmaier M, Zeidler C,
Welte K. G-CSF receptor mutations in patients with con-
genital neutropenia. Curr Opin Hematol 2008: 15: 332
337.
40. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA,
Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D,
145
Syndromic aggressive periodontal disease
-
8/12/2019 SM1 3periodontology 2000,65th vol
13/15
Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H,
Lacher M, Nustede R, Woellner C, Baumann U, Salzer U,
Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S,
Snapper SB, Grimbacher B, Klein C. Inflammatory bowel
disease and mutations affecting the interleukin-10
receptor.N Engl J Med2009: 361: 20332045.
41. Halinen S, Sorsa T, Ding Y, Ingman T, Salo T, Konttinen
YT, Saari H. Characterization of matrix metalloproteinase
(MMP-8 and -9) activities in the saliva and in gingival
crevicular fluid of children with Downs syndrome.
J Periodontol1996: 67: 748754.
42. Hicks J, Wartchow E, Mierau G. Glycogen storage diseases:
a brief review and update on clinical features, genetic
abnormalities, pathologic features, and treatment.Ultra-
struct Pathol2011: 35: 183196.
43. Introne W, Boissy RE, Gahl WA. Clinical, molecular, and
cell biological aspects of ChediakHigashi syndrome. Mol
Genet Metab 1999: 68: 283303.
44. Izumi Y, Sugiyama S, Shinozuka O, Yamazaki T, Ohyama
T, Ishikawa I. Defective neutrophil chemotaxis in Downs
syndrome patients and its relationship to periodontal
destruction.J Periodontol1989: 60: 238242.
45. Kaplan J, De Domenico I, Ward DM. ChediakHigashi
syndrome.Curr Opin Hematol2008: 15: 2229.
46. Khocht A, Viera-Negron YE, Ameri A, Abdelsayed R. Peri-
odontitis associated with ChediakHigashi syndrome in a
young African American male.J Int Acad Periodontol2010:
12: 4955.
47. Kleinfelder JW, Topoll HH, Preus HR, Muller RF, Lange
DE, Bocker W. Microbiological and immunohistological
findings in a patient with PapillonLefevre syndrome.
J Clin Periodontol1996: 23: 10321038.
48. Komatsu T, Kubota E, Sakai N. Enhancement of matrix
metalloproteinase (MMP)-2 activity in gingival tissue and
cultured fibroblasts from Downs syndrome patients.Oral
Dis2001: 7: 4755.
49. Kunkel SL, Remick DG, Spengler M, Chensue SW. Modu-
lation of macrophage-derived interleukin-1 and tumornecrosis factor by prostaglandin E2. Adv Prostaglandin
Thromboxane Leukot Res1987: 17A: 155158.
50. Kusters MA, Verstegen RH, Gemen EF, de Vries E. Intrinsic
defect of the immune system in children with Down
syndrome: a review. Clin Exp Immunol 2009: 156: 189
193.
51. Lana-Elola E, Watson-Scales SD, Fisher EM, Tybulewicz
VL. Down syndrome: searching for the genetic culprits.
Dis Model Mech2011: 4: 586595.
52. Liongue C, Wright C, Russell AP, Ward AC. Granulocyte
colony-stimulating factor receptor: stimulating granulo-
poiesis and much more. Int J Biochem Cell Biol2009: 41:
23722375.
53. Liu R, Cao C, Meng H, Tang Z. Leukocyte functions in 2cases of PapillonLefevre syndrome. J Clin Periodontol
2000: 27: 6973.
54. Lundgren T, Parhar RS, Renvert S, Tatakis DN. Impaired
cytotoxicity in PapillonLefevre syndrome. J Dent Res
2005: 84: 414417.
55. Lundgren T, Renvert S. Periodontal treatment of patients
with PapillonLefevre syndrome: a 3-year follow-up.J Clin
Periodontol2004: 31: 933938.
56. Lundgren T, Renvert S, Papapanou PN, Dahlen G.
Subgingival microbial profile of PapillonLefevre patients
assessed by DNA-probes.J Clin Periodontol1998:25: 624
629.
57. Lundgren T, Twetman S, Johansson I, Crossner CG, Bir-
khed D. Saliva composition in children and young adults
with PapillonLefevre syndrome. J Clin Periodontol1996:
23: 10681072.
