Ligneous Periodontitis Research Articles

Ligneous periodontitis exacerbated by Behçet’s disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report

BackgroundPlasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia.We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity.Case presentationThis case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated.ConclusionsCollaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

Ligneous Periodontitis Associated with Plasminogen Deficiency: A Review of the Literature with Two Additional Cases

Ligneous Periodontitis Associated with Plasminogen Deficiency: A Review of the Literature with Two Additional Cases

Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier.

Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we report that the clotting factor fibrin is a critical regulator of neutrophil function at the oral mucosal barrier. We demonstrate that commensal microbiota trigger extravascular fibrin deposition in the oral mucosa. Fibrin engages neutrophils through the αMβ2 integrin receptor and activates effector functions, including the production of reactive oxygen species and neutrophil extracellular trap formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis in mice and humans. Concordantly, genetic polymorphisms in PLG, encoding plasminogen, are associated with common forms of periodontal disease. Thus, fibrin is a critical regulator of neutrophil effector function, and fibrin-neutrophil engagement may be a pathogenic instigator for a prevalent mucosal disease.

Plasminogen gene polymorphisms [c.924C>T and IVS 8+14 G>A] in periodontitis and familial Mediterranean fever: A case-control study.

The plasminogen (PLG) activation system plays an essential role in severe inflammation based diseases such as periodontitis, destructive membranous periodontal disease (ligneous periodontitis), familial Mediterranean fever (FMF), and amyloidosis. We have aimed to evaluate variations in PLG and the associations between PLG and MEFV genotypes in patients with FMF/ FMF-related secondary amyloidosis and periodontitis. A total of 247 individuals who were either diagnosed with FMF or systemically healthy were recruited to this human observational study with a cross-sectional design. All individuals were also diagnosed with periodontitis or periodontally healthy. Blood samples were obtained from patients with FMF and systemically healthy controls. Clinical periodontal indicators were recorded. All polymorphisms located in exons 6 and 8 of PLG and mutations located on exons 2 and 10 of the MEFV gene were analyzed by DNA Sanger Sequencing. Genotypes and allele frequencies of PLG and MEFV were detected and tested by the Hardy-Weinberg equilibrium. Serum levels of amyloid A (SAA), high-sensitive C-reactive protein (hs-CRP), PLG, and salivary PLG levels were determined by using enzyme-linked immunosorbent assay (ELISA). Two polymorphisms were identified in PLG: G to A polymorphism on the 14th nucleotide of intron 8 and C to T polymorphism on the 924th nucleotide of the coding region (IVS 8+14 G>A and c.924C>T, respectively). In IVS 8+14 G>A polymorphisms, wild-type genotype: GG, heterozygote genotype: GA and homozygote genotype: AA. In c.924C>T polymorphism, wild-type genotype: CC, heterozygote genotype: CT and homozygote genotype: TT. The frequency of the heterozygous polymorphisms of PLG was significantly increased (17.6%) in FMF patients with periodontitis (p = .027). A large proportion of the test group that was heterozygous for MEFV-R202Q also had heterozygous PLG polymorphisms. Remarkable exacerbation in periodontal parameters was observed in patients with FMF and amyloidosis. SAA and hs-CRP levels were significantly correlated with salivary PLG levels in patients with periodontitis and heterozygous PLG. The current study describes IVS 8+14 G>A (rs2295368) and c.924C>T (rs1380916375) polymorphisms for the first time in the periodontal literature, which might play an important role in the pathogenesis of periodontitis, FMF, or amyloidosis. The elucidation of PLG polymorphisms is beneficial from a public health perspective by increasing the quality of life in these patients and reducing the mortality and morbidity associated with inflammatory diseases such as periodontal disease, FMF, and FMF-related amyloidosis.

Painting the Clinical Picture of Congenital Plasminogen Deficiency (C-PLGD) through a Comprehensive Case Study Review

