SlideShare verwendet Cookies, um die Funktionalität und Leistungsfähigkeit der Webseite zu verbessern und Ihnen relevante Werbung bereitzustellen. Wenn Sie diese Webseite weiter besuchen, erklären Sie sich mit der Verwendung von Cookies auf dieser Seite einverstanden. Lesen Sie bitte unsere Nutzervereinbarung und die Datenschutzrichtlinie.
SlideShare verwendet Cookies, um die Funktionalität und Leistungsfähigkeit der Webseite zu verbessern und Ihnen relevante Werbung bereitzustellen. Wenn Sie diese Webseite weiter besuchen, erklären Sie sich mit der Verwendung von Cookies auf dieser Seite einverstanden. Lesen Sie bitte unsere unsere Datenschutzrichtlinie und die Nutzervereinbarung.
Consanguinity is the quality of being descended from the same ancestor as another person. Consanguinity, kinship characterized by the sharing of common ancestors. The word is derived from the Latin consanguineus, “of common blood,” which implied that Roman individuals were of the same father and thus shared in the right to his inheritance. Most cases reported in the Middle East (Saudi Arabia) and India, but a few other reports in different areas of the world like Japan and Europe.
You need 2 copies of the recessive gene in order to express the recessive trait. Autosomal recessive: A genetic condition that appears only in individuals who have received two copies of an autosomal gene, one copy from each parent. The gene is on an autosome, a nonsex chromosome. The parents are carriers who have only one copy of the gene and do not exhibit the trait because the gene is recessive to its normal counterpart gene. If both parents are carriers, there is a 25% chance of a child inheriting both abnormal genes rr and, consequently, developing the disease. There is a 50% chance of a child inheriting only one abnormal gene rR and of being a carrier, like the parents, and there is a 25% chance of the child inheriting both normal genes RR.
This rare genetic disorder includes onset of severe periodontitis in the primary or transitional dentition. It is easily identified on clinical exam by the findings of hyperkeratosis of the palms of the hands and soles of the feet. (A thickening of the skin) These children can also get hyperkeratosis on other areas of the body such as elbows and knees and lower back.
PLS patients have a mutation of a gene that regulates production of enzyme cathespin C Gene is located on the long arm (q) of chromosome 11 (11q14) CTSC gene removes dipeptides from the amino-terminus of protein substrates and mainly plays an immune and inflammatory role. Cathepsin C is also known as dipeptidyl aminopeptidase I which plays an essential role in the activation of granule serine proteases expressed in bone marrow-derived effector cells of both myeloid and lymphoid series. Cathepsin C (dipeptidyl peptidase I) is an enzymatic protein belonging to the peptidase C1 family, Cathepsin C is a lysosomal cysteine proteinase It is composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. It requires chloride ions for activity and can degrade glucagon. Dipeptidyl peptidase is an enzyme that exists in two forms each of which catalyzes the hydrolysis of dipeptides from polypeptides. Cathepsin C, or dipeptidyl aminopeptidase I (EC 126.96.36.199), is a lysosomal protease capable of removing dipeptides from the amino terminus of protein substrates. Cathepsin C is a large (200 kD) oligomeric protein an oligomer consists of a limited number of monomer units &quot;a few”, in contrast to a polymer which, consists of an unbounded number of monomers Among immune cells, the CTSC message is expressed at high levels in polymorphonuclear leukocytes and alveolar macrophages and their precursors.
