Ligneous Periodontitis and Ehlers-Danlos Syndrome

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  • Case Report

    Ligneous Periodontitis and Ehlers-Danlos Syndrome

    Viviane S.S. Pierro,* Ramon Vazquez-Sullca, Aurea Simone Barroso Vieira,*Christina Maeda Takiya, Gerson Carakushansky, and Eduardo J. Feres-Filho

    Background: Generalized membranous gingivalenlargement due to an accumulation of fibrin depositsassociated with severe alveolar bone loss (ligneousperiodontitis) is a rare condition, and plasminogende-ficiency seems to play a central role in its pathogene-sis. However, this condition has not been described inassociationwith syndromes. This article reports a caseof ligneous periodontitis in a boywith the classic typeof Ehlers-Danlos syndrome (EDS).

    Methods: A 12-year-old white male presented withgeneralized gingival overgrowth and severe alveolarbone loss. A physical examination revealed clinicalsigns of EDS (velvety skin with mild hyperextensibil-ity, marked hypermobility of the limb joints, atrophicscars on his knees, and easybruising),which is associ-atedwith a positive family history for joint hypermobil-ity. A biopsy of gingival tissues was submitted forroutine histology, hematoxylin and eosin (H&E), anddirect immunofluorescence (antifibrinogen). An evalu-ation of plasminogen activity was also performed.

    Results: Histopathology revealed chronic periodon-titis with fibrinoid material deposition, and direct im-munofluorescence proved to be positive for fibrin.Functional plasminogenwas reduced. A conclusive di-agnosis of ligneous periodontitis due to plasminogendeficiency associated with the classic type of EDSwas rendered.

    Conclusions: Ehlers-Danlos syndrome can be asso-ciated with ligneous periodontitis. In the present case,the histologic examination represented an importanttool in the differential diagnosis, because it ruled outEDS type VIII as the associated systemic factor to peri-odontal breakdown. J Periodontol 2006;77:123-128.

    KEY WORDS

    Child; deficiency; Ehlers-Danlos syndrome; gingivalovergrowth; periodontitis; plasminogen.

    The term ligneous periodontitis was first used byGunhan et al.1 to describe a destructive mem-branous periodontal disease characterized by

    gingival enlargement and periodontal tissue destruc-tion due to the accumulation of amyloid-like material.Most of the pseudomembranous gingival lesions havebeen reported in association with ligneous conjuncti-vitis.1-10 Therefore, these findings suggest that bothclinical manifestations are related.11

    Ligneous conjunctivitis is a rare form of chronicconjunctivitis that usually affects children, girls moreoften than boys (gender ratio of 3:1), but may occur atany age.11,12 This condition appears to be the ocularmanifestation of a systemic disease that might be ac-companied by formation of pseudomembranes on themucosa of the mouth (ligneous gingivitis or periodon-titis),1-10 the female genital tract (ligneous vulvovag-initis or cervicitis),3,13,14 the laryngotracheobronchialtree,3,14-17 the middle ear,14,17 and the mastoid sys-tem.17 Pseudomembranous inflammation simulta-neously involving the female genital tract, middleear, and oral mucosa, with no signs of ligneous con-junctivitis,18 also has been reported, as well as somecases in which pseudomembranes were present onlyin the gingival tissue.6-8,19

    It has been suggested that ligneous conjunctivitismight be an autosomal recessive disorder.20 Its cen-tral feature is an impaired wound-healing capacitywith an arrest at the stage of granulation tissue forma-tion and excessive fibrin deposition.11 The prominentfibrinous component observed in histologic ex-aminations of eye lesions has also been reportedas the most notable histologic feature of affectedtissues from other mucosal sites.1,3,4,6-8,13,17-19

    These descriptive findings have been related to amajor deficiency of (plasmin-mediated) extracellularfibrinolysis.11

    The report of a case in which pseudomembranouslesions arose as a side effect of tranexamic acid, anantifibrinolytic drug used in the treatment of menor-rhagia, linked plasminogen deficiency to the patho-genesis of ligneous conjunctivitis and ligneousperiodontitis.4 After this report, many studies foundthat pseudomembranous lesions (regardless oftheir location) were indeed caused by plasminogen

    * Department of Pediatric Dentistry and Orthodontics, School of Dentistry,Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

    Graduate Periodontics, School of Dentistry, Federal University of Riode Janeiro.

    Department of Histology and Embriology, Institute of Biomedical Sciences,Federal University of Rio de Janeiro.

    Department of Pediatrics (Genetic Service), School of Medicine,Federal University of Rio de Janeiro.