C-PLGD is a rare autosomal recessive multisystem disorder of the fibrinolytic system with a diverse spectrum of clinical manifestations, and is underdiagnosed and difficult to treat. Caused by mutations in thePLGgene, C-PLGD is characterized by extravascular fibrinous deposits on mucous membranes such as the conjunctiva, gingiva, linings of airways and genitourinary tract. The abnormal accumulation or growth of fibrin-rich pseudomembranous lesions have been termed ligneous for their "woody" appearance, and often result in tissue injury and/or organ dysfunction in C-PLGD patients. We present here the results of an exhaustive MEDLINE literature database review undertaken with the PubMed search engine using the key words; 'plasminogen deficiency,' 'hypoplasminogenemia' and 'ligneous conjunctivitis'. Objective:The goal of this review was 1) to achieve a better understanding of the type and prevalence of clinical manifestations of C-PLGD and their outcomes, and 2) to evaluate whether a relationship exists between endogenous plasminogen activity levels and disease manifestations in C-PLGD patients. Methodology: A MEDLINE literature search was conducted by three independent investigators. Publications containing the key words 'plasminogen deficiency,' 'hypoplasminogenemia' and/or 'ligneous conjunctivitis' and reporting human clinical information were selected. Patients' age, sex, endogenous plasminogen levels, and clinical manifestations were tabulated. Results: The search retrieved 414 total citations, and 130 papers with relevant human clinical data were identified for full-length text review. From these, 301 unique C-PLGD patients (237 pediatric and 64 adults) were found to be reported over an 80-year period (from 1957 to 2017) and presented the following outcomes and most common and/or serious clinical manifestations: ligneous conjunctivitis (255 cases), ligneous periodontitis (71 cases), tracheobronchial obstructions (53 cases), hydrocephalus (42 cases), other corneal lesion (15 cases), ligneous vaginitis (24 cases), blindness (6 cases), and death (10 cases). Differences in disease seriousness and prevalence were observed between pediatric and adult patient populations (Table1). Of note, death or hydrocephalus were reported only in pediatric patients. Historical information indicated that 62% of the 301 reported patients were females and 36% males, while 2% of them did not have their gender disclosed. The median age of reported onset of symptoms (and/or diagnosis) was 1 year old for the 176 patients with available data. Of the 130 papers retained and analyzed, 2 studies (Klammt et. al. Thromb Haemost 2011; Tefs et. al. Blood 2006) were selected for additional in-depth analysis. These studies included a subset of 58 C-PLGD patients whose clinical, molecular and plasminogen activity data were available and reliably reported. These patients had a spectrum of plasminogen activity level ranging from 2% to 59% and presented the main following clinical manifestations: ligneous conjunctivitis (52/58), ligneous periodontitis (16/58), tracheobronchial involvement (14/58), ligneous vaginitis (6/58), and hydrocephalus (4/58) (Table 2). Out of this 58-patient cohort, 26 reported a single lesion and had an average plasminogen activity level of 22% while the 32 remaining had 2 or more lesions and an average activity level of 20%, indicating that the level of plasminogen activity may not correlate with the clinical manifestations burden/seriousness. Conclusion:This comprehensive review confirmed that the heterogeneity challenges in clinical evaluation and the overall rarity of C-PLGD can contribute to delayed diagnosis, treatment variability and less than optimal outcomes. With lack of natural history studies or reports of C-PLGD, the data described here can be used to highlight the seriousness of long-term morbidity, promote early and effective management of C-PLGD, and support the ongoing development of novel plasminogen replacement therapy to address the primary underlying drivers of morbidity in C-PLGD. The implementation of natural history studies may play an important role in addressing the knowledge gap in phenotypic expression and long-term impact of C-PLGD on the quality of life of impacted patients. Disclosures Thibaudeau: Liminal BioSciences:Current Employment, Current equity holder in publicly-traded company.Robitaille:Liminal BioSciences:Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.Ledsham:Liminal BioSciences:Current Employment.Sandset:Liminal BioSciences:Other: Investigator Clinical Trial.

Ligneous Periodontitis: A Case Report with Different Treatment Approaches and Eleven Years of Follow Up

Ligneous mucosal disease is a rare, destructive condition of plasminogen deficiency characterized by generalized membranous gingival enlargement leading to rapid tooth loss. We report a case of long-standing, generalized ligneous periodontitis with an eleven years of follow- up. The patient did not have any extra oral lesions although she had been suffering from plasminogen deficiency. Treatment approaches had no benefit. An abnormal healing process is the main pathogenetic mechanism; still, intensive periodontal health care is essential for the patients who suffer from ligneous mucosal disease. This report describes a ligneous periodontitis case with a history of ligneous conjunctivitis and its clinical and histopathologic findings, therapeutic approaches and eleven years of follow-up.

