Describes conditions that show periodontal manifestations inherently and primary cause is the disease itself whereas bacterial plaque acts as a secondary factor.

1. Periodontitis as a manifestation of
systemic disease
Dr Lakkireddy Vasavi reddy
II MDS

2. Contents:
Introduction
Classification
Haemotological disorders
1.Leukemia
2.Acquired neutropenia
Genetic disorders
1.Familial and cyclic neutropenia
2. Down syndrome
3. Leukocyte adhesion deficiency
syndromes
4. Papillon-Lefèvre syndrome
5. Chediak-Higashi syndrome
6. Histiocytosis syndromes
7. Glycogen storage disease
8. Infantile genetic agranulocytosis
9. Cohen syndrome
10. Ehlers-Danlos syndrome (Types IV
and VIII)
11. Hypophosphatasia
12. Other
Conclusion

3. Introduction:
• Periodontitis as a manifestation of systemic disease is a category that
is used when the systemic condition is the major predisposing factor
and bacterial infection is a secondary feature of systemic disease.
• Main etiological factor : decreased resistance associated with
systemic disease
• Clinical manifestations of this category of periodontal disease to
occur at an early age.

4. Classification
of diseases:

5. Classification of systemic diseases and conditions that affect the periodontal supporting tissues
(adapted from Albandar et al.)

8. Hematological disorders:
• All blood cells play a role in the maintenance of a healthy periodontium
• White blood cells (WBCs) are involved in peripheral and inflammatory reactions
• Red blood cells (RBCs) are responsible for gas exchange and nutrient supply to the periodontal
tissues and platelets and are required for normal hemostasis
• Disorders of the blood or blood-forming organs can have a profound effect on the periodontium
• Certain oral changes such as hemorrhage may suggest the existence of a blood disturbance;
specific diagnosis, however, requires a complete physical examination and a thorough hematologic
study

9. Leukemia:
The leukemias are malignant neoplasias of WBC precursors characterized by
(1) diffuse replacement of the bone marrow with proliferating leukemic cells,
(2) abnormal numbers and forms of immature WBCs in the circulating blood,
and
(3) widespread infiltrates in the liver, spleen, lymph nodes, and other body
sites.

10. • According to their evolution,
leukemias can be acute, which is
rapidly fatal; subacute; or chronic.
• All leukemias tend to displace
normal components of the bone
marrow elements with leukemic
cells, resulting in reduced
production of RBCs, WBCs, and
platelets and leading to anemia,
leukopenia (reduction in number of
nonmalignant WBSs) and
thrombocytopenia.
• Some patients may have normal
blood counts while leukemic cells
reside primarily in the bone
marrow; this type of disease is
called aleukemic leukemia

11. Oral and periodontal
manifestations
• Oral and periodontal
manifestations of leukemia
consist of leukemic infiltration,
bleeding, oral ulcerations, and
infections. The expression of
these signs is more common in
acute and subacute forms of
leukemia than in chronic forms.
• Leukemic cells can infiltrate the
gingiva and less frequently the
alveolar bone. Gingival
infiltration often results in
leukemic gingival enlargement
Barret, A.P., 1984. Gingival Lesions in Leukemia. J Periodontol, 55,
pp.585-588.

12. Gingiva:
• Leukemic gingival enlargement is not found in edentulous patients or in
patients with chronic leukemia.
• Leukemic gingival enlargement consists of a basic infiltration of the gingival
corium by leukemic cells that increases the gingival thickness and creates
gingival pockets where bacterial plaque accumulates, initiating a secondary
inflammatory lesion that contributes to the enlargement of the gingiva.
• A gingival (bacterial) infection in leukemic patients can be the result of an
exogenous bacterial infection or an existing bacterial infection (e.g.,
gingival or periodontal disease).
• Acute gingivitis and lesions resembling necrotizing ulcerative gingivitis are
more frequent and severe in terminal cases of acute leukemia.
Gingiva appears initially bluish red and cyanotic
Rounding and tenseness of the gingival margin
It increases in size, most often in the interdental papilla
and partially covering the crowns of the teeth

