Periodontology 2000, Vol. 65, 2014, 134–148  2014 John Wiley & Sons A/S.
& Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
Aggressive forms of periodontitis
secondary to systemic disorders
A H M E D K H O C H T & J A S I M M. A L 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 more
susceptible 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 Ôprepubertal
periodontitisÕ 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-
odontologyÕs classification of periodontal diseases,
aggressive forms of periodontal diseases secondary to
a systemic condition are termed Ôperiodontitis as a
manifestation of systemic diseaseÕ (12). More recent
studies suggest that prepubertal children with severe
134
PERIODONTOLOGY 2000
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

pain, stress fracture of the metatarsals and dental
abnormalities (107). Chondrocalcinosis and osteoar-
thropathy may develop with age. In the mild form of
the disease, loss of teeth and ⁄ or severe dental caries
are the only manifestations, with no systemic symp-
toms (22). This latter form was termed odontohypo-
hypophosphatasia and it shows only mildly reduced
serum alkaline phosphatase levels, whereas in the
more severe forms there is pronounced reduction or
complete lack of tissue-nonspecific alkaline phos-
phatase. Osteomalacia distinguishes adult hypo-
phosphatasia from odontohypophosphatasia.
The prevalence of hypophosphatasia varies
depending on the form of the disease and the pop-
ulation studied. The prevalence of the severe form,
which includes the perinatal and infantile forms, is
estimated to be 1 ⁄ 100,000 in Canada (36) and
1 ⁄ 300,000 in France (63). However, the prevalence of
the mild ⁄ moderate forms of hypophosphatasia,
which includes childhood, adult and odontohypo-
phosphatasia forms, is thought to be much higher
and was estimated to be 1 ⁄ 6,370 among the Euro-
pean population (63).
Hypophosphatasia is caused by more than 200
distinct mutations in the ALPL gene (62). Both auto-
somal-recessive and autosomal-dominant transmis-
sion have been shown in patients with mild or
moderate forms of hypophosphatasia. The diagnosis
of this disease is usually based on clinical examina-
tion and laboratory assays, and, more recently, DNA
sequencing of the causative gene has been performed
to further verify the diagnosis.
Patients with hypophosphatasia do not show in-
creased gingival inflammation or periodontitis (106)
and their immune response to infections is not
defective. However, they have various dental defor-
mities, including thin dentin, hypocalcified enamel,
large-diameter dentinal tubules, and enlarged pulp
chamber and root canals. Furthermore, the dental
cementum is absent, hypocalcified or dysplastic
(101). For this reason the roots of the teeth in these
patients are not adequately anchored to the alveolar
bone via the periodontal ligament and the teeth are
lost prematurely.
Diseases associated with
neutrophil disorders
Neutrophils form the major part of leukocytes in
humans and are an essential component of the
innate immune system. These cells are the first line of
defense against infection, and they have a short
Syndromic aggressive periodontal disease
lifespan (69). Hence, a significant decrease in the
number of neutrophils may compromise the hostÕs
response to infection, and as such is an important
etiological factor for certain forms of periodontal
diseases (76, 81).
Quantitative neutrophil disorders
Familial and cyclic neutropenia
Cyclic neutropenia is a rare genetic disorder charac-
terized by a cyclical decrease in the number of cir-
culating neutrophils. The decrease in the number of
circulating neutrophils tends to occur every 3 weeks
and lasts for 3–6 days at a time. The decrease in the
number of circulating neutrophils is caused by
changes in the rates of cell production in the bone
marrow. The condition is caused by mutations in the
gene that encodes neutrophil elastase (10, 104). In
humans, neutrophil elastase is encoded by the ELA2
gene, and mutations in this gene may impede neu-
trophil maturation. The mutations are passed down
through family members by autosomal-dominant
inheritance, and therefore the condition tends to
affect several members of the same family.
The neutropenic phase is characteristically associ-
ated with clinical symptoms such as recurrent fever,
malaise, headaches, anorexia, pharyngitis, ulcers of
the oral mucous membrane and gingival inflamma-
tion (27). Several reports in the literature indicate that
affected individuals tend to have periodontal
problems. The importance of regular oral hygiene,
removal of subgingival plaque and calculus and
periodic professional tooth cleaning are indicated to
control the progression of periodontal disease in af-
fected individuals (65). Local antibiotic application in
periodontal pockets was recommended, in a case
report (65), to help manage the periodontal prob-
lems during neutropenic periods. Treatment with
recombinant granulocyte colony-stimulating factor
has been shown to result in resolution of the oral
ulcerations and of other clinical symptoms (68), and
a combination treatment using granulocyte colony-
stimulating factor and nonsurgical periodontal ther-
apy may lead to an improvement of the periodontal
condition of the affected patients (58).
Infantile genetic agranulocytosis
Infantile genetic agranulocytosis is a rare autosomal-
recessive disease caused by a defect in the granulo-
cyte colony-stimulating factor receptor (39).
Granulocyte colony-stimulating factor receptor
stimulates the bone marrow to produce granulocytes
135
Khocht & Albandar
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 diseases cause
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 storage
diseases. 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 reticulum
where 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
136
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 may
result 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 COH1 gene). 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 believed
to 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

