Periodontal disease in children: Associated systemic conditions

INTRODUCTION — Soft tissue lesions of the oral cavity are common in children, and distinguishing between findings that are normal and those that are indicative of gingivitis, periodontal disease, local or systemic infection, and potentially life-threatening systemic conditions is important. The loss of periodontal attachment in children, manifest by tooth mobility or premature loss, can be a symptom of neoplasia, immunodeficiency, or metabolic defects [1,2]. The early detection and treatment of these conditions can be life-saving.

Systemic conditions associated with childhood periodontitis will be reviewed here. Soft tissue lesions and periodontitis not associated with systemic conditions are discussed separately. (See "Soft tissue lesions of the oral cavity in children" and "Gingivitis and periodontitis in children and adolescents".)

LANGERHANS CELL HISTIOCYTOSIS — Langerhans cell histiocytosis (LCH; previously known as histiocytosis X or eosinophilic granuloma) is a rare disorder that affects infants, children, and young adults and is characterized by histiocytic infiltration of the bones, skin, liver, or other organs [3,4]. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

LCH presents with single- or multiple-site involvement. The skin, oral mucosa, bone, and lymph nodes are typical locations for single-site involvement. Multisite involvement occurs in the liver, spleen, lungs, bone marrow, and gastrointestinal and central nervous systems.

Between 20 and 30 percent of patients present with infiltration of the oral cavity, usually the posterior mandible [3,5]. The typical dental presentation of LCH is eruption of the primary molars at or soon after birth (picture 1). Additional oral manifestations include pain; ulceration; enlargement, inflammation, or recession of the gingiva; and mobility of teeth because of expansion of the alveolar bone [6-8]. In a case series of nine patients, the most common oral manifestation was ulceration on the hard palate [8]. Dental radiographs may show discrete, destructive bone lesions that make the teeth appear to be "floating on air" [4,7]. Periosteal new bone formation and slight root resorption also may be present [9]. Cases may present as aggressive periodontitis lesions that do not respond to routine periodontal therapy [10], despite the presence of bacteria typically associated with periodontitis [11].

When periodontal involvement is suspected to be a manifestation of LCH, biopsy of the gingiva or periodontal tissues is needed [7,10-12]. The diagnostic evaluation for children in whom a diagnosis of LCH is being considered is extensive and should be performed in consultation with a pediatric hematologist. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Diagnosis'.)

The treatment of LCH, discussed in detail separately, can result in the loss or arrested development of teeth. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Lytic bone lesions' and "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Adults'.)

LEUKEMIA — Leukemia, particularly myelogenous leukemia, can cause gingival enlargement because of infiltration of the gingival tissues [13,14]. Leukemic gingival enlargement is typically painless, shiny, red, and edematous (picture 2); bleeding is common and can make it difficult to maintain oral hygiene. Necrotic ulceration and involvement of the underlying bone also can occur [15]. The inflammation that results may act as a stimulus for further gingival swelling [16]. Additional symptoms include fever, malaise, easy bruising or bleeding, and bone or joint pain.

The diagnosis of leukemia should be considered in patients who have hemorrhagic gingival edema and anemia, thrombocytopenia, or abnormal leukocyte and differential counts on complete blood count. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

As in Langerhans cell histiocytosis, the treatment of leukemia (both lymphocytic and myelogenous leukemia) can have oral complications, including [17-19]:

●Mucositis (picture 3)

●Oral infection with candida, herpes simplex virus, or other opportunistic organisms

●Gingival inflammation (gingivitis)

●Spontaneous gingival bleeding (because of thrombocytopenia)

●Gingival squamous cell carcinoma (as a complication of graft versus host disease in hematopoietic cell transplant recipients)

The chemotherapy-induced oral complications in patients with leukemia are more prevalent immediately after administration of chemotherapy [20]. They occur irrespective of the chemotherapy protocol used [20].

