Systemic conditions associated with periodontitis in childhood and adolescence.
A review of diagnostic possibilities
Condiciones sistémicas asociadas con periodontitis en la infancia y la adolescencia.
Una revisión de las posibilidades diagnósticas

 

Thomas P. Sollecito ⁽¹⁾, Kathleen E. Sullivan ⁽²⁾, Andres Pinto ⁽³⁾, Jeffrey Stewart ⁽⁴⁾, Jonathan Korostoff ⁽⁵⁾

(1) Profesor Asociado. Associate Professor, Oral Medicine. University of Pennsylvania
(2) Profesor Asociado. Associate Professor, Immunology. The Children's Hospital of Philadelphia
(3) Director, Medically Complex Patient Care. University of Pennsylvania
(4) Profesor Asociado. Associate Professor, Oral Pathology. University of Oregon
(5) Profesor Asociado. Associate Professor, Periodontics. University of Pennsylvania

Address:
Andres Pinto DMD
240 S. 40th St.
Robert Schattner Center
Philadelphia, Pennsylvania 19104
Phone:215.572.2440 / Fax:215.573.7853
E-mail: apinto@pobox.upenn.edu

Received: 28-05-2004. Accepted: 10-10-2004

 

 

INTRODUCTION

In the past, clinicians distinguished between adult and early onset forms of periodontitis. The clinical manifestations of adult forms of the disease were defined as appearing during the fourth decade of life and tended to display a relative slow rate of progression. In contrast, the early onset diseases occurred during the first, second or third decades and exhibited a rapid rate of periodontal destruction. The early onset forms of disease were further classified as prepubertal, juvenile or rapidly progressive periodontitis, each of which may have involved isolated teeth (localized) or the entire dentition (generalized). In order to address perceived inadequacies in the existing diagnostic nomenclature, a World Workshop was convened in 1999 to reclassify the various periodontal diseases and conditions. (1) In addition to many other changes, the terms adult and early-onset periodontitis were eliminated. Periodontitis is now classified as either chronic, aggressive, or as being a manifestation of systemic disease. (1)

SYSTEMIC CONDITIONS ASSOCIATED WITH PERIODONTITIS

Systemic disorders that might present as rapidly destructive periodontal disease can be loosely divided into those patients with hematologic abnormalities and those without any hematologic alteration (Table 1). Hematologic abnormalities often involve alteration in leukocyte function or number and include disorders of neutrophils, macrophages and T lymphocytes. Non-hematologic disorders affecting the pediatric periodontium include diabetes, hypophosphatasia, Langerhan's cell histiocytosis, and other genetic syndromes. (2) This paper describes medically significant disorders associated with periodontal disease.

HEMATOLOGIC ABNORMALITIES

Primary Immunodeficiencies

Primary immunodeficiencies are genetic disorders that affect the immune system. As a result,there is a weakened response against self antigens, infections and neoplasms. This review will focus on select primary immunodeficiency syndromes with reported periodontal manifestations.

- Lymphocyte Deficiencies: T-Lymphocytes and Combined Deficiencies

Many of the inherited pediatric T-cell disorders are associated with a predisposition to periodontal disease. The mechanism underlying this association is not well understood. Hypotheses include dysregulated cytokine production by the impaired T-cells, which facilitates bone loss or infection by unusual organisms. There is experimental support for both of these hypotheses. Overproduction of both IL-1 and tumor necrosis factor has been implicated. (3,4) In addition, it is likely that there are secondary humoral and neutrophil abnormalities in the setting of profound T-cell dysfunction.

