INTRODUCTION

Plasminogen is a proenzyme which is converted into active plasmin by plasminogen activators on the fibrin surface. Plasminogen plays an important role in many events, such as cell migration, angiogenesis, and fibrinolysis. It passes into the bloodstream in proenzyme form after being synthesized in the liver and turns into plasmin, the active enzyme format. During the healing of a wound surface, it activates the “tissue plasminogen activator” and thus leads to the destruction of the fibrin.¹ Mucosal areas acquire a coarse appearance due to the accumulation of fibrin in the absence of complete or partial plasminogen. For this reason, the term “ligneous”, which means “woody” in Latin, is used.² The term “ligneous periodontitis” was first defined by Günhan et al.³ as a periodontal disease characterized by membranous gingival overgrowth and severe bone loss due to the accumulation of amyloid-like material.

Plasminogen deficiency, which can be congenital or acquired, is characterized by the development of fibrin-rich pseudo-membranes on mucosal surfaces such as the mouth, eyes, nasopharynx, trachea, and genital mucosa as a result of impaired fibrin organization and delayed wound healing.⁴

Ligneous mucosal diseases are very rare (0.3-0.4%) autosomal recessive conditions characterized by fibrin deposition in the tissue due to plasminogen deficiency.⁵ Generally, children are affected, but this disease can occur at any age.⁶ Ligneous mucosal diseases may show involvement in several tissues. However, gingival and conjunctival involvements are often observed in childhood.⁷

Among these rare involvements, gingival tissue is a remarkable early sign which is characterized by asymptomatic gingival enlargement and severe periodontal tissue damage.⁸ Local factors, such as poor oral hygiene, infections, irritations, and surgical procedures are predisposing factors in the formation of ligneous periodontal lesions.⁹ The course of this disease is progressive and typically results in early tooth loss. In the hypoplasminogenemic condition, the rare periodontal disease, characterized by ulcerated gingival tissue and rapid tooth loss is defined as “destructive membranous periodontal disease” or “ligneous periodontitis”.¹⁰

In this case report, we share the cases of two siblings with ligneous periodontitis and their long-term therapeutic results in order to (1) bring attention to and foster greater familiarity with the clinical and histopathologic features of this condition among dentists, which is essential for its timely diagnosis and management, and (2) review the literature for features and treatment options about this rare disease.

MATERIALS AND METHODS

Cases

The patients (18- and 21-year-old females) were referred to our clinic with nodular, fragile, and painless gingival overgrowth at the maxilla and mandible. Prior to their dental examination, they were also referred to the department of ophthalmology for various eyelid lesions and they were diagnosed with ligneous conjunctivitis. The conjunctival lesions were detected at 6 months in the younger sibling, and at 10 years in the older sibling.

Their medical examinations revealed hydrocephalus and respiratory distress for the younger sibling and vision loss in the left eye and bilateral hearing loss (30%) for the older sibling.

Both siblings were very similar in a clinical perspective in respect to the appearance and the extension of their ligneous lesions. The brown-yellow gingival overgrowths were prone to bleeding and covered the teeth (Figure 1). Radiographic examination showed severe bone destruction and floating teeth in both siblings (Figure 2). Since the older sibling could not get approval for general anesthesia due to hydrocephalus, she was treated using only pharmaceutical methods.¹¹ This treatment included 2% corticosteroid eye drops applied every 2 hours for 4 weeks for ligneous conjunctivitis and chlorhexidine mouthwash combined with systemic doxycycline for ligneous periodontitis. The younger sibling was operated on under general anesthesia with the support of the replacement of plasminogen. All overgrowth gingival tissue was removed along with the teeth. After clinical healing was established, a total prosthesis was fabricated in order to restore/regain/maintain oral function and esthetics (Figure 3). Recurrence was observed at a 1-year follow-up. One of the siblings was treated with a combination of surgical and pharmaceutical treatment, and the other was given only pharmaceutical treatment because general anesthesia was contraindicated, yet recurrence was found in both.

The histological findings of our cases revealed acanthotic squamous epithelium showing hyperplasia on the surfaces, accumulation homogeneous eosinophilic fibrinous material deposition and inflammatory reactions around the underlying epithelium. These histological findings revealed ligneous periodontitis.