14. Microscopic picture:
• Microscopically, the gingiva exhibits a dense,
diffuse infiltration of predominantly immature
leukocytes in the attached and marginal
gingiva.
• The blood vessels are distended and contain
predominantly leukemic cells, and the RBCs
are reduced in number.
• The epithelium presents a variety of changes
and may be thinned or hyperplastic. Common
findings include degeneration associated with
intercellular and intracellular

15. • The periodontal ligament and alveolar bone may also
be involved in acute and subacute leukemia.
• The periodontal ligament may be infiltrated with
mature and immature leukocytes. The marrow of the
alveolar bone exhibits a variety of changes, such as
localized areas of necrosis, thrombosis of the blood
vessels, infiltration with mature and immature
leukocytes, occasional RBCs, and replacement of the
fatty marrow by fibrous tissue.
• Oral bleeding has been reported as a presenting sign
in 17.7% of patients with acute leukemia and in 4.4%
of patients with chronic leukemia. Bleeding may also
be a side effect of the chemotherapeutic agents used
to treat leukemia.

16. • In leukemia the response to bacterial plaque or
other local irritation is altered; the cellular
component of the inflammatory exudate differs
both quantitatively and qualitatively from that in
nonleukemic individuals.
• Granulocytopenia
• Discrete, punched-out ulcers penetrating deeply
into the submucosa and covered by a firmly
attached white slough can be found on the oral
mucosa.

17. • A study of 1076 adult patients with leukemia showed that 3.6% of the patients
with teeth had leukemic gingival proliferative lesions, with the highest incidence
in patients with acute monocytic leukemia (66.7%), followed by acute myelocytic-
monocytic leukemia (18.7%) and acute myelocytic leukemia (3.7%). It should be
noted, however, that monocytic leukemia is an extremely rare form of the
disease.

19. Acquired
neutropenia:
• An individual with an absolute neutrophil count (ANC) of
less than 1500 cells/μl is considered to be neutropenic.
o Neutropenia has numerous causes; it can be genetic or
drug induced or may result from a viral infection.
• There are three general guidelines used to classify the
severity of neutropenia based on the Absolute Neutrophil
Count (ANC) measured in cells per micro liter of blood:
• Mild neutropenia (1000 <= ANC < 1500) — minimal risk
of infection
• Moderate neutropenia (500 <= ANC < 1000) — moderate
risk of infection
• Severe neutropenia (ANC < 500) — severe risk of
infection

20. Types:
a)Length: acute, chronic.
b)State of medullar reserve: preserved or low.
c)Severity: mild, moderate or severe.
1)Acquired: medication:
•Anticonvulsant:
•Antihistaminic:
•Barbiturates.
•chemotherapeutic drugs
•Diuretics.
•Sulfonamides/antibiotics.
2) Congenital:
•Kostmann disease.
•Cyclic neutropenia.

21. Genetic disorders:
• Immune alterations: Cyclic neutropenia, severe congenital
neutropenia (SCN) or infantile genetic agranulocytosis or
Kostmann syndrome (IGA), Chediak-Higiashi syndrome,
Down syndrome, Papillon-Lefèvre syndrome,
hyperimmunoglobulinemia E syndrome, lazy leucocyte
syndrome, leucocyte adhesion deficiency, Cohen syndrome
• Connective tissue alterations: Ehler Danlos syndrome.
• Metabolic alterations: Glycogen storage disease,
Hypophosphatasia.

22. CHRONIC
BENIGN
NEUTROPENIA
It was first reported by Glansslen in 1941.
• prolonged noncyclic neutropenia as the
sole abnormality, with no underlying
disease.
• common form in infants and children less
than 4 years old, with 90% of the cases
presenting before 14 months of age.
Clinical manifestation:
• Individuals with this condition often have
increased incidences of otitis media, oral
ulcerations, furuncles, upper respiratory
infections, cellulitis, lymphadenopathy,
pneumonia, and sepsis as a result of
limited neutrophil response to infection

23. ORAL
MANIFESTATIONS –
Hyperplastic, fiery red
gingiva with areas of
desquamation confined to
attached gingiva.
Bleeding on mild
provocation, pocket
formation, premature loss of
deciduous teeth, bone loss,
increased mobility
Treatment included oral
hygiene instruction, scaling
and root planing, and an
antimicrobial mouthrinse
once a day. Three-month
recall/maintenance visits
were recommended.

