Hereditary gingival fibromatosis with a recessive mode of inheritance. Case reports

Steven L. Singer, BDS, FDSRCPS(Glasg), MSc(Lond), DOrth(Eng)* Jack Goldblatt, MB, ChB, MD(C'town), FCP(SA), FRACPt L. A. Hallam, BSc, MB, BCh(Wales), MRCPath(Lond)$ John C. Winters, BDSc, MDSc(WA)*

Key words: Hereditary gingival fibromatosis, may be involved in both the and autosomal recessive. and the degree of hyperplasia may vary even between individuals within the same family. The Abstract inconsistent clinical presentation of affected Hereditary gingival fibromatosis is characterized by individuals in the same kindred suggests a genetic varying degrees of attached gingival hyperplasia and defect with a variable expression.'.6 The degree of may in rare cases present as a feature of a gener- gingival coverage of the dentition does not affect alized syndrome. It is usually inherited as an the eruption of the teeth to a normal bony level.' autosomal dominant condition though recessive This report documents the clinical and patho- forms are described. The dental and genetic logical features, the family history and the dental features of an affected brother and sister with a prob- management of siblings with a previously un- ably unique autosomal recessive hereditary reported syndrome. fibromatosis syndrome are presented.

(Received for publicationApril 1992. Accepted July Case reports 1992.) Case 1 An 11 year old Caucasian girl was seen at the Introduction Princess Margaret Hospital Genetic Clinic for Hereditary gingival fibromatosis is a rare condi- investigation of hereditary gingival fibromatosis. tion (1:750,000)' which can present as an isolated She had a distinctive facial appearance character- disorder or more rarely as a syndrome component.* ized by hypertelorism with anti-mongoloid slanting Males and females are equally affected3 and trans- palpebral fissures and the eyebrows were bushy mission is thought to be via an autosomal dominant with synophrys. There was flattening of the nasal gene.'.4-6 though Jorgenson' and Andersons have and hypoplastic nares. The were prom- reported families probably manifesting a recessive inent and she had a cupid bow (Fig. 1). mode of inheritance. There was relative macrocephaly with a head The hyperplastic tissue is normal in colour, has occipito-frontal circumference (OFC) of 550 mm a firm consistency and an abundance of ( > 97th centile). Intraoral examination revealed the of the attached gingivae. Buccal and lingual tissue patient to be in the mixed dentition. The level of was good. There was an anterior open- bite from 53 to 63. The dental arches were broad and rounded anteriorly and were characterized by *Dental Department, Princess Margaret Hospital, Penh, Western generalized attached gingival hyperplasia affecting Australia. both buccal and lingual regions in the maxilla and tDirector of Genetic Services, Princess Margaret Hospital, Penh, Western Australia. mandible. The excessive gingival tissue was $Department of Anatomical Pathology, Princess Margaret producing a bulbous arch form in the bucco-lingual Hospital, Perth, Western Australia. plane. Gingival hyperplasia was most evident in the

Australian Dental Journal 1993;38(6):427-32. Fig. 1. -Case 1. Note bushy eyebrows, synophrys, flattened nasal bridge with hypoplastic nares and a cupid bow mouth with prominent lips. Fig. 2. -Case 1. Frontal intra-oral view showing spacing of the upper and lower and only partial eruption of the teeth due to attached gingival hyperplasia present. Note retention of the 52. Fig. 3.-Case 1. Panoramic radiograph showing non-eruption of the 16 and 26 with eruption of the permanent dentition anterior to the first molars to a normal bony level.

maxillary tuberosity region and labial to the maxil- Case 2 lary and mandibular incisors. The tissue was pink The girl's 15 year old brother had similar orofa- and healthy and firm on probing. There was gener- cia1 features with hypertelorism and anti-mongoloid alized spacing of the upper and lower labial slanting palpebral fissures, bushy eyebrows, segments with a prominent median diastema (Fig. synophrys, a broad flattened nasal bridge with 2). The 52 was retained palatally to the erupted 12 hypoplastic nares and relative macrocephaly with and there was non-eruption of the 16 and 26. The a head circumference (OFC) of 577 mm (>97 permanent dentition showed incomplete eruption centile) (Fig. 4). The dental arches were broad and into the mouth due to the hyperplastic gingival rounded anteriorly with hyperplasia involving all tissue though radiographic examination showed buccal and lingual attached gingival regions in the eruption of teeth to a normal bony level (Fig. 3). maxilla and mandible. Gingival excess was most The mucosa overlying the 16 and 26 was excised evident in the tuberosity region (Fig. 5). The denti- under local anaesthetic to allow the eruption of tion had not fully erupted into the oral cavity due these teeth. A sample of the gingival tissue was sent to gingival bulk though non-eruption of permanent for routine histological examination. The retained teeth was not a feature. He had a history of delayed 52 was extracted. The patient was then placed loss of which had necessitated their under periodic review to monitor occlusal develop- extraction to allow the eruption of their permanent ment. It is planned to carry out corrective successors. The mucosa was pink, healthy and firm orthodontic treatment on establishment of the to probing. Occlusal features of note included an permanent dentition. incomplete and a non-displacing