The number of patients with significant inherited T-cell disorders is small and they are often treated with a curative bone marrow transplant (BMT) before periodontal disease can establish itself. It has been assumed that the mechanisms underlying the association of periodontal disease to these conditions are the same as in secondary immunodeficiency states such as HIV. Therefore, it is likely that periodontal disease can be seen in any setting where T-cell function is compromised, including secondary deficiencies such as those seen in lymphoma and malnutrition.(5) One of the inherited disorders specifically known to be associated with gingivitis and periodontitis is Wiskott-Aldrich syndrome, an X-linked disorder presenting with thrombocytopenia, defective cellular and humoral function and eczema. (6) Patients with ataxia telangiectasia often develop periodontal disease as they age. In this disorder, patients present with ataxia at about a year of age, ocular telangiectasias at about seven years of age, and have progressive immunodeficiency. Originally propsed as an humoral deficiency, hyper IgM has a T-cell component, due to the appearance of fungal infections and Pneumocystis carinii pneumonia. (7) Hyper IgM is associated with recurrent aphthous ulcers, recurrent sinopulmonary infections. (8) Over time, the aphthous ulcers can begin to erode the gingiva and may mimic periodontal disease. Generally, these three disorders have a mild predisposition to periodontal disease and the other features of the immunodeficiency are dominant. Other primary T cell disorders may be associated with periodontal disease, although it is seldom a defining feature.

- Antibody Deficiencies

Agammaglobulinemia is an X-linked immune deficiency. The genetic defect results in failure of maturation of pre-B cells into B cells. Few studies have observed a positive relationship between agammaglobulinemia and periodontal disease. Reports in the early 70's describe gingival inflammation and ulceration, but case series published in the 90's failed to support this association. Job's Syndrome (hyper-immunoglobulinemia E) is another rare genetic condition in which an unknown defect leads to aberrant chemotaxis. (9) In each case, periodontal disease may be seen. In the case of hyperimmunoglobulinemia E syndrome, failure to shed primary teeth and other developmental defects of dentition are also seen. No association has been reported between common variable immune deficiency (CVID), IgA deficiency, and periodontal disease. However, oral mucosal ulcerations and lichenoid-like lesions have been reported in these patients.

- Phagocyte Defects

Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency (LAD) is a group of functional neutrophil disorders. (10) These disorders are caused by inherited defects in the expression of adhesion molecules leading to a defect in the neutrophil's ability to leave the vascular space. There are at least three genetic types of LAD. In LAD I, aberrant expression of ß 2 integrins impairs emigration from the bloodstream. In LAD II, sialyl- Lewis X is deficient leading to poor rolling with failure to stick to venule endothelium. In LAD I variant, the defect is somewhat milder and while ß2 integrin expression is intact, adhesive function via these integrins is impaired. In all three cases, PMNs are not able to adhere or emigrate properly even in the presence of the appropriate chemotactic factors. LAD is also associated with a defect in the neutrophil's ability to process opsonized particles. (11) LAD is clinically associated with susceptibility to systemic infections in infancy, especially recurrent staphylococcal and gram negative bacterial infections. Patients with LAD usually have a baseline neutrophilia and the most universal feature of LAD is rapidly destructive periodontal disease resulting in significant bone loss and ultimately tooth loss. (12,13) In the milder cases of LAD, periodontal disease is often the presenting symptom and is often the most troubling feature.

-Chronic granulomatous disease

Chronic granulomatous disease (CGD) is a group of genetic disorders in which neutrophils, monocytes, basophils, eosinophils and macrophages are able to phagocytose but are not able to kill certain bacteria and most fungi. There is a defect in the microbicidal activity due to mutations in the components of NADPH oxidase, an enzyme necessary for leukocytes to produce superoxide. (14) There are five genetic types of CGD, but all are associated with defective superoxide production and the same range of infections. Patients with this disorder are often susceptible to fungal infections. Recurrent or persistent infections may affect many organ systems including the lymph nodes, lung, liver, spleen, bone and skin. (14) This disorder clinically presents with a significant gingivitis. Periodontal disease with bone loss has not been described. Patients are also known to develop recurrent aphthous-like ulcerations of the oral mucosal membranes.