24. Cyclic neutropenia:
• Cyclic neutropenia is a rare genetic disorder
characterized by a cyclical decrease in the number
of circulating 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.
• In humans, neutrophil elastase is encoded by the
ELA2 gene, and mutations in this gene may impede
neutrophil maturation.
• Autosomal-dominant inheritance.

25. The neutropenic phase is characteristically associated with clinical symptoms such as
recurrent fever, malaise, headaches, anorexia, pharyngitis, ulcers of the oral mucous
membrane and gingival inflammation
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 affected individuals
Combination treatment using granulocyte colony stimulating factor and nonsurgical
periodontal therapy may lead to an improvement of the periodontal condition of the
affected patients , Local antibiotic application in periodontal pockets was
recommended

26. Infantile genetic
agranulocytosis
or Kostmann’s
syndrome:
• Infantile genetic agranulocytosis is a rare autosomal
recessive disease caused by a defect in the
granulocyte colony-stimulating factor receptor.
• Children born with defects in granulocyte colony-
stimulating factor receptor cannot make neutrophils
and are therefore susceptible to infections, including
periodontal diseases.
• Only few studies described 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
severe alveolar bone loss.
• It has been suggested that a therapeutic regimen
consisting of scaling and root planing, soft-tissue
curettage and the use of selected antimicrobial
agents could be successful in the resolution of
periodontal infection in subjects inflicted with this
syndrome

28. Chediak–Higashi
syndrome
• Chediak–Higashi syndrome is a rare autosomal
recessive genetic disorder of granule
morphology and function affecting multiple
organ systems.
• Mutation in LYST gene(lysosomal trafficking
regulation) may be responsible.
• The pathological hallmark of Chediak– Higashi
syndrome is the presence, in all white blood
cells and in certain other cell types, of massive
lysosomal inclusions in the cytoplasm of the
cells

29. Manifestations:
• Subjects with Chediak–Higashi syndrome have
immune-system abnormalities, recurrent infections,
bleeding abnormalities and muscle weakness.
• Progressive damage to the peripheral nervous
system, partial albinism and sensitivity to light are
associated with the disease. Slight cognitive
impairment.
• 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.
• Treatment with bone marrow transplantation may
be helpful in correcting neutrophil dysfunction in
some patients

30. • Chediak–Higashi syndrome is associated with significant
periodontal symptoms, including profound gingival
inflammation, deep probing depth generalized to most of the
dentition and severe alveolar bone loss.
Ahmed Khocht et al Periodontitis Associated with Chediak-Higashi Syndrome in a Young African American
Male Journal of the International Academy of Periodontology 2010 12/2: 49–55

31. • Tempel et al. (1972) described two young Caucasian female patients with
severe gingival inflammation, tooth mobility and increased probing depth.
Histopathology of the gingival tissues showed heavy infiltration of chronic
inflammatory cells.
• Hamilton and Giansanti (1974) reported a case of CHS in a 10-year-old
African American boy. They described excessive early periodontal
breakdown, gingival swelling and tooth migration.
• Shibutani et al. (2000) reported a longitudinal follow-up of a case of a
young Asian female patient with severe gingival swelling and mobility. Their
attempts to control the periodontal problems were unsuccessful.

32. Leucocyte
adhesion
deficiency
• Leukocyte adhesion deficiency syndrome is a
rare immunodeficiency disorder inherited in an
autosomal-recessive trait and characterized by
defects in adhesion receptors of the white
blood cells.
• LAD type-I, the integrin is defective,
LAD type II, defects of the selectin system.
Clinical maifestations:
• skin infections, pneumonia and severe
periodontitis associated with very high
neutrophil blood counts (20–80 9 109 cells/l)
(neutrophilia).

33. Manifestations:
• Extremely acute inflammation and
proliferation of the gingival tissues with rapid
destruction of bone are found.
• Profound defects in peripheral blood
neutrophils and monocytes and an absence of
neutrophils.
• Frequent respiratory tract infections and
sometimes otitis media.
• Both primary and permanent teeth are
affected, often resulting in early tooth loss.