Perforin is a Membrane perturbing protein that mediates Granzyme entry into target cell cytoplasm, molecule of cell-mediated destruction of target cells. Perforin can permeabilize target cells directly as well as facilitate the delivery of granzymes which in turn induce apoptosis. Expressed at high levels in various immune cells including polymorphonuclear leukocytes, macrophages, and their precursors. Loss of appropriate function of cathepsin C gene results in altered immune response to infection and may effect integrity of junctional epithelium surrounding the tooth Polymorphonuclear neutrophils form a primary line of defense against bacterial infections using complementary oxidative and non-oxidative pathways to destroy phagocytized pathogens. The three serine proteases elastase, proteinase 3 and cathepsin G, are major components of the neutrophil primary granules that participate in the non-oxidative pathway of intracellular pathogen destruction. Neutrophil activation and degranulation results in the release of these proteases into the extracellular medium as proteolytically active enzymes, part of them remaining exposed at the cell surface. Extracellular neutrophil serine proteases also help kill bacteria and are involved in the degradation of extracellular matrix components during acute and chronic inflammation. But they are also important as specific regulators of the immune response, controlling cellular signaling through the processing of chemokines, modulating the cytokine network, and activating specific cell surface receptors. Neutrophil serine proteases are also involved in the pathogenicity of a variety of human diseases. These proteases are implicated in a wide variety of immune and inflammatory processes, including phagocytic destruction of bacteria and local activation or deactivation of cytokines and other inflammatory mediators. CTSC is also required for processing and activation of the T-lymphocyte granzymes A (GZMA; 140050) and B (GZMB; 123910), the key agents of T cell-mediated cell killing. The lack of a generalized T-cell immunodeficiency in PLS suggests that other pathways can compensate for loss of cathepsin C in most tissues. The PLS phenotype also suggests a role for cathepsin C in epithelial differentiation or desquamation. Aberrant epithelial differentiation may affect the junctional epithelium that binds the gingiva to the tooth surface, possibly weakening the mechanical barrier to periodontal pathogens . Cathepsin C expressed at high levels in various immune cells including polymorphonuclear leukocytes, macrophages, and their precursors Critical for appropriate immune response of myeloid and lymphoid cells Important in protein degradation and proenzyme activation in PMNs and T-cells CTSC also required for processing and activation of the T-lymphocyte granzymes A and B, the key agents of T cell-mediated cell killing Cathepsin C gene is expressed in the epithelial region (palms, soles, knees) and keratinized oral gingiva Important in structural growth and development of skin Loss of function of CTSC gene results in altered immune response to infection and may effect integrity of JE surrounding the tooth Absence of cathepsin C leads to: Loss of activity of the serine proteinases in PMNs of PLS patients Reduction in the amount of the proteins themselves Research in Medicine: Cathepsin C-deficient mice and humans, the N-terminal processing and activation of neutrophil elastase, cathepsin G and proteinase-3 is abolished and is accompanied by a reduction of protein levels. These findings demonstrate that near complete inhibition of multiple serine proteases can be achieved with cathepsin C inhibitors , and that cathepsin C inhibition represents a viable, but challenging approach for the treatment of neutrophil-based inflammatory diseases . (patients with chronic inflammatory diseases, such as atopic dermatitis, arthritis, and asthma)
Granzyme B and Perforin Induce Apoptosis in Target Cells Perforins : Upon release from Tc cell vesicles, these proteins self-assemble within the plasma membrane of the target cell, and form a pore . This pore can allow the passage of water and salt molecules, and damage the target molecule to a limited extend. In addition, these pores will allow the passage of the other class of cytotoxins, Granzyme into the target cell. Without granzymes, perforin has limited toxicity via osmosis. Granzyme: A group of serine/threonine proteases, including several iso-enzymes. Granzymes need to enter into the cytoplasm of the target cell, where they activate an intracellular protease pathway that eventually leads to apoptosis. If Granzymes are prevented from entering the target cell, in the presence or absence of perforin, the target cell survives. Cytotoxic T (Tc) cells are the main effector cells of Cell Mediated Immunity (CMI), i.e. in the elimination of infected cells. They perform their function by inducing Apoptosis in those cells that express their specific antigen:MHC I complex. Remember, once activated, Tc cells do not need co-stimulation. MHC I plus antigen is enough. Granzyme A, the most abundantly expressed Granzyme in CTLs, initiates Perforin-dependent events that lead to apoptosis It exists as a disulfide-linked homodimer and works in an independent yet synergistic manner with Granzyme B to initiate apoptosis. Granzyme A does not induce typical oligonucleosomal DNA fragmentation but elicits distinctive single stranded DNA nicks. Granzyme B is the most widely studied member of the Granzyme family, and it is a potent activator of Caspase-dependent and independent apoptosis. It is an Aspase, cleaving after aspartic acid residues, although hydrolysis is dependent upon extended substrate interactions with an optimal P4-P2 substrate. Granzyme B has an increasing array of cellular substrates that contribute to apoptosis. For instance, it initiates a Caspase-dependent pathway via cleavage of the Bcl-2 family member BID. Cleaved BID (tBID) then translocates to the mitochondria initiating Bax/Bak-mediated ??m and a release of Cytochrome c.102-105 Granzyme B may also indirectly initiate BID cleavage by targeting and activating Procaspase-8.106 Cytotoxic T cells (CTL) and natural killer (NK) cells share common cytotoxic pathways that are critical for defence against microbe-infected or transformed cells. It is now established that CTL/NK cells induce target cell death (apoptosis/necrosis) via two dominant mechanisms, a) granule exocytosis, associated with secretion of perforin (perf) and granzymes (gzm) A and B, and b) interaction of their Fas-ligand (FasL) with the Fas (death) receptor (Fas) on target cells. After specific recognition of peptide–MHC complexes, cytotoxic T lymphocytes release lytic granules that contain perforin and granzyme B. Perforin polymerizes and forms pores in the target cell membrane, while mannose 6-phosphate/insulin-like growth factor II receptor (man-6-P/IGF II R) allows granzyme B — a serine protease able to directly activate effector caspases and apoptosis — to enter the cell. Caspase activation is amplified by granzyme-mediated cleavage and activation of BID, a pro-apoptotic member of the BCL2 family that leads to cytochrome c release from mitochondria, allowing the formation of a high-molecular-weight complex that contains cytochrome c, APAF-1 and caspase-9, which activates downstream caspases (mitochondrial apoptotic pathway). This process is antagonized by BCL2 and BCL-XL.