-Chediak Higashi Syndrome

Chediak Higashi Syndrome is a rare, often fatal, autosomal recessive disorder that features abnormal giant lysosomal granules within the leukocytes. (15,16) Patients are also typically mildly neutropenic. The giant granules form secondary to a defect in lysosomal trafficking. Consequently, intracellular killing and chemotaxis are defective. In addition, patients with Chediak Higashi Syndrome have impaired natural killer cell function, multiple recurrent bacterial infections, and oculocutaneous albinism. These patients have an increased tendency for post operative bleeding and may have peripheral neuropathy. Chediak-Higashi syndrome is typically recognized by early childhood and treated with bone marrow transplantation which eliminates the predisposition to periodontal disease. Milder forms may have a later presentation and develop extensive periodontal disease before diagnosis.

Other Disorders Affecting the Numbers of Neutrophils and/or Macrophages

-Congenital Agranulocytosis

In addition to disorders of neutrophil function, there are disorders associated with low neutrophil number (neutropenia). Neutropenia can be divided into three categories depending on the absolute neutrophil count (ANC). An absolute neutrophil count below 2000/mm³ and above 1000/mm³ is considered mild neutropenia. Patients with ANC between 1000/mm³ and 500/mm³ are considered to be moderately neutropenic. (17) Patients with an ANC below 500/mm³ are considered severely neutropenic. Neutropenia is most often due to medications or intercurrent illness, but can be due to inherited defects in neutrophil production. One such disease resulting in neutropenia is congenital agranulocytosis. Congenital agranulocytosis is a term which is usually associated with the complete absence of peripheral granulocytes. Monocytes, basophils and eosinophils are actually elevated. Some patients have defects in a receptor required for neutrophil growth and other patients have mutations in the elastase gene. Nearly all patients with congenital agranulocytosis have frequent infectious diseases and ultimately succumb early in life without intervention. The disorder may be managed with the administration of recombinant granulocyte-colony stimulating factor (G-CSF). It has been shown that co-administration of G-CSF with stem cell factor provides an effective correction of neutrophil maturation. (18) Unless the neutrophil count is appropriately corrected, patients will develop periodontitis.

-Cyclic neutropenia

Patients with cyclic neutropenia have a defect in the pluripotent stem cell maturation process. There are cyclical episodes where neutrophil counts are diminished. In addition to idiopathic cyclic neutropenia, there can be neutropenia induced by pharmaceutical agents. This group includes phenothiazides, semi-synthetic beta lactam penicillins, phenylbutazone and sulfonamides. (17) The cycling neutrophil levels have occasionally been associated with significant periodontal bone loss.

Other types of neutropenias include chronic idiopathic neutropenia, autoimmune neutropenia, chronic benign neutropenia, as well as others. Additional diseases, including systemic lupus erythematosus in which neutrophils are sequestered in tissue components, thus lowering the circulating neutrophil count, have the potential of contributing to rapidly destructive periodontal disease.

Miscellaneous syndromes

Other less common neutrophil disorders include myeloperoxidase deficiency, specific granule deficiency, and myelokathexis. (19)

THERAPY FOR HEMATOLOGIC DISORDERS

The therapeutic approach for the conditions described above focuses on restoring or improving the leukocyte capacity to fight infection. Granulocyte colony stimulating factor has been used as an initial approach to elevate neutrophil counts in congenital agranulocytosis. Interferon alpha (α) and gamma (γ) are cytokines produced by T cells that play a vital role in stimulating superoxide production and increasing phagocytosis. Interferon- γ specifically increases the production of nitric oxide (NO), contributing to enhanced intracellular killing by phagocytes -; as a result, patients with CGD are usually treated with interferon- γ In recent years, gene therapy has been used to effectively treat severe combined immunodeficiency. (20, 21)

NON HEMATOLOGIC ABNORMALITIES

This section aims to review some of the most frequent systemic diseases that occur with periodontal manifestations. A detailed review of each one of these entities is out of the scope of this paper.

Diabetes mellitus

A rapidly destructive form of periodontal disease has been associated with diabetes mellitus (DM) type 1 and 2. (22,23) Patients with DM tend to exhibit more severe gingivital inflammation and attachment loss compared to non-diabetic controls. In type 1 diabetics it has been noted that the longer the period of time that the patient has been diagnosed with DM, the greater the attachment loss.