The oral complications of chemotherapy can be diminished by aggressive preventive care, including comprehensive oral examination before the initiation of cancer therapy [21-23]. The oral cavity is a reservoir for many microorganisms with the potential to cause systemic infection in the immunocompromised host. In addition, dental plaque causes gingivitis and gingival bleeding. Careful brushing with a soft toothbrush should be continued throughout therapy. Although it has been recommended that toothbrushing be suspended or replaced by cleaning with sponge-tipped brushes ("toothettes") when platelet counts are low, these approaches are not adequate for plaque removal, and available evidence suggests problems are more likely to arise when oral hygiene is poor [19,24]. The prevention and treatment of chemotherapy-related mucositis are discussed in detail separately. (See "Oral toxicity associated with systemic anticancer therapy", section on 'Mucositis'.)

LEUKOCYTE-ADHESION DEFICIENCY SYNDROMES — Leukocyte-adhesion deficiency (LAD) syndromes are autosomal recessive disorders characterized by inability of the neutrophils to exit the circulation in response to inflammation, including inflammation related to periodontitis-associated species in the LAD subgingival microbiome. The migration defects include abnormal neutrophil motility, adherence, or rolling (table 1). (See "Leukocyte-adhesion deficiency".)

Patients with LAD may present with delayed separation of the umbilical cord or recurrent bacterial infections of the ears, sinuses, lungs, and skin. Wounds and abscesses heal poorly, and minimal pus is formed. The number of peripheral neutrophils is increased by their inability to leave the circulation and can be as high as 100,000/mm³. LAD is usually diagnosed on the basis of recurrent infection before oral manifestations occur.

Oral manifestations of LAD are seen in the early primary dentition and include severe gingival inflammation, rapid bone loss around nearly all teeth, and mobility and premature loss of teeth. The LAD-associated destruction of periodontal tissues is determined primarily by the unregulated localized increase of proinflammatory cytokines, not the lack of local antibacterial defenses [25]. The periodontitis associated with LAD has been called generalized prepubertal periodontitis in the dental literature [26].

The diagnosis and treatment of LAD are discussed separately. Meticulous oral hygiene is necessary to control the periodontal disease associated with LAD, but restoration of gingival health may require bone marrow transplantation [27]. In a case report, off-label use of anticytokine therapy dramatically reduced the periodontal pathologic features within weeks [28]. (See "Leukocyte-adhesion deficiency".)

NEUTROPENIA — Neutropenia is a hematologic disorder characterized by reduced numbers of circulating neutrophils. It is diagnosed when the absolute neutrophil count (ANC) is less than 1500/microL [29]. (See "Overview of neutropenia in children and adolescents", section on 'Definitions and normal values' and "Approach to the adult with unexplained neutropenia", section on 'Definitions and normal values'.)

Neutrophils are an important component of the host response to pathogenic dental plaque in the gingival sulcus, and patients with neutropenia are at risk for severe gingivitis and pronounced alveolar bone loss (picture 4). Periodontal disease occurs in the following types of childhood neutropenia:

●Congenital neutropenia

●Autoimmune neutropenia (AIN)

●Cyclic neutropenia

Congenital — Congenital neutropenia occurs in several conditions where there is a marked decrease in (or lack of) circulating neutrophils from the time of birth. These conditions include infantile agranulocytosis (Kostmann syndrome), Shwachman-Diamond syndrome, myelokathexis, congenital dysgranulopoietic neutropenia, and the Chediak-Higashi syndrome. These are rare disorders, with an estimated frequency of two cases per million population [30]. (See "Congenital neutropenia".)