Patients with PLS have a very complex subgingival microflora including recognized periodontal pathogens. No particular periodontopathogen is invariably associated with PLS. A mitogen is a chemical substance, usually some form of a protein, that encourages a cell to commence cell division, triggering mitosis. Chemotaxis: movement toward or away from a chemical stimulus. Chemotaxis is a cellular function, particularly of neutrophils and monocytes, whose phagocytic activity is influenced by chemical factors released by invading microorganisms. Phyagocytosis: the process by which certain cells engulf and destroy microorganisms and cellular debris. The process includes five steps: (1) invagination, (2) engulfment, (3) internalization and formation of the phagocyte vacuole, (4) fusing of lysosomes to digest the phagocytosed material, and (5) release of digested microbial products.
Many cells in our body are capable of phagocytosis, but only two are good enough to be considered professional: neutrophilic polymorphonuclear leukocytes (PMN, neutrophils) and macrophages, which are derived from monocytes The neutrophil is a small cell, about 9-10 µm in diameter, and is the most abundant leukocyte in blood, with mean concentrations of 4.4 x 106 cells/ml (about 1:1000 of the red blood cell concentration) accounting for 33-75% of all leukocytes.
Neutrophils are protective against periodontal disease. (example neutropenia) PMN- acute response myeloid-chronic response (macrophages and T-cells)
Leukocyte Defect Decreased phagocyte chemotaxis, phagocytosis, MPO deficiency, overproduction of superoxide, low integrin expression Diminished chemotaxin binding affinity NK, T-cell, monocyte problems Neutrophil locomotion defect Decreased migration toward a chemotactic factor Decreased random migration Decreased chemotactic and phagocytic function of neutrophils Leukocyte -a type of immune cell. Most leukocytes are made in the bone marrow and are found in the blood and lymph tissue. Leukocytes help the body fight infections and other diseases. Granulocytes, monocytes, and lymphocytes are leukocytes. Also called WBC and white blood cell. There are several different types of white blood cells. A major distinguishing feature of some leukocytes is the presence of granules; white blood cells are often characterized as granulocytes or agranulocytes: Granulocytes (polymorphonuclear leukocytes): leukocytes characterised by the presence of differently staining granules in their cytoplasm when viewed under light microscopy. These granules are membrane-bound enzymes which primarily act in the digestion of endocytosed particles. There are three types of granulocytes: neutrophils, basophils, and eosinophils, which are named according to their staining properties. Agranulocytes (mononuclear leucocytes): leukocytes characterized by the apparent absence of granules in their cytoplasm. Although the name implies a lack of granules these cells do contain non-specific azurophilic granules, which are lysosomes. The cells include lymphocytes, monocytes, and macrophages. NAPH oxidase deficiency- no perio disease
Aggressive Periodontitis of both primary and secondary dentitions
Similar to Localized Aggressive Juvenile Periodontits, PLS patients seem to have increased susceptibility to infections with periodontitis-associated pathogens such as A. actinomycetemcomitans. A. actinomycetemcomitans strains are classified into five distinct serotypes: a, b, c, d, and e. The serologic specificity is defined by the polysaccharides on the surface of the organism and the serotype-specific polysaccharide antigens (SPAs) are immunodominant antigens in the organism. The serotypes of A. actinomycetemcomitans strains may have differences in virulence potential. Serotype b-specific polysaccharide antigen of A. actinomycetemcomitans plays an important role in resistance to phagocytosis and killing by human polymorphonuclear leukocytes. Takahashi et al. (23) reported that the ability of SPAs from serotypes a and c to induce the release of interleukin-1 by murine macrophages is lower than that of SPA from serotype b. Pajukanta et al. (15) demonstrated variation in the antimicrobial susceptibility patterns of different serotypes of A. actinomycetemcomitans. Patients are usually infected by only one serotype, not multiple serotypes, and the serotypes are stable over time. The frequency distribution of A. actinomycetemcomitans serotypes differs among populations. In the United States, serotype b is detected more frequently than serotypes a and c in patients with localized juvenile periodontitis. Proportions of serotype b of A. actinomycetemcomitans are significantly greater in culture-positive patients with aggressive periodontitis than those with chronic periodontitis. Virulance factors: Host tissue cell adherence and invaion Elaboration of leukotoxin Collagenase Endotoxin (LPS) CDT Fibroblast-inhibiting factor Bone resorption-inducing factor
The repeat-in-toxin (RTX) family is a group of related protein toxins found in gram-negative bacteria, specific subset of the larger family of pore-forming toxins. Major effect: their pore-forming capacity, resulting in plasma membrane lesions and osmotic lysis. (named repeats b/c members of the family share a number of nonapeptide repeats that bind calcium, characterized by variable numbers of carboxyl-proximal repetitions of a nonapeptide motif LXGGXG(D/N)DX) Inhibit PMN migration and fxn and induction of expression of pro-inflamatory mediators. Cathepsin G is an enzymatic protein belonging to the peptidase or protease families, it is coded by the CTSG gene. Found in azurophil granules of neutrophilic polymorphonuclear leukocytes Participates in the killing and digestion of engulfed pathogens, and in connective tissue remodeling at sites of inflammation.