Literature Review

A literature search was performed to gather articles published in English using the PubMed database. The literature review was based on the following terms and words: (ligneous periodontitis) OR (ligneous periodontal disease) OR (ligneous gingivitis) OR (ligneous) AND [English (Language)]. We evaluated the features of ligneous lesions, including age, age at onset, gender, nationality, presence of consanguineous marriage, medical condition, oral findings, histopathological findings, affected organs other than the mouth, treatment, recurrence, and follow-up (Table 1, 2). Lesions which were not located in the gingiva were excluded.

RESULTS

Our PubMed search identified 31 articles and 72 cases with ligneous gingival lesions dating from 1973 to 2020. The demographic features of all reported cases are given in Table 1 and the characteristic features of all reported cases are given in Table 2. The treatment approaches with different success rates are listed in Table 3. In the literature, different treatment results were reported with varying success and recurrence rates. The recurrence and follow-up results are very important and these are summarized in Table 4.

DISCUSSION

Since ligneous periodontitis is a rare disease, it is usually presented as case reports in the literature. There are also reviews which focus on the genetic sequences and plasminogen levels of ligneous diseases.^4,12 Biopsy is the gold standard in the diagnosis of ligneous diseases. Fibrin deposition is diagnosed by hematoxylin, eosin staining, and a negative response to Congo Red. The patient is investigated systemically for plasminogen deficiency and ligneous disease is diagnosed after a biopsy.⁹ Since there is no comprehensive review of the clinical features and treatment of cases, a literature review was needed regarding the clinical evaluations of this disease.

Features of Population

As stated before, this condition may be congenital or acquired. The patients in the literature are reported with a wide age range (1 to 66 years old).

Plasminogen deficiency is an autosomal recessive disease caused by homozygous or compound heterozygous mutations of the plasminogen gene (PLG).¹² Plasminogen deficiency is a rare condition with autosomal recessive inheritance OMIM (Online Mendelian Inheritance in Man): 217090 and its incidence increases with the consanguineous marriage of parents. There are few articles focusing on this condition.^1,10,12-17 Our review is the first comprehensive review in which consanguineous marriage was questioned. Unfortunately, there was no data regarding consanguineous marriage in 44 out 74 cases. Furthermore, among 30 cases reporting on the presence of consanguineous marriage, only 19 cases were positive (1.7:1).

The Turkish population constitutes the majority of cases involving ligneous lesions in the literature.^{1-3,10,13,16,18-22} In our review, focusing on gingival involvement, a total of 74 cases were included, and nearly half of them (30/74) were reported as being of Turkish origin (40.5%). It is estimated that the reason why many cases are seen in the Turkish population is due to the prevalence of consanguineous marriages, especially in rural areas.

In a genetic disorder with an autosomal recessive inheritance pattern, a female-to-male ratio of 1:1 is expected. However, according to the literature, the female/male ratio in ligneous lesions ranges from 1.4:1 to 2:1.²³ In a 2012 review in which only oral ligneous lesions were evaluated, the female/male ratio was reported to be 3.4:1 (77%).²⁴ Similarly, the female (n=55)/male (n=19) ratio was 2.89:1 (74.3%) in our review.

Clinical Features of Lesions

The characteristic clinical features of ligneous gingival lesions are solid, painless, nodular, fragile erythematous, hyperplastic, white-yellow fibrinous pseudomembrane-covered gingival enlargements involving the marginal and attached gingiva, generalized severe periodontal tissue destruction, and ulceration with generalized gross plaque accumulation.^{3,10,12,25,26}

The intraoral clinical examination of our cases had characteristic clinical features as described above. The extension of the gingival overgrowth along with the severe periodontal tissue and alveolar bone destruction both in the maxilla and mandible had the tendency to bleed. A floating teeth appearance within the overgrowth tissue was observed.