58. Matarasso S, Daniele V, Iorio Siciliano V, Mignogna MD,
Andreuccetti G, Cafiero C. The effect of recombinant
granulocyte colony-stimulating factor on oral and peri-
odontal manifestations in a patient with cyclic neutrope-
nia: a case report. Int J Dent2009: 2009: 654239.
59. Megarbane A, Ravel A, Mircher C, Sturtz F, Grattau Y,
RethoreMO, Delabar JM, Mobley WC. The 50th anniver-
sary of the discovery of trisomy 21: the past, present, and
future of research and treatment of Down syndrome.
Genet Med2009:11: 611616.
60. Morgan J. Why is periodontal disease more prevalent and
more severe in people with Down syndrome? Spec Care
Dentist2007: 27: 196201.
61. Morinushi T, Lopatin DE, van Poperin N. The relationship
between gingivitis and the serum antibodies to the mic-
robiota associated with periodontal disease in children
with Downs syndrome.J Periodontol1997: 68: 626631.
62. Mornet E. The tissue nonspecific alkaline phosphatase
gene mutations database, 2012.
63. Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy
B. A molecular-based estimation of the prevalence of
hypophosphatasia in the European population.Ann Hum
Genet2011: 75: 439445.
64. Mrak RE, Griffin WS. Trisomy 21 and the brain.J Neuro-
pathol Exp Neurol2004: 63: 679685.
65. Nakai Y, Ishihara C, Ogata S, Shimono T. Oral manifesta-
tions of cyclic neutropenia in a Japanese child: case report
with a 5-year follow-up.Pediatr Dent2003:25: 383388.
66. Pacheco JJ, Coelho C, Salazar F, Contreras A, Slots J,
Velazco CH. Treatment of PapillonLefevre syndrome
periodontitis. J Clin Periodontol2002: 29: 370374.
67. Page RC, Bowen T, Altman L, Vandesteen E, Ochs H,Mackenzie P, Osterberg S, Engel LD, Williams BL. Prepu-
bertal periodontitis. I. Definition of a clinical disease en-
tity.J Periodontol1983: 54: 257271.
68. Page AV, Liles WC. Colony-stimulating factors in the
prevention and management of infectious diseases. Infect
Dis Clin North Am2011:25: 803817.
69. Pillay J, den Braber I, Vrisekoop N, Kwast LM, de Boer RJ,
Borghans JA, Tesselaar K, Koenderman L. In vivo labeling
with 2H2O reveals a human neutrophil lifespan of
5.4 days.Blood2010: 116: 625627.
70. Price PA, Toroian D, Chan WS. Tissue-nonspecific alkaline
phosphatase is required for the calcification of collagen in
serum: a possible mechanism for biomineralization.J Biol
Chem2009: 284: 45944604.71. Ralls SA, Marshall EC. Dental management of a patient
with glycogen storage disease type I.J Am Dent Assoc1985:
110: 723726.
72. Reuland-Bosma W, Liem RS, Jansen HW, van Dijk LJ, van
der Weele LT. Cellular aspects of and effects on the gingiva
in children with Downs syndrome during experimental
gingivitis. J Clin Periodontol1988: 15: 303311.
73. Reuland-Bosma W, van den Barselaar MT, van de Gevel JS,
Leijh PC, de Vries-Huiges H, The HT. Nonspecific and
specific immune responses in a child with Downs
146
Khocht & Albandar
-
8/12/2019 SM1 3periodontology 2000,65th vol
14/15
syndrome and her sibling. A case report. J Periodontol
1988: 59: 249253.
74. Reuland-Bosma W, van der Reijden WA, van Winkelhoff
AJ. Absence of a specific subgingival microflora in adults
with Downs syndrome.J Clin Periodontol2001:28: 1004
1009.
75. Robertson KL, Drucker DB, James J, Blinkhorn AS, Hamlet
S, Bird PS. A microbiological study of PapillonLefevre
syndrome in two patients.J Clin Pathol2001:54: 371376.
76. Ryder MI. Comparison of neutrophil functions in aggres-
sive and chronic periodontitis.Periodontol 20002010: 53:
124137.