Lots of antibody, not effective Immunoglobins appear to be influenced by both genetic and environmental factors. IgG2 specific for high molecular weight lipopolysaccharide , targets sugar glycoprotein IgG2 is preferentially expressed in antibodies to carbohydrate antigens whereas IgG1 subclass is commonly associated with antibodies to protein antigens. Because of this association with carbohydrate antigens, values for IgG2 in serum are often used as an index of immunocompetence against carbohydrate antigens Antibodies assist in clearance by: opsonizing the organism allowing neutrophil Fc receptor-mediated recognition and killing facilitating complement deposition Antibodies that bind to surface antigens on a bacterium attract the first component of the complement cascade with their Fc region and initiate activation of the &quot;classical&quot; complement system. This results in the killing of bacteria in two ways. First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization ; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly . Adaptive immune responses: antigen-specific defense mechanisms that take several days to become protective and are designed to remove a specific antigen. This is the immunity one develops throughout life. 2 major branches of the adaptive immune responses: humoral immunity and cell-mediated immunity Humoral immunity involves the production of antibody molecules in response to an antigen and is mediated by B-lymphocytes. CMI involves production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells and cytokines in response to an antigen and is mediated by T-lymphocytes. Antibodies contribute to immunity in three ways: they prevent pathogens from entering or damaging cells by binding to them; they stimulate removal of pathogens by macrophages and other cells by coating the pathogen; and they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway. Antibodies that bind to surface antigens on a bacterium attract the first component of the complement cascade with their Fc region and initiate activation of the &quot;classical&quot; complement system. This results in the killing of bacteria in two ways. First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly.
Rapid generalized periodontal destruction of alveolar bone (primary and permanent teeth), the bottom pan is a younger patient who has prematurely lost their primary molars before the premolars have had a chance to erupt. Palmar-plantar hyperkeratosis Group of disorders known as palmar plantar keratodermas (PPK) are characterized by diffuse or localized hyperkeratosis of the palms and soles with additional skin abnormalities. Clinically three patterns have been identified: diffuse over the palm and sole, focal with large keratin masses at points of friction, and punctate with tiny drops of keratin on the palmoplantar surface.
There are a number of additional features reported in Haim-Munk syndrome that include: long, thin, pointed fingers (arachnodactyly) bone loss in the fingers or toes (acroosteolysis) abnormal changes of the nails a claw-like deformity of the hands Mutation of cathepsin C gene Closely related disease to PLS, also exhibits palmoplantar keratosis, progressive periodontal disease, recurrent skin infections, and several skeletal malformations The skin manifestations are more severe and periodontal disease is milder than PLS A normal life span has been reported for individuals with Haim-Munk syndrome
While cases of PLS had been identified throughout the world, HMS had been described only in members of the Jewish religious isolate from Cochin, India. Haim-Munk syndrome is also known as Cochin Jewish disorder or congenital keratosis palmoplantaris. Haim-Munk syndrome is a rare genetic disorder characterized by the development of red, scaly thickened patches of skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), frequent pus-producing (pyogenic) skin infections, overgrowth (hypertrophy) of the fingernails and toenails (onychogryposis), and degeneration of the structures that surround and support the teeth (periodontosis). Periodontosis usually results in the premature loss of teeth. Additional features associated with the disorder may include flat feet (pes planus); abnormally long, slender fingers and toes (arachnodactyly); loss of bone tissue at the ends of the fingers and/or toes (acroosteolysis); and/or other physical findings. Haim-Munk syndrome is inherited as an autosomal recessive trait.