Children with congenital neutropenia are susceptible to recurrent infection, often due to staphylococci and streptococci. Oral lesions, otitis media, respiratory infection, cellulitis, and skin abscesses are the most common. These infections heal slowly and may be fatal. Oral manifestations of congenital neutropenia include ulcers, severe gingivitis, alveolar bone loss, gingival recession, tooth mobility, and premature tooth exfoliation. An observational study suggests that mutations in the elastase gene are particularly significant for the development of periodontal disease in patients with congenital neutropenia [31]. However, other genetic diseases whose phenotype includes congenital neutropenia in the absence of elastase gene mutations, such as Cohen syndrome [32], may also have significant periodontal involvement characterized by severe gingivitis, alveolar bone loss, and premature tooth loss [33].

The treatment of congenital neutropenia usually involves the administration of granulocyte colony-stimulating factor (G-CSF) [31] and is discussed in detail separately. (See "Congenital neutropenia", section on 'Treatment'.)

Autoimmune — AIN is caused by granulocyte-specific antibodies. AIN has been associated with a variety of underlying diseases, including viral infection, collagen vascular disease, primary abnormalities of B or T lymphocytes or natural killer cells, immune thrombocytopenia, and autoimmune hemolytic anemia [34]. In most cases, however, AIN is not associated with other illness or underlying disease and is referred to as chronic benign neutropenia of infancy and childhood [35,36]. (See "Immune neutropenia", section on 'Autoimmune neutropenia'.)

Benign neutropenia of infancy and childhood typically occurs in infants between the ages of 5 to 15 months, but the range extends from one month to adulthood [37]. Spontaneous recovery occurs within 24 months in the majority of patients (95 percent in one study) [35,36]. Until they recover, children with this disorder are subject to recurrent, albeit mild, infection [35,38]. Although the neutropenia is severe (ANC less than 500/microL), the ANC can rise temporarily in response to acute infection. This temporary increase in neutrophil count can help in attenuating the severity of acute infection but has little effect on periodontal disease, which is a chronic infection. Severe gingivitis and periodontal disease may result without preventive measures (picture 4) [39].

Cyclic neutropenia — Cyclic neutropenia is characterized by regular oscillations in the numbers of circulating neutrophils, monocytes, eosinophils, lymphocytes, and reticulocytes [40-42]. The cycles typically occur at 21-day intervals, but the intervals can range from 15 to 35 days. Neutrophil counts fluctuate between normal and less than 500/microL [42]. The monocyte, eosinophil, platelet, and reticulocyte oscillations usually fluctuate from normal to high levels, and the periodicity of these cycles is typically the same as that for the neutrophils [41]. During periods of neutropenia, the bone marrow is usually hypoplastic, with myelocyte arrest [43]. (See "Cyclic neutropenia".)

Cyclic neutropenia can have onset in childhood or adulthood. Childhood onset is more common and appears to be a genetic condition with autosomal dominant inheritance [42,44]. Among families with autosomal dominant disease, the spectrum of severity ranges from asymptomatic to life-threatening [44].

Periods of severe neutropenia typically last one week during each cycle; during these periods, patients are prone to malaise, fever, aphthous stomatitis, and occasionally serious cutaneous and subcutaneous infections [40,41]. The severity of infections varies in relation to the severity of neutropenia. Gingival inflammation, edema, and recession can occur; alveolar bone support may be lost in the preschool-age child, resulting in premature tooth mobility and loss (picture 5). Without vigilant management, death from infection is a possibility [43].

The diagnosis and treatment of cyclic neutropenia are discussed in detail separately. (See "Cyclic neutropenia".)

Dental management — Early dental referral and highly motivated caregivers are the keys to successful dental management of children with neutropenia. Neutropenia predisposes the child to hemorrhagic gingivitis and periodontal disease, but the progression of bone loss is because of the host response to pathogenic subgingival plaque. Thus, scrupulous oral hygiene, antimicrobial rinses, frequent professional tooth cleaning, and targeted antibiotic therapy can delay or halt periodontal bone loss.