428 Australian Dental Journal 1993;38:6. Fig. 4. -Cure 2. Note bushy eyebrows, synophrys, flattened nasal bridge with hypoplastic nares and a cupid bow mouth with prominent lips. Fig. 5.-Cuse 2. Occlusal view of maxilla. Note tissue excess in the tuberosity region.

involving 26 and 25. The permanent canines were the rete ridges. The showed variable unerupted. On eruption of the permanent canines keratinization, predominantly orthokeratosis with corrective orthodontic treatment will be carried out. focal parakeratosis (Fig. 6a). The papillary stroma was loose with plump and thin walled Familial observation vessels (Fig. 6b). The deeper tissue was expanded Their brother was entirely normal, there was no by rich in interlacing bundles of parental consanguinity and no other family history dense that was compressing fibroblasts and of gingival fibromatosis. Dental and genetic exam- vessels (Fig. 6c). This dense connective tissue ination of the parents failed to reveal any abnormal extended down (470 pm) to the deep resection orofacial features. The affected children were of margin. was minimal with scattered normal intelligence and had no associated syndromic mononuclear cells in the papillary stroma occasion- features and were not on known to ally passing into the overlying epithelium. Mast induce gingival fibromatosis. cells were present but not particularly numerous between collagen bundles and around vessels in the Histopathology deeper tissue. A specimen was obtained from Case 1, a wedge of grey tissue 9 mm x 5 mm x 5 mm partly Discussion covered by epithelium. Examination of the speci- Hereditary gingival fibromatosis (HGF) may men by light microscopy showed the epithelium to occur as an isolated feature or rarely as part of a be hyperplastic (37 pm from the base of the ridges syndrome. The cases presented had a previously to the surface) with elongation and anastomosis of undescribed condition with distinctive facial

Australian Dental Journal 1993;38:6. 429 Fig. 6a. - Case 1. Lower power photomicrograph showing hyperplastic epithelium overlying dense paucicellular connective tissue down to the deep resection margin. H & E. Fig. 6b.-Case 1. Higher power view of epithelium illustrating anastarnoses of the ridges and keratinization in the superficial layers. Papillae contain plump fibroblasts and thin walled vessels embedded in loose connective tissue. Scattered lymphocytes are seen migrating into the epithelium. H & E. Fig. 6c.-Case 1. High power view of the connective tissue underneath epithelium consisting of interlacing bundles of dense collagen compressing fibroblasts and vessels. H & E. features in association with the oral signs of HGF. everted by the excess tissue bulk and are unable to The syndromic characteristic most commonly seen in HGF is hypertrich~sis~which is occasionally In the cases presented both children had a similar associated with mental retardation and epilepsy.8,10 degree of gingival excess with generalized tissue These manifestations and other rare associations hyperplasia in all buccal and lingual regions of such as multiple hyaline (Murray-Peretuc attached gingivae in both the maxilla and mandible. Drescher syndrome), corneal dystrophy (Rutherford As previously reported the hyperplastic syndrome) ear, nose, bone and nail defects with can physically prevent the eruption of permanent splenomegaly (Labland syndrome) progressive deaf- teeth and cause a delay in shedding deciduous ness (Jones syndrome) and microphthalmia, mental teeth.'f3 This was observed in Case 1 with the non- retardation, athetosis and hypopigmentation (Cross eruption of the 16 and 26 and late loss of decidious syndrome) were not observed in either of the two teeth in both patients. In both cases the dentition children who were of normal intellect. The presence erupted to a normal bony level despite a decrease of the disorder in male and female siblings with both in the amount of eruption due to the exces- parents unaffected is most consistent with auto- sive gingival bulk. soma1 recessive inheritance. Most of the HGF The condition was first noted by the parents at syndromes are dominantly inherited and for this the commencement of the mixed dentition due to family to have an autosomal dominant condition the late loss of deciduous teeth and late eruption would necessitate postulating germinal mosaicism of their permanent successors. The actual diagnosis or non-penetrance in one parent which are less of the condition did not occur, however, until the likely genetic explanations. children were examined for orthodontic investiga- Oral manifestations of HGF can vary from focal tion of their dental . Though the mixed sites of gingival hyperplasia to generalized involve- dentition is commonly described as a period of onset ment that can as in the described cases inhibit the of gingival fibromatosisl it has been noted shortly complete eruption of the permanent dentition into after birth6 and on the eruption of the deciduous the oral In extreme cases the lips are teeth.4.9 It may be that gingival hyperplasia was