Prepubertal periodontitis (PPP) is a rare and rapidly progressive disease of young children that results in destruction of the periodontal support of the primary dentition Identification of a cathepsin-C missense mutation indicates that this form of non-syndromic prepubertal periodontitis is also an allelic variant of type-IV palmoplantar ectodermal dysplasia (like PLS) The radiographic presentation of alveolar bone loss in prepubertal periodontitis in many cases appears similar to that observed in PLS, but it is differentiated from PLS by the absence of associated palmoplantar keratoderma Prepubertal periodontitis is another rare genodermatosis with an etiology attributed to a cathepsin-C gene mutation. It is characterized by rapidly progressive early-onset periodontitis with destruction of the periodontium of the deciduous and permanent teeth. Prepubertal periodontitis may be localized or generalized . It may occur as part of a recognized syndrome or as an isolated non-syndromic disorder . Both autosomal dominant and autosomal recessive patterns of familial transmission have been described for prepubertal periodontitis. Identification of a cathepsin-C missense mutation indicates that this form of non-syndromic prepubertal periodontitis is also an allelic variant of type-IV palmoplantar ectodermal dysplasia. The radiographic presentation of alveolar bone loss in prepubertal periodontitis in many cases appears similar to that observed in PLS, but it is differentiated from PLS by the absence of associated palmoplantar keratoderma The classical diagnostic feature of generalized form of prepubertal periontitis is the fiery red acute inflammation pervading the marginal and attached gingiva around all the teeth, gingival proliferation, cleft formation, and recession. Onset is at the time of tooth eruption. Alveolar bone destruction may couple with the destruction of the tooth root and occurred at the alarming rate. Peripheral white blood cell count is markedly elevated
Neutrophils from patients with localized juvenile periodontitis (LJP) show several functional abnormalities LJP is localized to certain anterior or front teeth and first molars, and is seen following puberty, often clustered within families Genetic predisposition identified as a neutrophil defect associated with reduced chemotaxis Patient with localized juvenile periodontitis have antibodies specific to the antigenic determinants of the Actinobacillus actinomycetemcomitan . Children with a neutrophil chemotactic defect become colonized by A actinomycetemcomitans in early life, presumably by contact with infected household members. The colonization spreads to those permanent teeth that erupted at ages 5 to 7, but remains quiescent as an infection during the time that the primary or baby teeth are lost, and new permanent teeth appear at about ages 11 to 13. The individual entering puberty, has a dentition composed of first molars and incisors that are colonized by A. actinomycetemcomitans and newly erupted teeth that either are not colonized or only minimally colonized. The LJP patient must be strictly controlled in terms of oral hygiene and a proper maintenance program.
PLS Additional symptoms and findings associated with PLS may include frequent pyogenic skin infections, nail dystrophy, and excessive perspiration (hyperhidrosis).
The palmoplantar keratoderma typically has onset between the ages 1 to 4 years The sharply demarcated erythematous keratotic plaques may occur focally, but usually involve the entire surface of palms and soles resulting in foul-smelling odor Well-demarcated psoriasiform plaque occur on elbows and knees, this may worsen in winter and be associated with painful fissures
Emollients are substances that soften and soothe the skin. They are used to correct dryness and scaling of the skin. They are a key component in the manufacture of lipstick, lotions, and other cosmetic products. Emollients are key ingredients in moisturizers and cleansers. They are chemicals that remain in the stratum corneum to act as lubricants. They help maintain the soft, smooth, and pliable appearance of the skin. Emollients are often thought of as &quot;filling in the crevices&quot; between corneocytes that are in the process of desquamation (shedding). The emollient used in a moisturizer plays a key role in its &quot;skin slip,&quot; the smooth feeling imparted to the skin after application. Salicylic acid is a keratolytic (peeling agent). Salicylic acid causes shedding of the outer layer of skin. Urea is an emollient (skin softening agent). Urea helps to moisturize the skin. The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth. any of a large class of natural or synthetic, photosensitive chemical compounds that are similar to vitamin A, including retinoic acid and retinal Oral retinoids such as acitretin, etretinate, and isotretinoin were reported to be beneficial for both dental and cutaneous lesions of PLS. Retinoid treatment may end up with normal dental development if started during eruption of permanent teeth ACITRETIN is used to treat severe psoriasis. This medicine is not a cure, but it helps reduce the redness, thickness, and scaling that occur with psoriasis. This medicine can cause serious side effects, including birth defects if given to someone who is pregnant. The oral retinoids isotretinoin (Accutane) and etretinate are uniquely effective in the treatment of severe cystic acne and keratinisation disorders. Because of their known teratogenicity, there are strict prescription guidelines Efficacy and toxicity of oral retinoids in the pediatric population. The acute mucocutaneous toxicities commonly observed are typically well tolerated, readily treatable, and reversible. Systemic toxicities include teratogenicity and effects on the musculoskeletal, neurologic, and gastrointestinal systems. Children, like adults, generally tolerate short-term retinoid therapy without major complications. Concerns regarding serious systemic side effects are greater for those on high doses of oral synthetic retinoids for longer periods of time. Close patient monitoring and patient education can minimize the occurrence of complications. Retinoids have been a mainstay of acne therapy for decades, starting with systemic therapy with oral vitamin A (retinol). Oral isotretinoin, discovered in the late 1960s, affects all the underlying pathophysiologic processes of acne and would be the ideal treatment if it did not have significant side effects. (2,9) During oral isotretinoin therapy, sebum production is reduced by 90% or greater. (1,9) As a result, P. acnes levels decrease substantially. As well as decreasing the size and secretion of the sebaceous glands, isotretinoin also normalizes follicular keratinization and prevents the formation of new comedones. (1,9) Isotretinoin also evidences anti-inflammatory effects. However, because of its toxicity, it is usually reserved for severe nodular acne. (1,9) Current trends favor its use in recalcitrant moderate acne. (9) Common adverse effects with oral isotretinoin include dry chapped lips, and dry skin and eyes, and secondary skin infections are not uncommon. Some patients have muscle aches and back aches, and some have mild headaches at the start of therapy, but these often resolve during the course of treatment. It is not clear whether depression and other significant psychiatric side effects are a consequence of isotretinoin therapy. Isotretinoin is a potent teratogen, and women of childbearing age must not start therapy until a negative pregnancy test result has been obtained.