Histological Features of Lesions

Early studies in the literature suggested that this disease was caused by a substance which accumulated in the eyes. This amyloid-like eosinophilic material was found to be fibrin. Subepithelial and perivascular fibrin deposition became the characteristic finding of this disease in later studies.²⁴

Characteristic histological features in ligneous lesions are areas of ulceration and hyperkeratosis, acanthosis, granulation tissue formation, an amorphous, fibrin‐rich, amyloid‐like substance deposition due to insufficient fibrin degradation, subepithelial, and perivascular mixed inflammatory cell infiltrate as neutrophils, lymphocytes, and plasma cells.^12,13,19,27

Other Involvements

Ligneous lesions can occur in all organs covered by mucous membranes. Initial studies of ligneous mucosal diseases focused on ligneous conjunctivitis, where the disease is more serious and disruptive. Severe hypoplasminogenemia often presents with ligneous conjunctivitis. The most frequently affected organs in the literature were reported as conjunctiva (81%) and gingiva (30%), respectively.^12,23,24 In more than 12% of the patients, hydrocephalus was also present.²⁸

In parallel with the literature, the most frequently affected organs in our review were conjunctiva (60.8%), genital tract (17.5%), respiratory tract (14.8%), ear (10.8%), skin (4%), hydrocephalus (4%), vocal cords (2.7%), and peritoneum (1.3%).

Treatment Approaches

There is no clear-cut treatment regimen for the management of ligneous lesions.⁴ Various pharmacuetical, surgical, or combined treatment approaches have been tried for these lesions, and most have been found to be successful. The clinician may prefer a more precise and effective treatment method by surgically removing the lesion, as in one of our cases, or consider a pharmaceutical approach in early lesions. In the surgical method, although the patient has postoperative pain, recurrence is expected to occur later as the lesion is eliminated.^1,12,19,29 The total number of cases which provided information about treatment was 55 out of all 74 cases. Surgical methods were preferred in 36.3% (n=20) of the reported cases with a 29.4% (n=5) success rate (no recurrence), whereas pharmaceutical methods were preferred in 43.6% (n=24) of the cases with a 64.2% (n=9) success rate; there are also combined (surgical + pharmaceutical) method reports found in 20% (n=11) of all cases with a 83.3% (n=5) success rate (Table 3).

Systemic or topical corticosteroids, systemic warfarin, low-dose doxycycline, chlorhexidine rinsing, cyclosporine A, PLG eye drops, PLG oral preparations, fresh frozen plasma eye drops, oral contraceptives, topical heparin, topical plasminogen, and azathioprine are some agents of these treatments.^{3,4,14,17,19,26,27} The most popular agents preferred were antibiotics (doxycycline or tetracycline) with chlorhexidine rinsing.^{3,12,19,21,27,30} However, it must be emphasized that evaluation of success is generally dependent on the initial response to any kind of treatment, including surgery.

Glu-plasminogen,³¹ a new treatment method at the approval stage, achieved clinical efficacy and improved disease management by increasing patients’ plasminogen levels. Glu-plasminogen is defined as the naturally circulating form of the plasminogen molecule. Plasmin is activated much more efficiently when bound to cells than in solution. This plasmin binds to plasminogen receptors and produces plasminogen. Thus, Glu-plasminogen therapy promises to increase patients’ plasminogen levels. This promising treatment, whose effect on ligneous periodontitis lesions and its recurrence rate are not yet known, requires more studies and clinical trials.³²

Recurrence Rates According to the Treatment Approaches

The total number of patients for whom information about recurrence was available was 37. The reported recurrence rate was 50%, and there was no information about recurrence in 37 of them. Recurrence was observed in 48.6% (n=18) of all 37 cases. No information was reported about recurrence in 3 out of 20 cases who were treated surgically, while recurrence was observed in 70.5% (n=12) of the remaining 17 patients, and recurrence was not observed in 29.4% (n=5) of them. No information about recurrence was reported in 10 out of 24 patients who were treated with pharmaceuticals, recurrence was observed in 35.7% (n=5) of 14 patients, and recurrence was not observed in 64.2% (n=9) of them. There is a gap regarding recurrence among 5 out of 11 patients who were treated with the combined method, and recurrence was observed in 16.6% (n=1) out of 6 (Table 3). The rate of recurrence seems to be higher in those cases treated only surgically when the follow-up period is not considered.

Follow-up Periods According to the Treatment Approaches

The follow-up periods were classified into three groups in order to estimate the long-term success of treatment modalities given in the literature. The categories were determined as: up to one-year, 1-3 years, and more than 3 years. Considering the follow-up periods according to treatment approaches, no information was reported about the follow-up periods in 11 out of 20 cases who were treated with surgery, and follow-up rates were 22.2% (n=2) for up to one year, 66.6% (n=6) for 1-3 years, and 11.1% (n=1) for more than 3 years in 9 cases. The recurrence rate in surgically treated patients with follow-up information was 66.6% (n=6).