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  • deficiency.8-10,14-16,18,19,21-23 This condition is con-sidered rare, with a prevalence of about 0.4% in thegeneral population.24 The severity of the disease ap-pears to be inversely related to the level of functionalplasminogen activity.10 Gingival lesions due to plas-minogen deficiency may be progressive and resultin tooth loss despite treatment attempts with subgin-gival curettage, gingivectomy, and antibiotics.1,6,7

    Gingival enlargement with or without severe peri-odontitis has also been described in association withEhlers-Danlos syndrome (EDS),25,26 especially typeVIII.27-29 EDS is a heterogeneous group of heritableconnective tissue disorders, characterized by articularhypermobility, skin hyperextensibility, and tissue fra-gility.30 The pattern of inheritance and the clinicalmanifestations vary with the type of EDS being exam-ined.31 The prevalence of EDS has been estimated tobe about one in 5,000 births,32 and diagnosis is basedprimarily on clinical findings.30

    This case report describes a case of ligneous peri-odontitis in a boy with the classic type of Ehlers-Danlos syndrome.

    CASE REPORT

    A 12-year-old male of Italian descent presented to thepediatric dental clinic for special-needs patients atthe Federal University of Rio de Janeiro, Brazil, witha history of gingival overgrowth since the eruptionof primary molars. Previous medical history includeda 5-day hospital stay caused by a severe urinaryinfection episode at 2 weeks old, and a longer hospitalstay (15 days) as a result of an episode of acuteasthma at 2 years old. His parents also reported a de-lay in speech and walking that was associated withgeneralized muscle hypotonia. For this reason, thepatient had been taking speech therapy and physio-therapy sessions since he was 2 years old. Physiother-apy sessions were interrupted when he turned 6because the therapist noticed an uncommon hyper-mobility of his hip joint. On presentation, he wasotherwise healthy, and medications included dailymethylphenidatek prescribed by his neurologist forthe treatment of attention deficit disorder (ADD).

    Intraoral examination revealed a permanentdentition presenting generalized gross plaque accu-mulation and a painless, massive, nodular fragilegingival enlargement involving both maxilla and man-dible. The enlargements were covered with whiteyellowish membranes, with a tendency to bleed (Figs.1A and 1B). A panoramic radiograph revealed exten-sive bone loss (Fig. 2), and bitewings confirmed theabsence of carious lesions. The buccal aspect of gin-gival tissues from the left mandibular side was biop-sied. Half of the specimen was processed for lightmicroscopy, while the other half was frozen and pro-cessed for direct immunofluorescence using antibody

    against fibrinogen conjugated with FITC as describedelsewhere.33

    Despite a negative family history for gingival over-growth, there was a positive history for joint hypermo-bility (the childs uncle). For this reason, the patientwas referred to a geneticist. On referral, he presentedsmooth, velvety skin with mild hyperextensibility,marked hypermobility of the limb joints (e.g., thewrists and fingers), atrophic scars (having papy-raceous appearance) on his knees, and a positive his-tory for spontaneous ecchymoses (easy bruising)(Figs. 3A and 3B). Therefore, based on the patientsmedical and family histories, combined with clinicalfindings (especially his severe gingival overgrowthand aggressive periodontitis), his profile was consis-tent with Ehlers-Danlos syndrome type VIII.

    Reevaluation of the biopsied site showed rapidregrowth of the excised tissue, and a histologic ex-amination revealed areas of ulceration, granulationtissue, subepithelial inflammatory infiltration, and

    Figure 1.A) Extensive gingival overgrowth covered with whiteyellowishmembranes (frontal view). B) Lateral view.

    k Ritalina, Novartis Biociencias S/A, Sao Paulo, Brazil. Dako, Carpinteria, CA.

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  • amorphous nodular deposits of a homogeneous,eosinophilic substance beneath the gingival squa-mous epithelium (Fig. 4A). The microscopic diagno-sis was chronic hyperplasic gingivitis with ulcerationand fibrinoid deposits. Congo red staining for amy-loidosis was negative. Periodic acid-Schiff reactionand Sudan black staining proved to be negative aswell, thereby excluding the possibilities of infantilesystemic hyalinosis and lipid proteinosis, respec-tively. Direct immunofluorescence of the gingivalspecimen showed a positive staining for fibrinogen(Fig. 4B). Therefore, a recommendation was madeto evaluate plasminogen activity, and the functionalplasminogen and plasminogen antigen assays wererequested. The patient presented a low functionalplasminogen level of 13% (reference range, 70% to143%). His parents were asked about similar pseudo-membranous lesions in the patients conjunctivae.They reported that the lesions appeared when thepatient was about 6 months old, and that they weretre