77. Saglam F, Atamer T, Onan U, Soydinc M, Kirac K. Infantile
genetic agranulocytosis (Kostmann type). A case report.
J Periodontol1995: 66: 808810.
78. Sakellari D, Arapostathis KN, Konstantinidis A. Periodon-
tal conditions and subgingival microflora in Down syn-
drome patients. A casecontrol study. J Clin Periodontol
2005: 32: 684690.
79. Sakellari D, Belibasakis G, Chadjipadelis T, Arapostathis K,
Konstantinidis A. Supragingival and subgingival microbi-
ota of adult patients with Downs syndrome. Changes after
periodontal treatment.Oral Microbiol Immunol2001: 16:
376382.
80. Santos R, Shanfeld J, Casamassimo P. Serum antibody
response to Actinobacillus actinomycetemcomitans in
Downs syndrome.Spec Care Dentist1996: 16: 8083.
81. Scott DA, Krauss J. Neutrophils in periodontal inflamma-
tion.Front Oral Biol2012: 15: 5683.
82. Sherman SL, Allen EG, Bean LH, Freeman SB. Epidemi-
ology of Down syndrome.Ment Retard Dev Disabil Res Rev
2007: 13: 221227.
83. Shibutani T, Gen K, Shibata M, Horiguchi Y, Kondo N,
Iwayama Y. Long-term follow-up of periodontitis in a
patient with ChediakHigashi syndrome. A case report.
J Periodontol2000: 71: 10241028.
84. Shin M, Besser LM, Kucik JE, Lu C, Siffel C, Correa A.
Prevalence of Down syndrome among children and ado-lescents in 10 regions of the United States.Pediatrics2009:
124: 15651571.
85. Sohoel PD, Johannessen AC, Kristoffersen T, Haugstvedt
Y, Nilsen R. In situ characterization of mononuclear cells
in marginal periodontitis of patients with Downs syn-
drome.Acta Odontol Scand1992: 50: 141149.
86. Shoel DC, Johannessen AC, Kristoffersen T, Nilsen R.
Expression of HLA class II antigens in marginal peri-
odontitis of patients with Downs syndrome.Eur J Oral Sci
1995: 103: 207213.
87. Shoel DC, Jonsson R, Johannessen AC, Nilsen R. Gam-
ma delta T lymphocytes in marginal periodontitis in
patients with Downs syndrome. Adv Exp Med Biol 1995:
371B: 11351136.88. Springer TA, Miller LJ, Anderson DC. p150,95, the third
member of the Mac-1, LFA-1 human leukocyte adhesion
glycoprotein family.J Immunol1986:136: 240245.
89. Strydom A, Dickinson MJ, Shende S, Pratico D, Walker Z.
Oxidative stress and cognitive ability in adults with Down
syndrome. Prog Neuropsychopharmacol Biol Psychiatry
2009: 33: 7680.
90. Taubman MA, Valverde P, Han X, Kawai T. Immune re-
sponse: the key to bone resorption in periodontal disease.
J Periodontol2005: 76: 20332041.
91. Taylor GM. Altered expression of lymphocyte functional
antigen in Down syndrome.Immunol Today1987:8: 366
369.
92. Taylor GM, Williams A, DSouza SW, Fergusson WD,
Donnai D, Fennell J, Harris R. The expression of CD18 is
increased on Trisomy 21 (Down syndrome) lymphoblas-
toid cells. Clin Exp Immunol1988:71: 324328.
93. Terkeltaub RA. Inorganic pyrophosphate generation and
disposition in pathophysiology. Am J Physiol Cell Physiol
2001: 281: C1C11.
94. Thase ME. Longevity and mortality in Downs syndrome.
J Ment Defic Res1982: 26: 177192.
95. Toygar HU, Kircelli C, Firat E, Guzeldemir E. Combined
therapy in a patient with PapillonLefevre syndrome: a 13-
year follow-up.J Periodontol2007: 78: 18191824.
96. Trigg ME, Schugar R. ChediakHigashi syndrome: hema-
topoietic chimerism corrects genetic defect.Bone Marrow
Transplant2001: 27: 12111213.
97. Tsilingaridis G, Yucel-Lindberg T, Modeer T. Enhanced
levels of prostaglandin E2, leukotriene B4, and matrix
metalloproteinase-9 in gingival crevicular fluid from pa-
tients with Down syndrome.Acta Odontol Scand2003:61:
154158.