34. Clinical and radiographic appearance of patients with leukocyte adhesion deficiency (LAD
type 1). This disorder involves defects in neutrophil transendothelial migration, resulting
in a lack of extravascular neutrophils in periodontal lesions. However, dense infiltrates of
mononuclear leukocytes are found in the periodontal lesions

35. Lazy leucocyte
syndrome:
• Lazy leukocyte syndrome is a very rare
disorder that manifests in both
quantitative and qualitative neutrophil
defects. It is characterised by susceptibility
to severe microbial infections, and an
abnormal inflammatory response.
Etiopathology:
• The abnormal function of these
microfilaments leads to a defect in cell
deformability
• There is a severe neutropenia , defective
chemotaxis and random migration because
of defective microtubule integrity.

36. Manifestations:
• Painful stomatitis, gingivitis and recurrent ulcerations of the buccal
mucosa and tongue.
• Periodontitis progressing to the point of advanced alveolar bone loss
and tooth loss has been reported.
• Individuals diagnosed with lazy leukocyte syndrome are susceptible to
aggressive periodontitis .

37. Papillon–Lefèvre
syndrome
• Papillon–Lefevre syndrome is a rare genetic
disorder characterized by hyperkeratosis of the
palms, the soles of the feet, the elbows, the knees
and other organs, and, in addition, shows a rapidly
progressive, severe periodontitis that leads to early
loss of the primary and permanent teeth.
• 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.
• prevalence of the syndrome in the general
population is 1–3 per million, with no sex or race
preference.

38. Manifestations:
• The periodontal manifestations include gingival
inflammation, increased probing depth and
advanced radiographic alveolar bone loss.
• Typically, 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 cell.
• Lundgren et al. reported impaired salivary
secretions and somewhat altered salivary gland
function in children and young adults affected with
Papillon–Lefe `vre syndrome.

39. Pathogenesis
in
periodontitis:
Impaired neutrophil
functions, including
chemotaxis, phagocytosis
and bacterial killing, were
reported by some authors.
Severely depressed natural
killer cell cytotoxicity has
also been reported in
affected individuals.
Increased levels of
interleukin-1beta
Matrix metalloproteinase-
8 in gingival crevicular
fluid and atypical activity
of the plasminogen
activating system with a
disturbed epithelial
function in the gingival
tissues of affected
individuals.
It has been suggested that
the periodontal
destruction seen in
individuals with Papillon–
Lefe `vre syndrome might
be attributed to a defect in
the epithelial barrier
defense system.

40. Microbial
profile:
Subgingival microbial profile in individuals with papillon–lefe `vre
syndrome closely resembled a profile characteristic of deep pockets in
patients with chronic periodontitis.
Albandar et al. conducted a comprehensive analysis of the subgingival
microbiota in subjects with Papillon–Lefe `vre syndrome using 16S
ribosomal RNA clonal analysis and the 16S ribosomal RNA-based
Human Oral Microbe Identification Microarray and concluded that the
subgingival microbiota in these patients is diverse and comprises
periodontal pathogens commonly associated with chronic and
aggressive periodontitis as well as opportunistic pathogens, the most
prevalent of which included Gemella morbillorum, G. haemolysans,
Granulicatella adiacens, Lachnospiracease, Parvimonas micra,
Selenomonas noxia and Veillonella parvula.
Velazco et al. reported the presence of cytomegalovirus and Epstein–Barr
virus type 1 in the subgingival sample of a patient

41. Treatment:
• A combined approach including meticulous
plaque control, administration of
chlorhexidine in combination with a systemic
antibiotic therapy for the eradication of
known periodontal pathogens in conjunction
with retinoids seems to be most promising

42. Haim-Munk
syndrome
• Haim-Munk syndrome is an extremely rare
autosomal recessive disorder characterized clinically
by
1. Arachnodactyly (long, thin, and pointed fingers)
2. Acroosteolysis (bone loss in the fingers or toes)
3. Onychogryphosis (overgrowth of the fingernails
and toe nails and a claw-like deformity)
4. pes planus (flat foot); and
5. psoriasis-like lesions.
• Classified as type IV palmoplantar keratoderma
• Also called as “Cochin Jewish disorder.”