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 chromosome
21, 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 around
the 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).
Chediak–Higashi syndrome
Chediak–Higashi 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
Syndromic aggressive periodontal disease
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
Chediak–Higashi syndrome have immune-system
abnormalities, recurrent infections, bleeding abnor-
malities and muscle weakness. Progressive damage to
the peripheral nervous system, partial albinism and
sensitivity to light are associated with the disease. In
addition, subjects with Chediak–Higashi 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).
Chediak–Higashi 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 Chediak–Higashi syndrome. Early
reports did not specifically address recommended
periodontal management and possible bleeding
complications. In a recent study, Khocht et al. (46)
described a severe case of Chediak–Higashi
Fig. 1. Clinical photograph of a 13-year-old African-
American boy with Chediak–Higashi 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
Khocht & Albandar
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).
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.
Papillon–Lefèvre syndrome
Papillon–Lefèvre 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 1–3 per million,
with no sex or race preference. The skin symptoms
vary greatly. In some affected individuals the hyper-
Fig. 3. Hyperkeratosis lesions on the knees and dorsal
surface of the palms of a 7-year-old white male child with
Papillon–Lefèvre syndrome (Adapted from Albandar et al.
(6). Reproduced with permission from the American
Academy of Periodontology).
138
Fig. 4. Clinical photograph of the boy with Papillon–
Lefèvre 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).
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 in
life 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 Papillon–Lefèvre
syndrome.
Several studies have investigated the pathogenesis
of periodontitis in individuals affected with Papillon–
Lefèvre syndrome. Impaired neutrophil functions,
including chemotaxis, phagocytosis and bacterial
killing, were reported by some authors (53, 102). Se-
verely depressed natural killer cell cytotoxicity has
also been reported in affected individuals (54). There
are also reports of increased levels of interleukin-1beta
Fig. 5. Panoramic radiograph of the boy with Papillon–
Lefèvre 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).

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 Papillon–Lefèvre syndrome
might be attributed to a defect in the epithelial barrier
defense system.
The subgingival microbial profile of subjects with
Papillon–Lefèvre syndrome has been investigated.
Studies using bacterial culture or DNA probes
showed that the subgingival microbial profile in
individuals with Papillon–Lefèvre 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 Papillon–Lefèvre 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 Epstein–Barr virus type
1 in the subgingival sample of a patient with Papil-
lon–Lefèvre syndrome and hypothesized that viruses,
in concert with subgingival periodontopathic bacte-
ria, may contribute to the development of peri-
odontitis in Papillon–Lefèvre syndrome-affected
individuals.
The treatment of periodontitis and the control of
periodontal tissue loss in Papillon–Lefèvre 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 Papillon–Lefèvre
syndrome by combining antibiotic therapy with
conventional 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,
Syndromic aggressive periodontal disease
together with a meticulous oral hygiene regimen by
the patient (95). Also, full-mouth rehabilitation of the
missing dentition in a patient with Papillon–Lefèvre
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 800–1,000
births (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 58–96% 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 hygiene
and 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
Khocht & Albandar
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.
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 protein
products 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-
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
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 detecting Aggregatibacter actinomycetem-
comitans, Capnocytophaga and Porphyromonas
gingivalis in the subgingival plaque of adolescents