Early onset of severe periodontitis Onset of severe periodontitis in the primary or transient dentition Major feature of PLS is severe periodontitis, which starts at the age 3 or 4 years. Development and eruption of deciduous teeth proceeds normally, but their eruption is associated with gingival inflammation and subsequent rapid destruction of the periodontium. The resulting periodontitis is unresponsive to traditional periodontal treatment modalities and the primary dentition is usually exfoliated prematurely by age 4 to 5 years . After exfoliation, the inflammation subsides and gingiva appears healthy. However, with eruption of the permanent dentition the process of gingivitis and periodontitis is usually repeated and there is subsequent premature exfoliation of the permanent teeth. The third molars are sometimes spared. Without treatment, most of the permanent teeth may also be lost by age 17. Accelerated periodontitis appears to be caused by defects in neutrophil function and multiple immune mediated mechanisms The cause of the periodontal disease and increased susceptibility to infection is attributed to decreased neutrophil phagocytosis, bacterial infection, and impaired reactivity to T- and B-cell mitogens. Radiographic features are characterized by generalized loss of alveolar bone, rapid boneloss.
Treatment may be more beneficial if it is started during the eruption and maintained during the development of the permanent teeth Therapy: aggressive local measures to control plaque including rigorous oral hygiene, chlorhexidine mouth rinses, frequent professional prophylaxis, and periodic appropriate antibiotic therapy needed for long-term maintenance The periodontitis in PLS is usually difficult to control. Effective treatment for the periodontitis includes extraction of the primary teeth combined with oral antibiotics and professional teeth cleaning It is reported that etretinate and acitretin modulate the course of periodontitis and preserve the teeth Amox + Clavulanate = Augmentin Therapy includes: scaling and root planing oral hygiene instruction systemic amoxicillin-metronidazole therapy (250 mg of each/3 times daily/10 days) which, based on follow-up microbiological testing, should be repeated after 4 months Oral retinoids, such as acitretin and isotretinoin
Treatment may be more beneficial if it is started during the eruption and maintained during the development of the permanent teeth Therapy: aggressive local measures to control plaque including rigorous oral hygiene, chlorhexidine mouth rinses, frequent professional prophylaxis, and periodic appropriate antibiotic therapy needed for long-term maintenance The periodontitis in PLS is usually difficult to control. These patients often end up wearing dentures or and implant-supported prosthesis
Pyogenic liver abscess is increasingly recognized as a complication of PLS because of impairment of the immune system. The risk of pyogenic liver abscess should be kept in mind in evaluating these patients when they present with fever of unknown origin. A liver abscess can develop from several different sources, including a blood infection, an abdominal infection, or an abdominal injury which has been become infected. The most common infecting bacteria include E. coli, Enterococcus, Staphylococcus and Streptococcus. Treatment is usually a combination of drainage and prolonged antibiotic therapy. A course of antibiotics should be tried to control the active periodontitis in an effort to preserve the teeth and prevent bacteremia and subsequently pyogenic liver abscess. Pyogenic liver abscess usually results from the seeding of the liver by pathogenic bacteria through a hematogenous route. The most common etiologic agent is S aureus, and most often a solitary abscess is found.Liver abscess may also result from contiguous spread of infection from within the liver or from an adjacent inflamed organ. In this setting, the infection is usually polymicrobial with Gram-negative enterics and anaerobes forming multiple liver abscesses. Unexplained or cryptogenic hepatic abscess accounts for ~20% of cases. Bacteremia occurs in normal and immunocompromised hosts; however, it is usually transient and rarely seeds the liver in immunocompetent individuals. Bacteremia during periods of extensive periodontal inflammation associated with the abnormal polymorphonuclear chemotaxis and oxygen consumption are known to occur in PLS patients. These 2 factors likely contribute to the development of the liver abscess. In our patient, the inflamed gingiva was the likely point of entry of S aureus that led to bacteremia and subsequently the liver abscess. Different immunologic defects have been described in patients with PLS..