43. Erciyas K, Inaloz S, Erciyas AF. Periodontal
manifestations in a patient with haim-munk
syndrome. Eur J Dent. 2010 Jul;4(3):338-40.

44. Aswath N, Swamikannu B, Ramakrishnan SN, Shanmugam R, Thomas J, Ramanathan A. Heterozygous Ile453Val codon
mutation in exon 7, homozygous single nucleotide polymorphisms in intron 2 and 5 of cathepsin C are associated with Haim-Munk syndrome. Eur J
Dent 2014;8:79-84.

45. Treatment approach:
• A multidisciplinary approach is important for the care of patients with
HMS and PLS.
• The skin manifestations are treated with topical emollients and
keratolytics including salicylic acid and urea.
• Oral retinoids including acitretin, etretinate, and isotretinoin are the
mainstay of treatment for both keratoderma and aggressive
periodontitis.
• The periodontal disease in both HMS and PLS usually responds poorly
to treatment. Effective therapy includes the extraction of the primary
teeth combined with oral antibiotics and professional teeth cleaning.

47. Histiocytosis syndromes
• Disorder of the reticuloendothelial system
which is characterized by an abnormal
proliferation of histiocytes and eosinophilic
leukocytes.

48. Oral manifestation
Sore mouth, ulcerative lesions, halitosis.
The gingival tissues are often inflamed, hyperplastic, and ulcerated.
Loosening of teeth in the area of the affected alveolar bone - precocious exfoliation of teeth

50. Down’s
syndrome:
• Down’s syndrome is an autosomal
chromosomal anomaly resulting from
trisomy of the chromosome 21
• The most common manifestations of the
syndrome include a characteristic physical
appearance and varied mental and physical
disorders, including congenital heart
disease, thyroid dysfunction, Alzheimer
disease and alteration of the immune
system, including granulocyte ⁄ monocyte
cell dysfunction.
• Infections, and respiratory infections in
particular, are an important cause of
mortality in Down syndrome

51. Periodontal manifestations:
• Periodontal disease is a common manifestation among
subjects with Down syndrome, with an estimated
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.
• The disease starts early in life, progresses with age and
eventually leads to tooth loss
• A high prevalence of chronic inflammatory periodontal
disease in children with Down’s syndrome has previously
been described by Cohen et al. and Johnson & Young, but it
was first recognized by Brousseau

52. Pathogenesis:
• Mental disability associated with down
syndrome is an important factor in the reduced
ability of patients to maintain adequate oral
hygiene and leads to an increased susceptibility
to periodontitis .
• Khocht et al. recently used a multivariate model
that included assessment of mental disability
and traditional risk factors of periodontitis, and
showed that loss of periodontal attachment in
individuals with Down syndrome was not
associated with mental disability.

53. Pathogenesis:
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.
1
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.
2
The increased
periodontal
inflammation
would lead to
elevated
production of
degrading
enzymes and
alter bone
remodeling.
3
loss and
destruction of
the
periodontium
4 tooth loss

54. Microbial profile:
• Barr-Agholme et al. reported increased frequency of detecting Aggregatibacter
actinomycetemcomitans, Capnocytophaga and Porphyromonas gingivalis in the
subgingival plaque of adolescents
• Amano et al. detected various periodontal disease-causing bacteria in very young
subjects with Down syndrome concluded that certain periodontal pathogens,
particularly P. gingivalis, play a key role in the initiation of gingival inflammation.
• Reuland-Bosma et al. 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 periodontopathic bacteria were
established, and the authors conclude that host factors are the most likely
explanation for the advanced periodontal disease associated with subjects with
Down syndrome.
Conclusion: Despite the lack of differences in microbial profiles, adults with Down syndrome still show
greater loss of periodontal attachment than do adults who do not have Down syndrome. 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.

55. Immune response
Neutrophil function: studies suggest that deficient neutrophil chemotaxis is a common
finding in subjects with Down syndrome and that this defect may be secondary to
increased oxidative stress associated with trisomy of chromosome 21. The oxidative
stress may impair internal cell functions and disrupt chemotaxis. It has been shown that
reduced chemotaxis is positively correlated with the severity of periodontitis.
Gingival cellular immune response: 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. the low presence of
gamma ⁄ delta T lymphocytes may increase the vulnerability of subjects with Down
syndrome to microbial noxious agents.