98. Ullbro C, Crossner CG, Nederfors T, Parhar R, Al Mohanna
F, Meikle MC, Reynolds JJ, Twetman S. Cytokines, matrix
metalloproteinases and tissue inhibitor of metallopro-
teinases-1 in gingival crevicular fluid from patients with
PapillonLefevre syndrome.Acta Odontol Scand2004:62:
7074.
99. Ullbro C, Kinnby B, Lindberg P, Matsson L. Tissue plas-
minogen activator (t-PA) and placental plasminogen
activator inhibitor (PAI-2) in gingival crevicular fluid from
patients with PapillonLefevre syndrome. J Clin Period-
ontol2004: 31: 708712.
100. Ulseth JO, Hestnes A, Stovner LJ, Storhaug K. Dental caries
and periodontitis in persons with Down syndrome. Spec
Care Dentist1991:11: 7173.
101. van den Bos T, Handoko G, Niehof A, Ryan LM, CoburnSP, Whyte MP, Beertsen W. Cementum and dentin in
hypophosphatasia. J Dent Res2005: 84: 10211025.
102. Van Dyke TE, Taubman MA, Ebersole JL, Haffajee AD,
Socransky SS, Smith DJ, Genco RJ. The PapillonLefevre
syndrome: neutrophil dysfunction with severe periodontal
disease.Clin Immunol Immunopathol1984: 31: 419429.
103. Velazco CH, Coelho C, Salazar F, Contreras A, Slots J,
Pacheco JJ. Microbiological features of PapillonLefevre
syndrome periodontitis. J Clin Periodontol 1999: 26:
622627.
104. Ward AC, Dale DC. Genetic and molecular diagnosis of
severe congenital neutropenia. Curr Opin Hematol 2009:
16: 913.
105. Ward DM, Shiflett SL, Kaplan J. ChediakHigashi syn-drome: a clinical and molecular view of a rare lysosomal
storage disorder.Curr Mol Med2002:2: 469477.
106. Wei KW, Xuan K, Liu YL, Fang J, Ji K, Wang X, Jin Y, Wa-
tanabe S, Watanabe K, Ojihara T. Clinical, pathological
and genetic evaluations of Chinese patients with autoso-
mal-dominant hypophosphatasia.Arch Oral Biol2010:55:
10171023.
107. Whyte MP. Atypical femoral fractures, bisphosphonates,
and adult hypophosphatasia. J Bone Miner Res 2009: 24:
11321134.
147
Syndromic aggressive periodontal disease
-
8/12/2019 SM1 3periodontology 2000,65th vol
15/15
108. Whyte MP. Physiological role of alkaline phosphatase ex-
plored in hypophosphatasia.Ann N Y Acad Sci2010:1192:
190200.
109. Wong AT, McMillan AS, McGrath C. Oral health-related
quality of life and severe hypodontia. J Oral Rehabil2006:
33: 869873.
110. Yamazaki-Kubota T, Miyamoto M, Sano Y, Kusumoto M,
Yonezu T, Sugita K, Okuda K, Yakushiji M, Ishihara K.
Analysis of matrix metalloproteinase (MMP-8 and MMP-2)
activity in gingival crevicular fluid from children with
Downs syndrome.J Periodontal Res2010:45: 170176.
111. Yavuzyilmaz E, Ersoy F, Sanal O, Tezcan I, Ercal D.
Neutrophil chemotaxis and periodontal status in
Downs syndrome patients. J Nihon Univ Sch Dent1993:
35: 9195.
112. Yildirim S, Yapar M, Kubar A. Detection and quantifi-
cation of herpesviruses in Kostmann syndrome
periodontitis using real-time polymerase chain reac-
tion: a case report. Oral Microbiol Immunol 2006: 21:
7378.
113. Zaldivar-Chiapa RM, Arce-Mendoza AY, De La Rosa-
Ramirez M, Caffesse RG, Solis-Soto JM. Evaluation of
surgical and non-surgical periodontal therapies, and
immunological status, of young Downs syndrome
patients.J Periodontol2005: 76: 10611065.
148
Khocht & Albandar