Antibiotic therapy for neutropenic children with periodontal disease is determined by microbial culture and susceptibility testing of a pooled sample of the gingival crevicular fluid (ie, the inflammatory exudate from the periodontal tissues) if it is possible to obtain these studies. If it is not possible to obtain culture and susceptibility testing of a pooled sample of gingival crevicular fluid, empiric antimicrobial therapy is prudent. Appropriate empiric regimens include one of the following agents: amoxicillin, clindamycin, or cephalexin.

The organisms most commonly cultured in children with periodontal disease include Prevotella intermedia, Actinobacillus actinomycetemcomitans, Eikenella corrodens, and Capnocytophaga sputigena [45]. Eradication and control of these pathogens is essential in the treatment of periodontal disease. Periodic surveillance cultures will help to determine the need for repetition of antibiotic therapy.

The treatment of neutropenic children with periodontal disease is usually more successful in children with localized than with generalized periodontal disease; generalized periodontal disease may be refractory to antibiotic therapy without correction of the underlying neutrophil defect. Treatment of the underlying disorder with administration of G-CSF, and normalization of neutrophil counts, may not be sufficient to maintain oral health because of possible associated functional neutrophil defects; this underscores the significance of professional dental care for such patients [46].

CHRONIC GRANULOMATOUS DISEASE — Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by defective phagocyte function and characterized by life-threatening bacterial and fungal infections and granuloma formation. CGD is genetically heterogeneous (resulting from mutations in various genes involved in the nicotinamide adenine dinucleotide phosphate oxidase complex [MIM #306400, MIM #233690, MIM #233700, MIM #233710, MIM #613960]). Most patients are diagnosed before the age of five years.

Oral pathology includes periodontitis, severe gingivitis, oral ulcers, and oral candidiasis. Periodontal attachment loss may manifest in the primary or permanent dentition [47,48]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)

CHEDIAK-HIGASHI SYNDROME — Chediak-Higashi syndrome (CHS) (MIM #214500) is a rare primary immunodeficiency characterized by recurrent pyogenic infections, partial oculocutaneous albinism, and progressive neurologic abnormalities. CHS is caused by mutations in the LYST gene. Patients are typically identified in infancy or early childhood because of their unusual coloring (ie, lighter than normal skin and sparse light blond, gray, or white hair that often has a metallic sheen (picture 6)). Patients develop severe pyogenic infections of the skin, respiratory tract, and mucous membranes, and typically succumb to these infections if not treated with hematopoietic cell transplant by mid-childhood [49].

Periodontitis is the most common oral complication; other common oral complications include ulcerations and gingival/periodontal abscesses [50,51]. Children with CHS may present with premature loss of the primary dentition [50,51]. Children with CHS who have received hematopoietic cell transplantation or have atypical CHS disease are less likely to develop severe periodontitis or experience early tooth loss [52]. While some children with a mild systemic phenotype may benefit from routine periodontal therapy, the periodontal disease in CHS is often refractory to treatment, resulting in tooth loss [53,54]. When the tooth loss is managed with dental implant rehabilitation, peri-implantitis is frequent [51]. (See "Chediak-Higashi syndrome".)

DIABETES MELLITUS — Adults and children with type 1 and type 2 diabetes mellitus have an increased risk for and earlier onset of periodontal disease, probably related to altered immune function [55-59] and decreases in localized innate immunity defense mechanisms [60,61]. Periodontal disease is present in 10 to 15 percent of adolescents with type 1 diabetes. In children and adolescents with type 2 diabetes, periodontal destruction appears to be associated with components of the metabolic syndrome and beta cell function [62]. Poor metabolic control increases the risk of periodontal disease through altered neutrophil chemotaxis [63]. Children with poorly controlled diabetes tend to have poorer oral hygiene practices [64] and have an increased plaque index and more severe gingivitis than healthy children [65-68]. Poor glycemic control has also been associated with increased diversity of gingival microbiota in children with diabetes [69,70]. Puberty aggravates periodontal disease in children with diabetes [71]. Periodontal disease, in turn, worsens diabetes control [72]. Glucose control, oral hygiene, and early diagnosis and treatment of periodontal disease are important for the overall health of children with diabetes. Children with diabetes mellitus may have accelerated tooth eruption. (See "Anatomy and development of the teeth", section on 'Accelerated eruption'.)