No information was provided in 21 out of 24 cases who were treated pharmaceutically, and follow-up data was only given for 33.3% of 3 cases (n=1) up to 1 year, and 66.6% of them (n=2) for more than 3 years. The recurrence rate of pharmaceutically treated (antibiotics) cases with follow-up information was 100% (n=3).

The follow-up period was not reported for 7 out of all 11 patients who were treated with the combined method. There was no case followed up to 1-year, the follow-up rate in 1-3 years was 75% (n=3), and more than 3 years was 25% (n=1) out of the 4 patients. No recurrence was reported among those patients with follow-up information for the combined method, and the success rate was 100% (n=3) (Table 4).

As stated in the literature, the follow-up period for most cases is between 1-3 years, and in many cases, the follow-up period was not reported. Since the recurrence rate is high regardless of the treatment, the follow-up of these cases is one of the most important stages of the treatment process.

Recurrence rates for advanced lesions were higher than early lesions in all treatment approaches. The advance of the lesion may be a factor which increases the recurrence rate. Clinicians may prefer the pharmaceutical method for early-stage ligneous periodontitis and the combined method which includes both pharmaceutical and surgical treatment for advanced ligneous periodontitis.

Based on the literature and the cases followed, the plasminogen values ​​of individuals should be followed, especially if there is consanguineous marriage in their history. Patients should be followed up by an ophthalmologist and dentist regularly, and treatment should be started as soon as any eye or gingival lesion occurs. If oral ligneous lesions occur, the clinician should keep the patient’s oral hygiene at a maximum level in order to keep the patient’s teeth functioning longer and slow bone loss, and also clean any lesions as much as possible at each appointment in order to create cleanable surfaces for the patient. The primary goal of clinicians in treating oral ligneous lesions is to keep teeth in the mouth or to improve the patient’s quality of life with a prosthesis which can facilitate the chewing function.

As a treatment approach in oral ligneous lesions, pharmaceutical methods can be used in early lesions and surgical methods in advanced cases. However, it can be said that there is no consensus on the treatment of oral ligneous lesions with a low recurrence rate based on the cases in which different treatments and recurrence rates have been reported in the literature. The possibility of recurrence should be considered for all treatment options.

CONCLUSION

Ligneous lesions are rare diseases characterized by fibrin deposition due to plasminogen deficiency and may affect the mucosal areas. Regular follow-up and maximum oral hygiene are essential for the maintenance of these lesions. The main purpose of this study was to inform clinicians about the features and treatment options for these lesions, although this was not fully achieved due to a lack of long-term follow-up and recurrence reports in the literature. Future studies on ligneous periodontitis lesions which investigate the host response with long-term clinical follow-up can be performed.

MAIN POINTS

• Ligneous lesions are rare and hard-to-manage lesions with high recurrence rates. Therefore, we aimed to present our two cases with a literature review including the features and treatment options of ligneous gingival lesions in this study.

• Ligneous lesions are autosomal recessive conditions characterized by impaired fibrin organization due to plasminogen deficiency. These lesions affect organs covered by mucous membranes such as the conjunctiva, gingiva and genital tract.

• Although there is no consensus about the treatment of ligneous lesions, both pharmceutical and surgical approaches may regress them, however, their recurrence rate is very high.

• Ligneous gingival lesions affect the quality of life and clinicians may not have a good command of their management. Although there is no definitive treatment, the pharmaceutical approach may be preferred in early lesions and radical surgery may be preferred in advanced cases. Regardless of the treatment approach, regular follow-up and maintenance of oral hygiene are essential.

ETHICS

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: K.B.K., B.B., Design: K.B.K., R.B.K.Ü., Supervision: K.B.K., T.Ç., Materials: K.B.K., B.B., T.Ç., Data Collection and/or Processing: K.B.K., B.B., T.Ç., Analysis and/or Interpretation: R.B.K.Ü., Literature Search: R.B.K.Ü., Writing: K.B.K., R.B.K.Ü., Critical Review: T.Ç.

DISCLOSURES

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study had received no financial support.