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October 16, 2007

Case 3-2007

This is the case of a 2½-year-old boy with persistent and progressive gingival hypertrophy.

Case Presentation

This child was referred by his pediatrician for an oral evaluation. The parents of this healthy 2½-year-old male noted the presence of a painless and gradual overgrowth of the attached gingiva, which was initially noted shortly after the primary dentition had erupted. There was associated interference with function, oral hygiene, and eruption pattern. Concurrently the parents noted the formation of painless, firm, subcutaneous masses over the forehead that may have arisen in association with trauma, but have been persistent and painless with slow growth evident.

History revealed no systemic disease, seizure disorder, ocular abnormality, or organomegaly. The usual developmental milestones had been met.

Physical examination revealed a well developed, well nourished child with appropriate motor and mental development. The facial skin was slightly eczematous, with no sign of papular or eruptive diseases elsewhere. Overall hair pattern and pinna morphology were normal. The head and neck examination further revealed the presence of multiple firm and painless masses over the forehead; these masses were surfaced by intact and normal-appearing skin (Figure 1). Each of the masses measured approximately 2.5 cm in diameter and essentially fixed to the epidermis, but was not attached to the periosteum. Further examination revealed the presence of similar scalp masses over the occipital region and left postero-lateral region.

Careful intraoral examination revealed a fully erupted normal primary dentition without caries, mobility or malposition. Markedly bulbous and multinodular gingival architecture dominated the oral examination with no sign of tissue friability, tenderness or bleeding (Figure 2). The level of the attached gingiva approached the incisal edges in both arches, with pseudopocketing evident but without periodontal attachment loss, though there was a slightly lesser degree of posterior gingival overgrowth. A normal radiographic survey was noted, with appropriate development of secondary dentition.

In view of impending incisal and occlusal functional disturbance secondary to the soft tissue proliferation, a conservative gingivoplasty with exposure of the clinical crowns was performed, with tissue submitted for pathologic evaluation. Microscopic analysis of the specimen demonstrated a thinned but intact overlying orthokeratinized epithelium over a uniformly well-vascularized stroma, where evenly but widely distributed fibroblasts were seen (Figure 3). Cytologic details were benign in nature. Of note, however, was an abundance of acellular hyaline eosinophilic zones containing narrow irregular collagen bundles between separated plump spindle-shaped and stellate fibroblasts. Fibroblast morphology was further characterized by an expanded cytoplasm, while the area surrounding these cells demonstrated a lacunar quality in some regions. There was no sign of a significant inflammatory component within the stroma.

The diagnosis was gingival fibromatosis with prominent hyaline alteration within the stroma. Several weeks following the gingival resection, the forehead lesions were removed by a plastic surgeon. The microscopic qualities present in the resected tissue were essentially identical to the gingival tissues, with the final pathology report noting the hyaline quality of the stromal component.

Differential diagnosis

Gingival architectural alterations characterized by diffuse and symmetric enlargement are noted over a wide spectrum of conditions. These conditions may be reactive, hereditary, or medication-related, and may be isolated and restricted to the oral cavity, or as a component of a systemic disease process. The enlargement may involve the interdental papillae, attached gingival, and marginal gingival, and include:

1. Drug-induced overgrowth (phenytoin, cyclosporine A, nifedipine)
2. Inflammation-based gingival enlargement
3. Neoplasia-related gingival overgrowth
4. Syndrome-associated or heredity-based gingival hypertrophy
   1. Cowden syndrome
   2. Prune belly syndrome
   3. Cross syndrome
   4. Zimmerman-Laband syndrome
   5. Murray-Puretic-Drescher syndrome
   6. Rutherfurd syndrome

The syndromes include many extraoral features and findings, such as mental retardation, progressive sensorineural hearing loss, seizure disorder, hypertrichosis, and cutaneous abnormalities with associated abnormalities of the distal phalanges.

Based upon the clinical findings of diffuse and symmetrical gingival enlargement, the presence of evolving subcutaneous masses, and the histopathology, the diagnosis was juvenile hyaline fibromatosis.

Future course

Over the ensuing four years several other clinical abnormalities developed, including more widespread distribution, and an increased number of subcutaneous lesions initially confined to the forehead and scalp. Hyaline fibromas were noted on the pinnae, within the nose, and importantly over the hands, feet and at the digits with associated osteolytic changes at the terminal phalanges of all extremities (Figures 4a and b).

In addition, the patient developed mild contracture-related functional deficits of the extremities. His younger brother was examined at age 2½, and was also found to have similar mucocutaneous lesions, though slightly less pronounced than his older brother at a similar age. The patient’s older sister did not demonstrate any stigmata of this condition. Genetic counseling and pedigree analysis failed to reveal any other affected family members.

Several gingival remodeling procedures and plastic surgical procedures (involving the ears, digits, and scalp) were performed into and beyond adolescence. Genetic counseling was performed with the family.

Discussion

A patient presenting with gingival overgrowth or hypertrophy offers the clinician an opportunity to fully evaluate the patient’s circumstances, beyond the oral findings and implications.

The specific syndrome in this case is termed the Murray-Puretic-Drescher syndrome (juvenile hyaline fibromatosis). As with the patient in this case, the syndrome is characterized by diffuse and symmetrical gingival fibromatosis, multiple cutaneous and subungual hyaline fibromas, and flexural contractures of the large joints of the extremities. Autosomal recessive transmission is stated, though in this case no family history was noted, nor was there consanguinity evident upon pedigree analysis. More recent studies have identified mutations in the gene responsible for the encoding of capillary morphogenesis protein 2, a transmembrane protein induced during capillary development that binds laminin and type 4 collagen by way of a von Willebrand factor A domain.1 The specific gene has been mapped to chromosome 4q21, with identification of 15 genetic mutations encoding the stated capillary encoding protein. More recently, differences in mRNA expression of fibronectin and laminin have been described where there are alterations in adhesion molecule and extracellular matrix mRNA expression.2,3 The related condition, infantile systemic hyalinosis, is a more severe clinical problem with visceral involvement and premature death. Of interest is the fact that both conditions are members of the same disease spectrum; gingival hypertrophy is a common component.4 Clinicians are reminded that gingival architectural alterations may point the way to a more complex set of diseases and conditions that may be emerging or previously undetected. Multidisciplinary investigation and management strategies are necessary, including strict gingival and periodontal maintenance.5

References

1. Hanks S, Adams S, Douglas J, et al. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet. 2003;73:791-800.
2. Hakki SS, Balci B, Hakki EE, et al. Identification of the difference in extracellular matrix and adhesion molecules of cultured human gingival fibroblasts versus juvenile hyaline fibromatosis gingival fibroblasts using cDNA microarray analysis. J Periodontol. 2005;76(12):2244-2253.
3. Rahman N, Dunstan M, Teare MD, et al. The gene for juvenile hyaline fibromatosis maps to chromosome 4q21. Am J Hum Genet. 2002;71(4):975-980.
4. Muniz ML, Lobo AZ, Machado MC, et al. Exuberant juvenile hyaline fibromatosis in two patients. Pediatr Dermatol. 2006;23(5):458-464.
5. Uslu H, Bal N, Guzeldemir E, et al. Three siblings with juvenile hyaline fibromatosis. J Oral Pathol Med. 2007;36(2):123-125.

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