Diabetes mellitus is associated with increased risk of peri-implantitis [73], although evidence suggests that implant survival rates are not affected by diabetes [74].

HYPOPHOSPHATASIA — Hypophosphatasia is a rare autosomal disease characterized by abnormal mineralization of bone and dental tissues [75-79]. It is caused by deficiency of tissue-nonspecific alkaline phosphatase due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene [80]. The phenotypic appearance varies; the earlier the presentation, the more severe the disease. Early loss of primary incisors may be the first and only sign in mild disease (picture 7). Early tooth loss without generalized gingival bleeding and inflammation helps to distinguish hypophosphatasia from other causes of periodontal disease in children.

The severe forms of the disease are autosomal recessive and present in the perinatal period (usually lethal) and in infancy (MIM #241500). Patients with the infantile form present within the first six months of life with generalized skeletal demineralization, hypercalcemia, hypercalciuria, fractures, craniosynostosis, short extremities, poor weight gain, and respiratory infections [81]. These clinical features are reproduced in mice in which the genes for alkaline phosphatase have been deleted [82].

The childhood (MIM #241510) and adult (MIM #146300) forms are less severe than the infantile form and can be dominant or recessive [76,77,83,84]. They have variable penetrance and expression but typically present with premature loss of deciduous teeth. The extraoral manifestations of childhood hypophosphatasia include craniosynostosis, short stature, bone pain, spontaneous fractures, and scoliosis. Demineralization and rachitic changes can be seen on radiographs [81]. Muscle pain, stiffness, and proximal lower-limb weakness also may occur [85]. In the adult form, dental disease often precedes the onset of symptomatic osteomalacia.

Hypophosphatasia leads to complete absence or marked reduction in the amount of cementum covering the root's surface [86]. The absence of cementum prevents normal anchoring of the fibers of the periodontal ligament and leads to premature tooth mobility and loss. The periodontal microbiota of children with hypophosphatasia appear to be no different from that of healthy controls [87]. Lower alkaline phosphatase activity and lower capacity for forming mineralized nodules by pulpal cells in hypophosphatasia may contribute to dentin dysplasia [88].

The teeth are affected in the order of formation; those that form earliest are more severely involved. Approximately three-quarters of affected children have premature exfoliation of primary teeth. Exfoliation of the primary incisors typically occurs before four years of age and may occur as early as 18 months of age in more severe disease. The other primary teeth are affected to varying degrees, and the permanent dentition usually is normal [75].

Hypophosphatasia is diagnosed through blood sampling that demonstrates low serum alkaline phosphatase concentration or elevated concentrations of phosphoethanolamine and pyrophosphate. Affected patients also may have increased urinary excretion of phosphoethanolamine [67].

Enzyme replacement therapy (asfotase alfa) is available for perinatal/infantile- and juvenile-onset hypophosphatasia [89]. Asfotase alfa is administered by subcutaneous injection three or six times per week.

In several open-label prospective studies including more than 100 patients with perinatal-, infantile-, or juvenile-onset hypophosphatasia, enzyme replacement therapy was associated with improved overall survival, ventilator-free survival, growth, and bone mineralization compared with a historic cohort [89,90]. In animal studies, enzyme replacement therapy prevented or improved dental/alveolar pathology [91]. Although such improvements in hypophosphatasia have not yet been reported in human trials [92,93], positive dental outcomes have been noted in case reports of children with infantile and childhood-type perinatal hypophosphatasia who received asfotase alfa at various ages [79,94,95]. These include improved mineralization of teeth under formation, improved stability of loose teeth, absence of early tooth loss (ie, at ≤3.5 years of age), and stabilization of the periodontal condition [79,94,95]; the positive dental outcomes varied by child and age at onset of treatment.