56. Antibody ⁄ immunoglobulin
production
• studies show inconsistent antibody responses in saliva and serum in
individuals with Down syndrome.
• While the salivary antibody response was low, the serum antibody
response to several periodontopathic bacteria was elevated.
• The low salivary antibody response to bacteria is associated with
decreased salivary flow in individuals with Down syndrome, and this
may facilitate the colonization of periodontal pathogens.
• The elevated serum antibody titers corroborate the increased
gingival immune cellular activity described previously in subjects
with Down syndrome
• Increased antibody levels in gingival tissues may also accentuate the
gingival inflammatory response through complement activation and
thus contribute to tissue loss.

57. Inflammatory response
• Studies indicate increased matrix metalloproteinase activity in the gingival tissues
of individuals with Down syndrome.
• Matrix metalloproteinases are involved in the breakdown of the extracellular
matrix, and their increased activity in the gingival tissues of individuals with
Down syndrome 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.

58. Cohen’s
syndrome:
• Cohen syndrome is a rare genetic disorder with an
autosomal-recessive mode of transmission.
• The etiology of this disease is mutations in the
VPS13B gene (frequently called the COH1 gene).
• Almost all affected individuals have abnormally
low counts of white blood cells
(granulocytopenia), and the neutrophil is the cell
type particularly affected (neutropenia).
• The disease is characterized by intellectual
disability, developmental delay and a unique
physical appearance including narrow hands and
feet with long, slender fingers.
• Most affected individuals have truncal obesity
(deposition of fat around the midsection of the
body) and prominent upper central incisors.
• Because of the low white-blood-cell counts,
affected individuals are susceptible to infections,
including periodontitis

59. Alaluusua, S., Kivitie-Kallio, S., Wolf, J., Haavio,
M.-L., Asikainen, S., & Pirinen, S.
(1997). Periodontal Findings in Cohen Syndrome
With Chronic Neutropenia. Journal of
Periodontology

60. Hyperimmunoglobulin E disease:
• Hyperimmunoglobulin E syndrome is a multisystem disorder inherited
as an autosomal dominant trait that affects the dentition, the
skeleton, connective tissues, and immune system.
• Classically, it has been characterized by a triad of symptoms including
skin abscesses, pneumonia, and elevated serum immunoglobulin E
levels(IgE; usually >2,000 IU /ml).
• Eosinophilia, candidiasis, arthritis, chronic eczematoid dermatitis and
other recurrent infections are also common.
• Recurrent infection is one of the chief features of
hyperimmunoglobulin E syndrome.

61. Pathogenesis:
HIES patients may experience an aggravated course of
periodontitis because of defective polymorphonuclear
leukocytes, deficient antibody responses, and changes in
the T-helper (Th)1/Th2 balance towards a Th2 response.
The Th2 predominance may accelerate periodontal
breakdown through an overproduction of IgE.
The elevated IgE level, resulting from the Th2
predominance and reduced interferon-γ level, may cause a
release of bone-resorbing prostaglandin-E2, IL-1β, and
tumor necrosis factor-α from monocytic cells.
Altogether, rapid periodontal tissue destruction in HIES
patients could be due to the combined effect of highly
virulent periodontopathic bacteria, deficient
polymorphonuclear leukocytes responses, increases in
potent bone-resorbing cytokines, and decreases in bone
resorption inhibitory cytokines.

62. Oral manifestations:
• Oral ulcerations and periodontitis
• Surprisingly retention of primary dentition has been
reported which is different from other genetic
disorders.
• Management strategies continue to be: (1) prophylactic
antibiotics; (2) timely treatment of infections; and (3)
surgical intervention as necessary.