Papillon-Lefèvre Syndrome Ashley L. Paulus, DDS
Papillon-Lefèvre Syndrome Ashley L. Paulus, DDS Pediatric Dentistry Resident April 13, 2009
Papillon-Lefèvre Syndrome <ul><li>First described by two French physicians, Papillon and Lefèvre, in 1924 </li></ul><ul><li>Prevalence of 1-4 cases per million persons </li></ul><ul><li>Consanguinity between parents in 1/3 of cases </li></ul><ul><li>Males and females are equally affected with no racial predominance </li></ul><ul><li>Rare genetic disorder </li></ul><ul><li>Autosomal recessive </li></ul>
Papillon-Lefèvre Syndrome <ul><li>Rapid generalized periodontal destruction of alveolar bone (primary and secondary dentition) </li></ul><ul><li>Palmar-plantar hyperkeratosis </li></ul>
CTSC gene <ul><li>In humans, Cathepsin C is coded by the CTSC gene </li></ul><ul><li>Located on chromosome 11q14-q21 </li></ul><ul><li>Encodes a cysteine-lysosomal protease known as dipeptidyl-peptidase I or Cathepsin C </li></ul><ul><ul><li>Appears to be a central coordinator for activation of many serine proteinases in immune/inflammatory cells </li></ul></ul>
Cathepsin C <ul><li>Found in PMN and leukocyte granules, important in protein degradation and proenzyme activation in PMNs and T-cells </li></ul><ul><ul><li>CTSC required for processing and activation of the T-lymphocyte granzymes A and B, the key agents of T cell-mediated cell killing </li></ul></ul><ul><ul><li>Activator of the PMN-derived serine proteinases elastase, cathepin G, and proteinase 3 </li></ul></ul><ul><ul><ul><li>These serine proteases are implicated in a wide variety of immune and inflammatory processes </li></ul></ul></ul><ul><li>A lack of functional cathepsin C may be associated with a reduced host response against plaque bacteria </li></ul>
Papillon-Lefèvre Syndrome <ul><li>The exact cause of periodontal disease in PLS has not been found but it has been attributed to: </li></ul><ul><ul><li>Neutrophil defects: </li></ul></ul><ul><ul><ul><li>Decreased neutrophil chemotaxis and phagocytosis </li></ul></ul></ul><ul><ul><li>Bacterial infection </li></ul></ul><ul><ul><ul><li>A. actinomycetemcomitans </li></ul></ul></ul><ul><ul><li>Natural killer cell defect: </li></ul></ul><ul><ul><ul><li>Cytotoxicity </li></ul></ul></ul>
Immunology <ul><li>Neutrophils create a barrier along the junctional epithelium and within the gingival crevice </li></ul><ul><li>Neutrophils are the first line of defense against dental plaque microorganisms </li></ul>
Neutrophils and Periodontal Disease <ul><li>Evidence that neutrophils are protective against periodontal destruction: </li></ul><ul><ul><li>First, primary neutrophil or myeloid abnormalities have been associated with severe periodontal destruction. </li></ul></ul><ul><ul><li>Second, otherwise healthy individuals with severe periodontal problems appear to have subtle defects in their neutrophils. </li></ul></ul><ul><ul><li>Third, experimental neutropenia in animals leads to rapid periodontal infection. </li></ul></ul>
A. actinomycetemcomitans <ul><li>Facultatively anaerobic nonmotile gram-negative rod </li></ul><ul><li>Produces virulence factors to promote its colonization and survival </li></ul><ul><ul><li>Leukotoxin is the prime virulence factor of A.a. </li></ul></ul><ul><li>Five distinct serotypes of A.a. </li></ul><ul><ul><li>Serotype B most commonly associated with diseased sites </li></ul></ul>
A. a. Leukotoxin <ul><li>116-kDa pore-forming leukotoxin belonging to the repeat-in-toxins (RTX) </li></ul><ul><ul><li>Effects myeloid cells, such as PMNs and monocytes, and causes degranulation </li></ul></ul><ul><li>Cathepsin G and elastase from PMNs degrade this toxin extracellulary </li></ul><ul><ul><li>Cathepsin C activates the PMN-derived serine proteinases elastase and cathepsin G </li></ul></ul><ul><ul><li>Decreases PMN ability to neutralize leukotoxin </li></ul></ul>