Adverse effects of asfotase alfa include injection site reactions, hypersensitivity reactions, lipodystrophy, and ectopic calcification in the eyes and kidney [89,90]. Recurrence and worsening of disease-associated laboratory and radiographic biomarkers in association with neutralizing has been reported in post-marketing surveillance, suggesting the possibility of immune-mediated disease progression [96].

Palliative therapy for the infantile form may include correction of hypercalcemia (with calcitonin), reduction of hypercalciuria (with chlorothiazide), reduction of dietary intake of calcium and vitamin D, and reduced exposure to sunlight. Secondary rickets can be prevented through the administration of between 200 and 400 international units (IU) of vitamin D per day. Serial monitoring of 25-hydroxyvitamin D levels is necessary to monitor and titrate intake [81,85].

DOWN SYNDROME — Individuals with Down syndrome have increased susceptibility to periodontal disease. Periodontal disease may be present in the primary dentition and develops in most patients by 30 years of age. The severity of periodontal destruction is greater than can be attributed to the increased levels of plaque in these patients [97]. The subgingival microbiota of patients with Down syndrome who have periodontitis does not differ from that of patients without Down syndrome who have periodontitis [98]. However, children with Down syndrome have substantially higher prevalence of periodontal pathogens in the primary dentition, in the absence of any periodontal involvement [99]. The periodontal involvement in Down syndrome patients has negative effects on quality of life [100]. Down syndrome is associated with abnormalities in the immune system, particularly lymphocyte function, which may contribute to their increased susceptibility to periodontal disease [101]. Molecular studies suggest involvement of the PI3K-Akt signaling pathway in the development of periodontitis in patients with Down syndrome [102,103].

In patients with Down syndrome, mechanical nonsurgical periodontal therapy alone may not provide the expected reduction in periodontal pathogenic bacteria, suggesting the need for adjunctive antimicrobial therapy [104]. In a systematic review, early institution of periodontal care; supervision of oral hygiene by parents, caregivers, or institutional attendants; frequent dental visits; and addition of chemical adjuvants (eg, chlorhexidine, plaque disclosing agents) were associated with improved periodontal outcomes in children with Down syndrome [105]. Dental implant therapy is not contraindicated in Down syndrome patients, although dental implant survival may be reduced [106,107]. (See "Gingivitis and periodontitis in children and adolescents", section on 'Periodontitis' and "Down syndrome: Clinical features and diagnosis", section on 'Immunodeficiency'.)

In addition, patients with Down syndrome commonly have high attachment of the anterior mandibular frenum that is associated with gingival recession [97]. (See "Soft tissue lesions of the oral cavity in children", section on 'Abnormalities of the labial frena'.)

PAPILLON-LEFÈVRE SYNDROME — The Papillon-Lefèvre syndrome (PLS; MIM #245000) is characterized by premature loss of the primary and permanent teeth and hyperkeratosis of the palms (picture 8), soles, and sometimes of the knees and elbows. It is caused by loss-of-function mutations in the cathepsin C gene (CTSC) on chromosome 11q14 [108-110].

The periodontal inflammation begins soon after eruption of the primary teeth. Bone loss is rapid and severe; primary teeth are lost by three to five years of age and permanent teeth within a few years of eruption (picture 9). Rare cases with absence of periodontal involvement in the permanent dentition have been reported [111]. Screening for lack of urinary cathepsin C activity soon after birth may allow early diagnosis, before tooth eruption and development of periodontal disease [112].

The severity of disease may be related to immunologic and microbiologic factors. Patients with PLS have abnormalities in neutrophil and natural killer cell function [109,110,113-115]. Molecular mechanisms implicated in the periodontal pathogenesis include the deficient processing and lack of cathelicidin (LL37) in gingival fluid [116]. The organisms typically cultured from the gingival sulcus of patients with PLS are similar to those cultured from children who have neutropenia, and include A. actinomycetemcomitans, Capnocytophaga species, Fusobacterium nucleatum, E. corrodens, and Aggregatibacter actinomycetemcomitans [116-118]. However, there are reports of patients with PLS who have salivary abundance of uncommon organisms (Archaea) [119].