63. Agammaglobulinemia:
• Agammaglobulinemia, or hypogammaglobulinemia, is an immune
deficiency resulting from inadequate antibody production caused by a
deficiency in B cells. It can be congenital (X-linked or Bruton's
agammaglobulinemia) or acquired (common variable immunodeficiency).
• Congenital agammaglobulinemia is caused by an X-linked, recessive gene
(Bruton's tyrosine kinase). It affects approximately 1:100,000 population.
• The disease (congenital or acquired) is characterized by recurrent bacterial
infections, especially ear, sinus, and lung infections. Patients are also
susceptible to periodontal infections. Aggressive periodontitis is a common
finding in children diagnosed with agammaglobulinimia

64. Glycogen
storage
disease:
• 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.
• 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.
• There are two different subtypes of type 1
glycogen storage disease: type 1a and type 1b.
• Glycogen storage disease type 1b is an
autosomal-recessive disease caused by a
deficiency of microsomal glucose-6-phosphate
translocase.

65. 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.
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 glycogen
storage disease type 1b is
endoplasmic reticulum
stress generated by
disruption of endogenous
glucose production.
Patients with glycogen
storage disease type 1b
have neutropenia
accompanied by
progressive defects of
neutrophil functions,
such as chemotaxis and
respiratory burst.
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-
6phosphate translocase.

66. Clinical features:
• dolllike’’ facial appearance,
• stunted growth, hypoglycemia,
• ketosis, lactic acidosis, hyperlipidemia, gout,
bleeding episodes brought on by impaired platelet function secondary to metabolic
disorders .
• neutropenia, neutrophil dysfunction,
• The two most frequent symptoms of the disease include enlarged liver and
hypoglycemia.
• Patients with glycogen 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 literature

68. Hypophosphatasia:
• Hypophosphatasia (Rathbun-syndrome) is
a congenital disease with an autosomal-
mode of transmission and characterized by
deficiency of serum alkaline phosphatase,
increased urinary excretion of
phosphoethanolamine and defective bone
and tooth mineralization, resulting in
cementum hypoplasia or aplasia and
premature exfoliation of the primary
teeth.
• Deficiency of serum alakaline phosphatase
leads to leads to the accumulation of
extracellular pyrophosphate, and this
causes inhibition of skeletal and dental
mineralization.

69. Types:

70. Clinical signs:
• In the severe form the bone does not mineralize, resulting in stillbirth. Early loss
of teeth is common to most forms of hypophosphatasia.
• Of the childhood form early exfoliation of the primary teeth, skeletal deformities,
short stature, waddling 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. Chondrocalcinosis
and osteoarthropathy 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 symptoms. This latter form was termed
odontohypohypophosphatasia 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 phosphatase.
• Osteomalacia distinguishes adult hypophosphatasia from
odontohypophosphatasia.

71. Periodontal
manifestations:
• Patients with hypophosphatasia do not show
increased gingival inflammation or periodontitis and
their immune response to infections is not
defective.
• However, they have various dental deformities,
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. 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.

72. Hypophosphatasia: diagnosis and clinical signs–a dentalsurgeon perspective
AGNES BLOCH-ZUPAN
International Journal of Paediatric Dentistry 2016

73. • Baab et al. evaluated laboratory findings and concluded that the results showed
no manifested suppressed neutrophil chemotaxis in the children, but a
significantly suppressed monocyte chemotaxis was observed.

74. Ehlers–Danlos
syndrome:
• Ehlers-Danlos syndrome is rare
hereditary collagen disorder
characterized with
dermatological and joint
disorders.
• Genetic defect in collagen and
connective tissue sysnthesis.
• Skin,joints and blood vessels are
affected.
• 10 different inhereted disorders

75. Manifestations:

76. • Oral mucosa –fragile and bruised easily
• Gingival tissues –fragile ,bled easily ,gingival
hyperplasia,fibrous nodules,
• Aggressive periodontitis-early loss of tooth
Hypermobility of TMJ-dislocation of joint
• Irregular dentin ,enamel hypoplasia,pulp stones
• Studies have reported a
connection between the
inflammatory classic complement
pathway and connective tissue
homeostasis in the aetiology of
periodontal EDS.