IgG2 <ul><li>Alteration in immunoglobins present in PLS </li></ul><ul><li>Elevated levels of salivary and serum IgG2 antibody to A.a. in PLS </li></ul><ul><ul><li>Serum antibody IgG2 = weak complement fixation activity and poor opsonization compared to other IgG subclasses </li></ul></ul><ul><li>IgG2 production dependant upon Th1 </li></ul>Name Percent Crosses placenta easily Complement activator Binds to Fc receptor on phagocytic cells IgG1 70% Y second highest high affinity IgG2 20% N third highest extremely low affinity IgG3 8% Y highest high affinity IgG4 2% Y N intermediate affinity
PLS vs Haim-Munk Syndrome PLS HMS Cathepsin C gene mutation 2126C T substitution 2127A G substitution Palmoplantar keratosis Y Y Progressive periodontal disease Y (more severe) Y Arachnodactyly N Y acroosteolysis N Y <ul><ul><li>Abnormal changes of the nails </li></ul></ul>N Y <ul><ul><li>A claw-like deformity of the hands </li></ul></ul>N Y
PLS vs Non-Syndromic Prepubertal Periodontitis PLS NS-PPP Cathepsin C gene mutation 2126C T substitution 1040A G substitution Palmoplantar keratosis Y N Progressive periodontal disease Y Y Teeth effected Generalized Generalized or Localized Patterns of familial transmission AR AD and AR
PLS vs LJP PLS LJP CTSC gene defect Y N A. a. Y Y Reduced chemotaxis Y Y PMN defect Y Y Teeth effected Generalized Localized
Hyperkeratosis of the palms of the hands and soles of the feet
Dermatologic Treatment <ul><li>A multidisciplinary approach is important for the care of patients with PLS, skin manifestations are usually treated with emollients </li></ul><ul><li>Salicylic acid and urea may be added to enhance their effects </li></ul><ul><li>Oral retinoids including acitretin, etretinate, and isotretinoin are used in treatment of both the keratoderma and periodontitis associated with PLS </li></ul>
Periodontal Treatment <ul><li>Early treatment and compliance with the prevention program are the major determinants for preserving permanent teeth in young PLS patients </li></ul><ul><li>By extracting all primary teeth and eradicating periodontal pathogens the patients adult teeth can erupt into a safe environment </li></ul>
References <ul><li>Ullbro C, Brown A, Twetman S. Preventive Periodontal Regimen in Papillon-Lefèvre Syndrome. Pediatric Dentistry 27:3, pages 226-231, 2005. </li></ul><ul><li>Yang, H. W., Asikainen, S., Dogan, B., Suda, R., Lai, C. H. Relationship of Actinobacillus actinomycetemcomitans serotype b to aggressive periodontitis: frequency in pure cultured isolates. Journal of Periodontology, Taichung, Taiwan. www.pubmedcentral.nih.gov/articlerender.fcgi?artid=88070 </li></ul><ul><li>Burne R, Lamont R, Lantz M, LeBlanc D. Oral Microbiology and Immunology. ASM Press. Washington, DC. 2006. </li></ul><ul><li>Hart TC, Shapira L. Papillon-Lefèvre syndrome. Periodontol 2000. 1994 Oct;6:88-100. </li></ul><ul><li>Gorlin RJ, Sedano H, Anderson VE. The syndrome of palmar-plantar hyperkeratosis and premature periodontal destruction of the teeth. J Pediatr 1964;65:895-908. </li></ul><ul><li>Rüdiger S, Petersika G, Fleming F. Combined systemic and local antimicrobial therapy of periodontal disease in Papillon-Lefevre syndrome. A report of 4 cases. J Clin Periodontol 1999;26:847-54. </li></ul><ul><li>Cury VF, Costa JE, Gomez RS, Boson WL, Loures CG, De ML. A Novel Mutation of the Cathepsin C Gene in Papillon-Lefevre syndrome. J Periodontol 2002;73:307-12. </li></ul><ul><li>Lundgren, T., Parhar, R.S., Renvert, S., Tatakis, D.N. (2005). Impaired Cytotoxicity in Papillon-Lefevre Syndrome. JDR 84: 414-417 </li></ul><ul><li>Moore SW, Millar AJW, Cywes S. Conservative initial treatment for liver abscesses in children. Br J Surg.1994; 81 :872 –874 </li></ul><ul><li>Noack, B., Gorgens, H., Hoffmann, Th., Fanghanel, J., Kocher, Th., Eickholz, P., Schackert, H.K. (2004). Novel Mutations in the Cathepsin C Gene in Patients with Pre-pubertal Aggressive Periodontitis and Papillon-Lefevre Syndrome. JDR 83: 368-370 </li></ul>