Additionally, patients who present with poor glycemic control tend to exhibit more severe bone loss than those that are relatively well controlled. Interestingly, the etiology associated with the rapid destruction seen in the periodontium of patients with diabetes is unclear, though a number of theories have been proposed. Vascular changes that are associated with DM may not allow for proper wound healing. Once a periodontal lesion is established, vascular changes may impede the proper stages of healing. Another theory suggests that hyperglycemia can be a stimulant of collagenase activity, and collagenase activity results in collagen breakdown and attachment loss. It has been proven that hyperglycemia can alter neutrophil function in periodontal tissues. Some or all of the noted proposed mechanisms may be the etiologic agent(s) for the rapid periodontal destruction observed in this patient population. It is important to be aware of the classic cardinal signs of DM, polyuria, polydipsia and polyphagia as well as the development of peripheral neuropathies in a young patient that presents with extensive periodontal disease.

The diagnosis of DM is based on fasting levels of circulating serum glucose and hemoglobin A1C concentration. The oral implications have been previously described elsewhere. (23) Management of DM depends on the type of defect in pancreatic beta cells and the capacity to synthesize insulin.

Langerhan's Cell Histiocytosis

Langerhan's cell histiocytosis (LCH) is a condition in where there is widespread proliferation of cells that display morphologic and immunophenotypic similarities to Langerhan's cells. This disease was formerly known as histiocytosis X. (6) Multiple diseases were traditionally grouped into sub-categories of histiocytosis X as eosinophilic granuloma, Letterer-Siwe disease and Hand Schüller Christian disease. Excessive proliferation of specialized bone marrow-derived Langerhan's cells characterizes the disease. Some patients may present with the triad of exophthalmoses, diabetes insipidus and destructive bony lesions. Upon periodontal examination, patients exhibit advanced alveolar bone loss, loosening of the teeth and premature tooth loss. The diagnosis of LCH is via routine and immunohistochemical studies of the affected tissue. Radiographically, this disease will present with characteristic "floating teeth". Management of LCH includes therapy with cytotoxic agents like vincristine, cyclophosphamide and methothrexate. Isolated lesions may benefit from radiation.

Hypophosphatasia

Hypophosphatasia is a condition associated with a decrease in serum alkaline phosphatase. Alkaline phosphatase levels correlate well with mineralization potential. There are four different phenotypic patterns of expression of the disease, all of which are associated with mutations in the alkaline phosphatase gene. Dentally, there is absence of cementum and taurodontism. (24) The absence of cementum does not allow proper attachment of the tooth to the periodontal ligament via Sharpey's fibers. Patients with hypophosphatasia may therefore have an associated rapidly destructive periodontal disease and early exfoliation of the primary and permanent dentition. Treatment for hypophosphatasia varies depending on its stage and classification, mostly focused on treating bony deformities and multisystemic involvement. Control of hypercalcemia is an important factor and vitamin D supplements can improve the clinical presentation.

Ehlers-Danlos Syndrome (EDS)

EDS refers to a heterogeneous group of connective tissue disorders characterized by skin elasticity, tissue fragility, and joint hypermobility. One type of EDS, EDS Type VIII, an inherited syndrome, has been associated with severe resorptive periodontitis, which can lead to early tooth loss. These patients share the classic features of EDS except they present with very mild joint hypermobility. (25)

Down's Syndrome

Down's syndrome is an inherited disorder resulting from trisomy of chromosome 21. This syndrome is a common cause of mental handicap in children. It has been associated with periodontal disease in children. The exact etiology for the periodontal disease associated with Down's syndrome is speculative, but various mechanisms have been proposed including dysregulation of matrix metalloproteinases, T-cell immunodeficiency, functional neutrophil defects and possible differences in collagen biosynthesis. (26)

Papillon-LeFevre Syndrome

Patients with Papillon-LeFevre Syndrome also exhibit a qualitative neutrophil disorder. Although there is still some controversy on neturophil function in this disease, neutrophils isolated from affected individuals can exhibit defects in neutrophil chemotaxis and impaired superoxide production.ref Clinical expression of the syndrome includes hyperkeratosis and pitting in palms and soles. Rapidly destructive periodontitis is an almost universal finding and may affect the primary and/or secondary dentitions. (27) In this syndrome, mutation of the gene encoding dipeptidyl peptidase I (DDRI), formerly known as aggressive cathepsin c, leads to a mild increase in infections overall, and a dramatic susceptibility to periodontitis.