LİGNÖZ PERİODONTİTİS : OLGU SUNUMU

Aim: Ligneous periodontitis is an infectious disease characterized by the inflammation of the supporting periodontal tissues, resulting in attachment and alveolar bone loss with plasminogen deficiency. This case report shows the treatment and follow-up of patient who have ligneous periodontitis. Case Report: Fifteen years old boy who had ligneous periodontitis applied to our periodontology clinic. Clinical and radiographic evaluation revealed severe periodontal breakdown around all teeth. Intraoral soft tissues were characterized by gingival reddening and swelling and the patient complained of periodic discharge of pus from the periodontal pockets, mobility, and severe pain. The probing depths were more than 7 mm %58 percent probing areas and there were radiolucent lesions around the teeth in panoramic radiograph. Full-mouth subgingival scaling and root planing under local anesthesia was performed and the pocket wall is gently retracted with a periodontal curette in an attempt to initiate drainage through the pocket entrance. Systemic amoxicillin and clavulanic acid applied for antibiotic therapy. Result: The goal of treatment was to create a clinical condition that is conducive to retaining as many teeth as possible for as long as possible but alveolar bone loss around the teeth was too severe. Systemic disorders such as plasminogen deficiency increase a patient's susceptibility to destructive periodontitis and have impacts on periodontal disease progression and severity. Key Words: Ligneous periodontitis, plasminogen deficiency, systemic diseases, alveolar bone loss

Ligneous Periodontitis and Conjunctivitis With Hyper‐Immunoglobulin E Syndrome

Introduction: Hyper‐immunoglobulin E syndrome (HIES) is a rare multisystem primary immunodeficiency caused by mutation in signal transducer and activator of transcription gene protein 3, associated with recurrent skin and sinopulmonary infection and high serum levels of immunoglobulin E (IgE). It is mostly sporadic, but familial inheritance with autosomal dominant and autosomal recessive forms are seen. Ligneous periodontitis and conjunctivitis are rare poorly defined conditions, characterized by pseudomembranous inflammation of mucosa. There is accumulation of fibrin in lamina propria mostly as a result of quantitative plasminogen deficiency.Case Presentation: An 18‐year‐old Indian girl with history of newborn rash had generalized pseudomembranous periodontitis, bilateral pseudomembranous conjunctivitis, multiple staphylococcal abscesses on the feet, right radial neck fracture after minor trauma, eosinophilia, and raised IgE. Subepithelial deposition of fibrin was seen in gingival and conjunctival biopsies. The National Institutes of Health scoring system for HIES was calculated to be 42 (HIES score >40 points indicates that the presence of autosomal dominant HIES genotype is highly likely). Segmental gingivectomies, topical heparin, and corticosteroids were not effective in dentate areas of gingiva, whereas edentulous areas healed normally. Oral and topical antibiotics caused resolution of the skin abscesses, whereas lubricating and corticosteroid eye drops caused improvement in conjunctival lesions.Conclusions: Ligneous periodontitis and conjunctivitis are novel manifestations in HIES recalcitrant to various treatments. Optimal therapy would be systemic plasminogen concentrate replacement, which is not commercially available. Extensive investigations and a multidisciplinary approach to diagnosis and management are required.

Plasmin Is Essential in Preventing Periodontitis in Mice

Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue- and urokinase-type plasminogen activators, developed periodontal disease similar to that in Plg-deficient mice; however, mice lacking only tissue- or urokinase-type plasminogen activator remained healthy. Supplementation by injection of Plg-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Plg-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases.

Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity

Inherited severe hypoplasminogenaemia is a multisystemic disorder leading to deficient extravascular fibrinolysis. As a clinical consequence wound healing capacity of mucous membranes is markedly impaired leading to ligneous conjunctivitis and several other manifestations. Here we report the molecular genetic and clinical findings on 23 new cases with severe hypoplasminogenaemia. Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10-7T/G). Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract. In contrast, involvement of the gastrointestinal or urogenital tract was not observed in any of the cases. Patients originated to a large extent (61%) from Turkey and the Middle East, and showed a comparably frequent occurrence of consanguinity of affected families and a greater female to male ratio than was derived from previous reports in the literature. Individual treatment of ligneous conjunctivitis included topical plasminogen or heparin eye drops, topical or systemic fresh frozen plasma, and surgical removal of ligneous pseudomembranes, mostly with modest or transient efficacy. In conclusion, the present study underscores the broad range of clinical manifestations in PLG-deficient patients with a trend to regional differences. Transmission of genetic and clinical data to the recently established Plasminogen Deficiency Registry should help to determine the prevalence of the disease and to develop more efficient treatment strategies.