Recommended periodontal treatment of young children with PLS includes identification of specific periodontal pathogens and antibiotic therapy targeted to these microorganisms if culture and susceptibility testing is available [120]. If culture and susceptibility testing is not available, empiric therapy with amoxicillin-clavulanate and metronidazole is reasonable [121]. In cases where antimicrobial therapy is unsuccessful, extraction of all erupted teeth or treatment with retinoids has been reported to preserve the unerupted permanent teeth [117,120,122,123].

Under proper maintenance care, use of dental implants to treat tooth loss in patients with PLS appears to be successful [124]. However, in the absence of consistent supportive periodontal therapy, peri-implantitis and implant loss are common [125].

PERIODONTAL TYPES OF EHLERS-DANLOS SYNDROME — Ehlers-Danlos syndrome (EDS) periodontal type 1 (MIM #130080) and EDS periodontal type 2 (MIM #617174) are types of EDS characterized by severe onset of periodontal disease and premature tooth loss in childhood [126,127]. EDS periodontal type 1 is caused by mutations of the C1R gene and EDS periodontal type 2 is caused by mutations of the C1S gene [127].

Patients with EDS have reported a delay between the first oral manifestation and diagnosis, often exceeding 15 years [128,129]. Both periodontal types of EDS have autosomal dominant inheritance and should be considered in the differential diagnosis of patients with dominant familial forms of severe periodontal disease with early onset. Generalized lack of attached gingiva is considered a pathognomonic feature in children and adults with periodontal types of EDS [130]. Patients with periodontal types of EDS who receive dental implants to replace lost teeth are at high risk for peri-implant disease and associated implant failure [131]. EDS-associated oral conditions have a negative impact on the patients' quality of life [128].

Patients with periodontal types of EDS may lack findings of classic EDS (eg, joint hypermobility, hyperextensible skin, tissue fragility), but signs of collagen disorganization are present microscopically. Periodontal EDS has been associated with adult-onset leukoencephalopathy [132] and vascular complications [133]. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)

Periodontal manifestations have been rarely reported in other types of EDS [134]. The coexistence of different forms of EDS in an individual is possible but extremely rare [135,136].

KINDLER EPIDERMOLYSIS BULLOSA — Kindler epidermolysis bullosa (KEB; MIM #173650) is a rare autosomal recessive type of epidermolysis bullosa associated with increased risk of mucocutaneous malignancy. (See "Kindler epidermolysis bullosa".)

Patients with KEB have spontaneous gingival bleeding, fragile and often desquamative gingiva, mild to severe gingival inflammation, and high-grade periodontitis characterized by early-onset and rapid progression [137-141]. The periodontitis appears to manifest following eruption of the permanent dentition, with minimal attachment loss reported in patients younger than 10 years of age [139].

The periodontitis of KEB is not necessarily associated with the typical virulent periodontopathogenic bacteria found in other forms of aggressive periodontitis, underscoring the significance of host susceptibility [137,139]. Histopathologically, gingival tissues exhibit disorganization at the basement membrane, blistering at the level of lamina lucida, and abnormal deposition of type VII collagen [138,142]. The adhesion of the junctional epithelium to the tooth may be severely compromised [140].

Limited evidence suggests that standard mechanical periodontal therapy followed by regular periodontal maintenance may result in moderate success when treating KEB patients [140,141], although the gingiva and oral mucosa may remain fragile and abnormal (lichenoid) in appearance [140]. Regular dental visits are crucial for the oral/periodontal management of patients with KEB [143].

INFECTIONS — Infections associated with oral lesions are discussed separately. (See "Soft tissue lesions of the oral cavity in children", section on 'Infections'.)