77. Summary:

78. Conditions affecting immune system:
Disease Defect Clinical features
Familial benign chronic
neutropenia
Decrease(noncyclic)in absolute number of
neutrophil
Recurrent oral ulcers, otitis media, upper
respiratory tract infections, hyperplastic,
edematous, fiery-red gingival tissues
Cyclic neutropenia Decrease(cyclic) in production and release of
neutrophils
Periodic fever, malaise, oral ulcers;
gingivitis/periodontitis
Chediak-Hagashi
Syndrome
Altered migration, degranulation and
phagocytosis secondary to intracellular
megabodies (giant dysmorphicgranules)
Aggressive periodontitis, oral ulceration,
oculocutaneous albinism, recurrent infections,
bleeding tendencies
Papillon-LeFe `vre
syndrome
Variable–deficits in chemotaxis, phagocytosis,
and intracellular killing
Palmo plantar hyperkeratosis, severe aggressive
periodontitis, premature tooth loss
Haim munk syndrome Variable–deficits in chemotaxis, phagocytosis,
and intracellular killing
Palmo plantar hyperkeratosis, severe aggressive
periodontitis, premature tooth loss, acro
osteolysis, atrophic changes of nails and
radiographic deformity of fingers

79. Disease Defect Clinical features
Down’s syndrome Variable–deficits in chemotaxis,
phagocytosis and intracellular killing
Mental retardation, increased susceptibility to infection, cardiac
malformations, periodontitis
Congenital neutropenia
(Kostmann syndrome)
Arrested maturation of myeloid
lineage in marrow
Severere current infections in first year of life, AgP
Lazy leukocyte
syndrome
Neutropenia, depressed chemotaxis Recurrent infections, fever, cough, oral ulcers, skin abscesses,
gingivitis, periodontitis
Leukocyte adhesion
deficiency(type1)
Impaired adherence to vascular
endothelium; impaired phagocytosis
Delayed umbilical core separation, persistent infections in
absence of purulence, severe periodontitis ,fiery-red mucosa
Leukocyte adhesion
deficiency(type2)
Impaired rolling along vascular
endothelium
Short stature, mental retardation, recurrent infections, skeletal
abnormalities, likely periodontitis
Hyperimmunoglobulin E
(Job) syndrome
Reduced chemotaxis, increased IgE Skin‘‘cold’’abscesses, pneumonia, coarse facial skin,facial
asymmetry, deep-set eyes, oral ulcerations/gingivitis/
periodontitis
Histiocytosis syndromes abnormal proliferation of histiocytes Affects bones and other organs, periodontal lesions similar to
aggressive periodontitis, loss of alveolar bone, premature loss of
teeth, oral mucosal ulceration, delayed wound healing,
suppuration and halitosis,

80. Conditions with metabolic alterations:
Disease Defect Clinical features
Glycogen storage disease type1b defects in glycogen synthesis or breakdown
which lead to accumulation of glycogen
affecting neutrophil chemotaxis.
Oral ulceration and periodontitis have been
reported in affected patients due to severe
neutropenia and impaired neutrophil
migration
Hypophosphatasia deficiency of serum alkaline phosphatase,
leading to impaired bone and tooth
mineralisation
rickets or osteomalacia, cementum
hypoplasia or aplasia and premature loss of
the primary teeth with intact roots,
periodontitis
Conditions with connective tissue alterations
Disease Defect Clinical features
Ehlers–Danlos syndrome (EDS) type
IV and type VIII
abnormality of type I or III collagen joint hypermobility, skin fragility, easy
bruising, cardiovascular disorders and
variable musculoskeletal symptoms, AgP

81. Conclusion:
• Selected group of systemic disorders involving the mineralization of
bone and dental tissues or affecting neutrophil counts or function
can impact on the periodontium.
• Aggressive forms of periodontitis almost always accompany these
systemic diseases.
• When dealing with or suspecting these disorders, it is
recommended to establish a differential diagnosis and attempt to
identify the underlying causal factors.
• Proper diagnosis is a prerequisite for proper management of the
periodontal problem.
• To establish a diagnosis it is important to review the medical history,
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 genetic testing may be indicated and may
help validate a clinical diagnosis.

82. • In most of these diseases controlling 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
deficiencies, may bring about remedies of the
underlying genetic defects, and such treatments
may significantly improve the outcome of
periodontal treatment in these patients.

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