with Down syndrome. A. actinomycetemcomitans was
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 of A. actinomycetemcomitans indicated 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, particularly P. 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
ÔcheckerboardÕ DNA–DNA 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 with
intellectual 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
Syndromic aggressive periodontal disease
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 between
individuals 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, defective
neutrophil 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 migration
and 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, 14–30 years of age (113).
Surgical and nonsurgical periodontal therapies were
141
Khocht & Albandar
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, 24–28 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 periodontitis
showed 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).
142
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
<1% (87). It was suggested that a defect in the pro-
liferative response of these cells might account for
their reduced numbers (82). The gamma ⁄ delta
T-lymphocytes usually reside within epithelial tissues
and encounter antigens on the surface of epithelial
cells. They bind to antigens that are intact proteins
and to antigens that are not presented within class I
or class II histocompatibility molecules. The low
numbers of gamma ⁄ delta T-lymphocytes in the
gingival tissues of individuals with Down syndrome
might be a factor in their increased susceptibility to
periodontal infections.
The results of these studies suggest presence of a
high level of a variety of immune cells within the
gingival tissues of subjects with Down syndrome and
periodontitis. An increased production of HLA class II
antigens on the surfaces of antigen-producing cells
suggests that the cells are locally engaged in specific
immune responses, and the low presence of
gamma ⁄ delta T lymphocytes may increase the
vulnerability of subjects with Down syndrome to
microbial noxious agents.
Antibody ⁄ immunoglobulin production. Several stud-
ies have investigated the level of specific antibodies to
periodontopathic bacteria in serum and saliva. The
serum antibody titers to A. actinomycetemcomitans
were assessed in 11 subjects with Down syndrome and
periodontitis, in five subjects with Down syndrome and
gingivitis and in 10 non-Down-syndrome healthy
controls (80). Significant differences were found
between the groups (P = 0.05), with the group of subjects
with Down syndrome and periodontitis having
the highest antibody response, followed by the sub-
jects with Down syndrome and gingivitis and then by
the controls. A study examined 75 subjects (2–18 years
of age) with Down syndrome, and assessed their gingi-
val health using a modified gingival inflammation
index and their serum antibody titers to periodontal
bacteria using a micro-ELISA (61). It was found that the
average antibody titers to A. actinomycetemcomitans,
Streptococcus mitis and Fusobacterium nucleatum
exceeded those of the normal adult reference serum
pool. In addition, IgG titers to P. gingivalis, A. actino-
mycetemcomitans, F. nucleatum, Selenomonas sputige-
na and S. mitis correlated significantly with gingival
inflammation. It may be inferred from these two

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 in
subjects with Down syndrome (50). In contrast, the
proportion of salivary IgG2, IgG3 and IgG4 subclasses
is not increased 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. actinomycetemcomitans and 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 34–60% lower in
parotid saliva. In the older age group the secretion
rates of subjects with Down syndrome were 77–100%
lower in whole saliva and 75–88% 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 that
Down 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.
Syndromic aggressive periodontal disease
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 alteration
in 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 E2
down-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,
9–17 years of age, relative to their age-matched sys-
temically and periodontally healthy controls. They
assessed clinical periodontal parameters and the
collagenase 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
Khocht & Albandar
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 indicate
that 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 in
the 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.
144
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 remarks
This 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 some
situations. 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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