SUMMARY

●Langerhans cell histiocytosis (LCH) – Dental presentations of LCH include eruption of the primary molars at or soon after birth (picture 1), aggressive periodontitis lesions that do not respond to routine periodontal therapy, and dental radiographs demonstrating discrete, destructive bone lesions that make the teeth appear to be "floating on air." (See 'Langerhans cell histiocytosis' above and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●Leukemia – Leukemia should be considered in patients who have hemorrhagic gingival edema (picture 2) and anemia, thrombocytopenia, or abnormal leukocyte and differential counts on complete blood count. (See 'Leukemia' above and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

●Leukocyte-adhesion deficiency (LAD) syndromes – Oral manifestations of LAD syndromes, which are seen in the early primary dentition, include severe gingival inflammation, rapid bone loss around nearly all teeth, and mobility and premature loss of teeth. (See 'Leukocyte-adhesion deficiency syndromes' above and "Leukocyte-adhesion deficiency".)

●Neutropenia – Children with congenital, autoimmune, or cyclic neutropenia are predisposed to hemorrhagic gingivitis and periodontal disease (picture 4), potentially complicated by alveolar bone loss, tooth mobility (picture 5), and premature exfoliation. Scrupulous oral hygiene, antimicrobial rinses, frequent professional tooth cleaning, and targeted antibiotic therapy are the keys to successful dental management. (See 'Neutropenia' above and "Congenital neutropenia" and "Immune neutropenia", section on 'Autoimmune neutropenia' and "Cyclic neutropenia".)

●Chronic granulomatous disease (CGD) – Oral manifestations of CGD include severe gingivitis, oral ulcers, oral candidiasis, and periodontitis of the primary and permanent dentition. (See 'Chronic granulomatous disease' above and "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)

●Chediak-Higashi syndrome (CHS) – Children with CHS may present with severe pyogenic infections, oral ulcerations, gingivitis and periodontitis of both primary and permanent dentition. Periodontitis in CHS is often resistant to treatment. (See 'Chediak-Higashi syndrome' above and "Chediak-Higashi syndrome".)

●Diabetes mellitus – Patients with type 1 and type 2 diabetes mellitus have an increased risk for and earlier onset of periodontal disease. Poor metabolic control increases the risk of periodontal disease. (See 'Diabetes mellitus' above.)

●Hypophosphatasia – Hypophosphatasia is a rare disease characterized by abnormal mineralization of bone and dental tissues. Oral manifestations include premature loss of deciduous teeth. Exfoliation of the primary incisors typically occurs before four years of age and may occur as early as 18 months of age in more severe disease (picture 7). (See 'Hypophosphatasia' above.)

●Down syndrome – Individuals with Down syndrome have increased susceptibility to periodontal disease. (See 'Down syndrome' above and "Down syndrome: Clinical features and diagnosis".)

●Ehlers-Danlos syndrome – Patients with periodontal types of Ehlers-Danlos syndrome experience premature tooth loss because of periodontal disease and are at high risk for peri-implant disease and dental implant failure. (See 'Periodontal types of Ehlers-Danlos syndrome' above.)

●Papillon-Lefèvre syndrome – The Papillon-Lefèvre syndrome is characterized by premature loss of the primary and permanent teeth and hyperkeratosis of the palms, soles, and sometimes of the knees and elbows. Periodontal inflammation begins soon after eruption of the primary teeth. Bone loss is rapid and severe; primary teeth are lost by three to five years of age and permanent teeth within a few years of eruption (picture 9). (See 'Papillon-Lefèvre syndrome' above.)

●Kindler epidermolysis bullosa – Patients with Kindler epidermolysis bullosa have spontaneous gingival bleeding, fragile and often desquamative gingiva, mild to severe gingival inflammation, and aggressive (early-onset) periodontitis, characterized by rapid progression. (See 'Kindler epidermolysis bullosa' above.)