430 Australian Dental Journal 1993;38:6. present in both individuals prior to its clinical detec- As yet, research has not been directed into the tion due to its benign nature. role of collagen catabolism in the aetiology of It is important that if an individual is seen with gingival fibromatosis. A possible explanation for the clinically enlarged attached gingival tissue a contradictory biochemical findings may be that thorough medical history be taken to eliminate gingival fibromatosis may be a common clinical acquired causes of gingival excess such as ingestion manifestation caused by several different biochem- of verapamil12 and nifedipine13 which are used in ical defects of genetic origin, rather than by one the treatment of angina and cardiac arrhythmias, distinct genetic defect. It is interesting to note that cyclosporin-AI4an anti-rejection drug, or phenytoin the fibroblasts investigated by Shirasuna" came which is used to treat epi1epti~s.l~A dentist must from a patient whose only anomaly was gingival be aware of such a medical condition if active dental hyperplasia. The tissue investigated by Johnson'* treatment is to be carried out. and OikarinenI9 came from individuals who had other associated anomalies. The oral location of this Histological examination of the oral mucosa condition may be related to the very high turnover removed to allow the eruption of the 16 and 26 in of gingival connective tissue22 which would be Case 1 showed the presence of hyperplastic especially high during the loss or eruption of teeth epithelium with elongation of the rete ridges which and result in the local amplification of any defect extended deeply into the underlying connective in connective tissue metabolism. tissue. These features, in addition to the loose In view of the benign nature of this condition network of connective tissue, plump fibroblasts and treatment is conservative and is aimed at allowing large vessels in the papillary region, in association the normal eruption of the permanent dentition into with dense collagen fibres that were compressing the oral cavity and removal of retained deciduous the surrounding fibroblasts and vessels in the deeper teeth. Reduction of excessive tissue bulk is indicated layers of the oral mucosa, are in agreement with if it is unsightly or causing a functional problem previous reports in the literature.1.6.16Calcified foci such as the inability to close the lips. To date, in as reported by Zackin et al. and Raesta et al. were the patients presented, treatment has been limited not ob~erved.~.~ to the surgical exposure of the 16 and 26 with the Though it is accepted that hereditary gingival extraction of the retained 52 in Case 1. Neither fibromatosis is a disease of genetic origin, the patient was troubled by the gingival aesthetics so mechanism which leads to the accumulation of a reduction has not been a require- excessive amounts of gingival tissue is not known. ment. It will, however, be necessary to carry out There is some evidence that the defect may lie in a reduction gingivectomy prior to corrective ortho- the anabolism of connective tissue products. dontic treatment in order to facilitate correct Shirasuna" found that during in vitro culture, placement of orthodontic attachments. It should be fibroblasts from an individual with gingival noted that the long-term effect of surgery is fibromatosis produced increased amount of collagen unpredictable. Several authors have reported the and glycosaminoglycans compared with fibroblasts recurrence of hyperplastic tissue following gingivec- from a normal individual, and suggested that the tomy necessitating a repeat of the pr0~edure.l.~The increase in gingival bulk was as a direct result of degree of hyperplasia is reported to decrease with the excessive production of components of connec- age.' tive tissue. These findings contrast with JohnsonI8 and Oikarinen.I9 They found that when fibroblasts from patients with hereditary gingival hyperplasia Conclusion and normal individuals were cultured in vitro, This paper reports the clinical features of a previ- though they produced similar amounts of protein, ously unreported HGF syndrome. The oral features the amount of collagen produced by the former was were noted during a routine orthodontic examina- reduced. An excessive accumulation of collagen tion and were characterized by attached gingival would occur in such a situation if there was an hyperplasia which involved all areas of the mouth. associated disturbance in collagen catabolism such Both patients had a history of delayed loss of as a reduction in activity, the principal deciduous teeth and late eruption of the permanent enzyme in regulating extracellular degradation of dentition and in one individual non-eruption of the co11agen,20,21or an increase in the extracellular first permanent molars was a feature. This presen- levels of tissue inhibitor of metalloproteinase which tation is characteristic of the condition. is the main extracellular regulator of the matal- Following routine genetic examination, previ- loproteinase enzyme system which is responsible ously unreported facial features were noted in both for catabolizing connective tissue constituents in the individuals. Investigation of the family history extracellular environment.21 suggested that the mode of transmission was re-