Ligneous Conjunctivitis with Oral Mucous Membrane Involvement and Decreased Plasminogen Level

Ligneous conjunctivitis (MIM 217090) is a rare autosomal recessive hereditary disorder. We report a case with both ligneous conjunctivitis and ligneous periodontitis in association with plasminogen type I deficiency. Diagnosis was based on the clinical and histological findings and most importantly, decreased serum level of plasminogen type I.

Ligneous periodontitis and gingival antioxidant status: Report of two cases

Ligneous periodontitis (LP) is a rare periodontal disease in which plasminogen deficiency and fibrin deposition both play a part, resulting in characteristic gingival enlargement and periodontal breakdown. Recent data suggest that oxidant/antioxidant changes are significant in the pathology of oral diseases. This study examines the gingival histopathology in 2 cases with LP. To examine the antioxidant (AO) status, the activity of the major AOs glutathione (GSH), catalase (CAT), and glutathione S-transferase (GST) and the malondialdehyde (MDA) levels, a product of lipid peroxidation, were measured and compared with healthy control subjects. The histopathologic examination of the gingiva revealed subepithelial fibrin accumulation and irregular extensive downward proliferation of the epithelium. Biochemical analysis showed that the CAT, GST, and MDA levels were higher in LP patients than in the control subjects, and the GSH level was lower. Our preliminary findings show that in LP, the AO capacity of the gingiva changes or decreases and lipid peroxidation increases, which suggests that oxidative stress is involved in the pathology of the periodontal breakdown observed in this disease.

A ligneous periodontitis and conjunctival lesions in a patient with plasminogen deficiency

Destructive membranous periodontal disease is a rare and poorly defined entity that is a part of a systemic disease due to accumulation of fibrin material. The disease is characterized by gingival enlargement and periodontal tissue destruction that leads to rapid bone loss despite treatment efforts. We present a case with ligneous periodontitis and conjunctivitis.

Ligneous Periodontitis and Ehlers‐Danlos Syndrome

Generalized membranous gingival enlargement due to an accumulation of fibrin deposits associated with severe alveolar bone loss (ligneous periodontitis) is a rare condition, and plasminogen deficiency seems to play a central role in its pathogenesis. However, this condition has not been described in association with syndromes. This article reports a case of ligneous periodontitis in a boy with the classic type of Ehlers-Danlos syndrome (EDS). A 12-year-old white male presented with generalized gingival overgrowth and severe alveolar bone loss. A physical examination revealed clinical signs of EDS (velvety skin with mild hyperextensibility, marked hypermobility of the limb joints, atrophic scars on his knees, and easy bruising), which is associated with a positive family history for joint hypermobility. A biopsy of gingival tissues was submitted for routine histology, hematoxylin and eosin (H&E), and direct immunofluorescence (antifibrinogen). An evaluation of plasminogen activity was also performed. Histopathology revealed chronic periodontitis with fibrinoid material deposition, and direct immunofluorescence proved to be positive for fibrin. Functional plasminogen was reduced. A conclusive diagnosis of ligneous periodontitis due to plasminogen deficiency associated with the classic type of EDS was rendered. Ehlers-Danlos syndrome can be associated with ligneous periodontitis. In the present case, the histologic examination represented an important tool in the differential diagnosis, because it ruled out EDS type VIII as the associated systemic factor to periodontal breakdown.

Non‐Hodgkin's lymphoma and auricular hypoplasia: associated with juvenile colloid milium or ligneous conjunctivitis?

The exact nature of amyloid-like hyaline material deposits in the skin is not well understood in some disorders. Three of those--ligneous conjunctivitis, ligneous periodontitis and colloid milium--have been rarely reported in a same patient. We report a case of mucosal and skin deposits of an amyloid-like homogeneous material associated with non-Hodgkin's lymphoma and congenital auricular hypoplasia. We discussed and reviewed the literature on these unique associations to determine whether these are the same pathological process. We also noted whether this case represents a new syndrome or a coincidental association.

Destructive membranous periodontal disease (ligneous periodontitis): a case report and 3 years follow-up

Destructive membranous periodontal disease is a rare, destructive and poorly defined entity, which is the part of a systemic disease due to plasminogen deficiency and fibrin deposition. The disease is characterised by gingival enlargement and periodontal tissue destruction that leads to rapid tooth loss despite treatment attempts. Biopsy is essential to rule out other periodontal disease in the differential diagnosis.