DIAGNOSTIC EVALUATION OF A PEDIATRIC PATIENT PRESENTING WITH PERIODONTITIS

When an underlying immunodeficiency is suspected in a young patient with periodontal disease, several laboratory studies are helpful. The clinical setting and history direct the laboratory evaluation. Most of the children with systemic disorders that require periodontal treatment have previously gone through a complete medical workup. However, in some cases oral features may precede other manifestations. The clinician should be aware of signs of recurrent oral infection in neonates and young children, persistent gingival bleeding with associated erythema and rapidly advancing bone loss. In many patients, the extent of periodontal destruction occurs in the relative absence of dental plaque and calculus.

For patients with a clinical history suggestive of neutrophil disease (recurrent abscesses, fungal disease, mucocutaneous non-healing ulcers, or recurrent Staphylococcal infections), it is important to evaluate neutrophil numbers and function. A CBC with a differential count will allow one to determine whether a patient has normal neutrophil number. Absolute neutrophil counts (ANC) greater than 1000/mm³ suffice to protect from bacteremia caused by dental procedures. While neutropenia is the most common neutrophil disorder associated with periodontal disease, alterations of function have specific interventions and should therefore be specifically investigated. Unfortunately, functional studies of neutrophils are not widely available and are often difficult to obtain because shipping adversely affects neutrophil function. Functional studies should be available at most tertiary care centers and can be invaluable in evaluating a patient for suspected neutrophil dysfunction. One such test for chronic granulomatous disease includes an assay test which detects superoxide production. (24) Other assays for neutrophil function include chemotaxis and phagocytosis testing. Other hematologic evaluations may also be helpful for diagnosis. Hyper IgE or Job's syndrome patients often present with a serum IgE >2000IU/ml (9,28)Hypophosphatasia is diagnosed by serum alkaline phosphatase levels and characteristic radiographic appearance of floating teeth. (24)

Patients with significant infections suggestive of a T-cell disorder such as opportunistic infections or difficulty in clearing viral or fungal infections should have an evaluation of T cell numbers and their function. T cell phenotype analysis by flow cytometry is widely available and requires a modest amount of blood. Data that can be obtained include the numbers of total CD3-positive T cells, CD4-positive T helper cells, and CD8-positive cytotoxic T cells. Since flow cytometry reports only a percent of the total population which bears the relevant marker, it is helpful to have a lymphocyte count from a complete blood count (CBC) so the absolute number of each cell type can be determined. T cell counts less than 1000/mm³ and CD4 or CD8 counts below 400/mm³ are abnormal for most age groups. T cell function analyses are not as widely available and are not standardized across the United States. These tests require substantial volumes of blood and are very expensive, but are certainly warranted when an immunodeficiency is strongly suspected. (29) The basis of these studies, which are often referred to as lymphocyte stimulation assays or lymphocyte mitogen analyses, is to maximally stimulate the lymphocytes to proliferate. A marker for proliferation (usually thymidine incorporation into newly synthesized DNA) is then measured after 3-5 days. (29)

The role of the dentist when treating periodontal disease in young patients with these disorders is to be aware of the potential role of infection and decreased response to inflammation found in some of them. Primary immune deficiencies will generally manifest during the early months of life, with the appearance of recurrent infections which are recalcitrant to antibiotic therapy. The need for frequent recall prophylaxis is emphasized. Limitation of surgical procedures to emergent situations and when overall patient status is known and allows for such intervention is prudent. Dentists should be aware of the side effects of medications used to treat these children and their impact on oral tissues, so that treatment can be modified in order to minimize these effects.

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