Australian Dental Journal 1993;38:6. 431 cessive. Most cases of syndromic presentation of 13. Lederman D, Lumerman H, Reuben S, Freedman PD. Gingival hyperplasia associated with nifedipine therapy. Oral HGF are due to a dominant gene. It is important Surg Oral Med Oral Pathol 1984;57:620-2. that possible drug Of gingival 14, Rateitschak-PlussEM, Hefii A, Lonschen R, Thiel G, Initial be ruled out before a definitive diagnosis is made. observation that cyclosporin-A induced To date, treatment has been limited to aiding the in man. J Clin Periodont 1983;10:237-46. eruption of the permanent dentition. 15. Hassell TM. Evidence for the production of an inactive collagenase by fibroblasts from phenytoin-enlarged human gingivae. J Oral Path 1982;11:310-7. References 16. Collan Y, Ranta H, Varito T, Perheentupa J, Raeste AM. 1. Fletcher JP. Gingival abnormalities of genetic origin: prelimi- Histochemical and biochemical study of hereditary fibrous nary communication with special reference to hereditary hyperplasia ofthe gingiva. Scand J Dent Res 1982;90:20-5. gingival fibromatosis. J Dent Res 1966;45:597-612. 17. Shirasuna K, Okura M, Watatani K, Hayashido Y, Saka M, 2. Gorlin RJ, Pindborg JJ, Cohen Jr MM. Syndromes of the Matsuya T. Abnormal cellular property of fibroblasts from head and neck. 2nd edn. New York: McGraw Hill, congenital gingival fibromatosis. J Oral Pathol 1989;7:381-5. 1976~329-36. 18. Johnson DB, El-Guindy M, Ammons WF, Narayanan AS, 3. Rushton MA. Hereditary or idiopathic hyperplasia of the Page RC. A defect in fibroblasts from an unidentified . Dent Pract 1957;7:136-46. syndrome with gingival hyperplasia as the prodominent 4. Savara AM, Suher T, Everett FG, Burns AG. Hereditary feature. J Periodont Rec 1986;21:403-13. gingival : Study of a family. J Periodontol 19. Oikarinen K, Salo T, Kaar M-L, Lahtela P, Altonen M. 1954;25: 12-21. Hereditary gingival fibromatosis associated with growth 5. Zackin SJ, Weisberger D. Hereditary gingival fibromatosis. hormone deficiency. Br J Oral Maxillofac Surg 1990;28: Report of a family. Oral Surg Oral Med Oral Pathol 335-9. 1961; 14:828-36. 20. Wilhelm SM, Javed T, Miller RL. Human gingival fibro- 6. Raeste AM, Collan T, Kilpinin E. Hereditary fibrous hyper- blast collagenase: Purification and properties of precursor plasia of the gingiva with varying penetrance and and active forms. Collagen Re1 Res 1984;4:129-52. expressivity. Scand J Dent Res 1978;86:357-65. 21. Meickle MC, Heath JK, Reynolds JJ. Advances in under- 7. Jorgenson RJ, Cocker ME. Variation in the inheritance and standing cell interactions in tissue resorption. Relevance to expression of gingival fibromatosis. J Periodontol the pathogenesis of and a new hypothesis. 1974;45:472-7. Oral Path 1986;15:239-49. 8. Anderson J, Cunliffe WJ, Roberts DF, Close H. Heredi- 22. Narayanan SA, Page RC. Connective tissues of the perio- tary gingival fibromatosis. Br Med J 1969;3:218-9. dontium: A summary of current work. Collagen Re1 Res 9. Horning GM, Fisher JG, Barker BF, Kilroy WJ, Lowe JW. 1983;3:33-64. Gingival fibromatosis with hypertrichosis: a case report. J Periodontol 1985;56:344-7. 10. Synder CH. Syndrome of gingival hyperplasia, hirsutism and convulsions. J Pediatr 1965;67:499-502. Address for correspondenceheprints: 11. Winstock D. Hereditary gingivofibromatosis. Br J Oral Surg Genetic Clinic, 1964;2:59-64. Princess Margaret Hospital, 12. Pernu HE, Oikarinen K, Hietanen J, Knuuttila M. Verapamil-induced gingival overgrowth: a clinical, histological, Thomas Street, and biochemical approach. J Oral Pathol Med 1989;18:422-5. Perth, Western Australia, 6008.

432 Australian Dental Journal 1993;38:6.