CLINICAL PRACTICE DIAGNOSTIC CHALLENGE Gingival enlargement Gregory A. Pette, DMD, MS; Michael A. Siegel, DDS, MS, FDS RCSEd; William B. Parker, DDS THE CHALLENGE scribed valproic acid. Approximately eight A 29-year-old woman visited the postgraduate months after the patient ceased taking pheny- periodontics clinic at the College of Dental Medi- toin, she visited the postgraduate periodontal cine, Nova Southeastern University, Fort clinic. The patient’s oral hygiene was poor and Lauderdale-Davie, Fla., for a consultation in June she had received no professional prophylaxis or 2009 because she was experiencing gingival deep scaling since her last dental appointment enlargement. The periodontist (G.A.P.) elicited a five years earlier. history of grand mal epilepsy. The onset of the Initial therapy consisted of deep scaling and epilepsy occurred at the time of puberty. The root planing in four quadrants followed by the patient reported having no other medical condi- at-home use of chlorhexidine gluconate 0.12 per- tions. She indicated that she had four to five grand cent for a two-week period. The periodontist re- mal seizures per year coincident with her men- evaluated her condition six weeks later (Figure strual cycle. She also reported that her seizures 2). Excessive fibrotic gingival tissue remained, were preceded by auras. She had been under the with mild to moderate pseudopocketing and care of a neurologist since the onset of her moderate to severe loss of attachment. The epilepsy. The neurologist had prescribed a regimen periodontist performed guided tissue regenera- of phenytoin to treat the patient’s seizures. tion with a recombinant platelet-derived growth Before the patient sought care at the postgrad- factor and beta tricalcium phosphate in the uate periodontics clinic, a general dentist in pri- maxillary right and left posterior sextants, then vate practice, who was a family friend, noted the performed open flap curettage with apically gingival enlargement approximately five years positioned flaps at all other sites. All perio- after the onset of the seizures and encouraged the dontal surgery took place with the patient patient’s private-practice neurologist of record to under enteral sedation with lorazepam (2 mil- perform an oral examination (Figure 1). The ligrams by mouth). During periodontal surgery, patient had not seen a dentist during this five-year the periodontist removed excess gingival tissue period, so the periodontist (G.A.P.) could not ascer- and subsequently sent it for microscopic evalu- tain whether the gingival en largement predated ation and interpretation (Figure 3). As of this the onset of the seizure disorder. The neurologist writing, the patient is undergoing orthodontic discontinued the phenytoin treatment, because it therapy while she remains on a three-month is known to cause gingival enlargement, and pre- periodontal maintenance schedule (Figure 4). Figure 1. Initial presentation, Figure 2. Presentation after Figure 3. Photomicrograph Figure 4. Presentation after showing marked inflammation initial periodontal therapy, showing marked increase in surgical therapy. There is an and displacement of teeth. showing significant improve- collagen fibers with a mixed absence of inflammation and a ment in gingival color and inflammatory infiltration, acan- marked improvement in the architecture. thosis and elongated rete pegs gingival architecture. (hematoxylin-eosin, original magnification ×5). Can you make the diagnosis? A. Drug-influenced gingival enlargement C. Leukemic infiltration B. Hereditary gingival enlargement D. Tuberculosis © 2011 American Dental Association. Republished by Medical Online Publication SAL with permission of American JADA 142(11) http://jada.ada.org November 2011 1265 Dental Association. All rights reserved. JADA 2011, Volume 142, No 11, Page 1265-1268 JADA Middle East vol 3 No 1 Jan-Feb 2012 55 CLINICAL PRACTICE DIAGNOSTIC CHALLENGE THE DIAGNOSIS A. drug-influenced gingival enlargement “Drug-influenced gingival enlargement” and increased number of fibroblasts histologically.8,19 “drug-induced gingival overgrowth” are the pre- These findings indicate that, at a molecular ferred terms for what previously was referred to level, one etiologic factor of drug-induced gin- as “gingival hyperplasia,” “gingival hypertrophy,” gival enlargement may be the inhibition of col- “gingival fibromatosis” and “elephantiasis gin- lagen phagocytosis by means of reducing the 6 givae.” The medications commonly associated expression of α2 β1 integrins. Research suggests with drug-influenced gingival enlargement that integrins transduce information from the include antihypertensive agents such as the cal- extracellular matrix to the inside of the cell by cium channel blockers (including nifedipine, dilti- triggering intracellular signaling pathways.6 azem and verapamil, as well as antiseizure med- Antiepileptic, immunosuppressant, antidepres- ications such as phenytoin, sodium valproate, sant and calcium channel blocker drugs are valproic acid, phenobarbital and primidone.1-13 known to act as calcium antagonists. Intracel- Immunosuppressants such as cyclosporin A also lular calcium plays a role in the regulation of are implicated in gingival enlargement. While α2 β1 integrin-mediated collagen phagocytosis by some spontaneous resolution has been associated altering integrin affinity. Furthermore, the with discontinuing the use of certain medications actin-binding protein gelsolin is considered an such as nifedipine, this generally is not the rule.13 important factor in gingival enlargement. Gel- At this patient’s initial visit to the neurologist, solin contributes to the maintenance of normal she was receiving only phenytoin treatment. tissue integrity by regulating collagen phagocy- Therefore, her history supports a diagnosis of tosis through its integrin-binding affinity to phenytoin-influenced gingival enlargement. How- collagens.6 ever, because the gingival enlargement did not Treatment. Risk factors associated with appear to improve after the elimination of the phenytoin-induced gingival enlargement may phenytoin, one also must consider sodium val- have a synergistic effect, and bacterial plaque proate as a cause of the drug-influenced gingival appears to be the most important determinant enlargement.14 of severe phenytoin-influenced gingival enlarge- The information in the patient’s medical, ment.9 Still, to date, the most effective long- dental and drug histories and the clinical presen- term treatment for gingival enlargement is drug tation usually are sufficient to attain a diagnosis withdrawal.5 In addition to discontinuation of of drug-influenced gingival enlargement; there- drug treatment, periodontal therapy often is fore, a biopsy is not necessarily mandated. How- recommended in conjunction with oral hygiene ever, to demonstrate such a diagnosis more defin- instructions. Dannewitz and colleagues20 itively, a biopsy procedure certainly is preferred. showed that in patients who were receiving cal- The clinician must consider a biopsy if there are cium channel blockers, nonsurgical therapy for signs and symptoms that suggest a serious gingival enlargement consisting of full-mouth underlying etiology such as leukemia or tubercu- gross debridement, scaling and root planing and losis. The typical features of drug-influenced gin- short-term (two weeks’) use of 0.12 percent gival overgrowth include an increase in collagen chlorhexidine gluconate mouthrinse resulted fibers, inflammatory infiltration, acanthosis and in only 6 percent of teeth’s requiring surgical elongated rete pegs.14,15 intervention. The prevalence of gingival enlargement in healthy populations has been estimated to be DIFFERENTIAL DIAGNOSIS between 4.0 and 7.5 percent.10,12 Prevalence has Hereditary gingival enlargement. Patients been known to vary from 10 to 50 percent in with hereditary gingival enlargement exhibit populations of patients receiving phenytoin clinical signs identical to those of the patient therapy.7,11,16,17 Although the pharmaceutical described here. This diagnosis can be excluded effect and primary target tissues of antiepileptic, by questioning the patient about whether his or immunosuppressant, antidepressant and cal- her family members have similar gingival cium channel blocker medications are different, enlargement. As an isolated abnormality, gin- they act similarly on gingival connective tissue, gival enlargement is inherited as an autosomal causing fibrous gingival enlargement.18 In cases dominant trait or, rarely, as an autosomal reces- involving gingival enlargement, gingival connec- sive trait.21,22 Gingival enlargement may arise tive tissue does not necessarily exhibit an owing to a spontaneous gene mutation, so a neg- 56 JADA Middle East vol 3 No 1 Jan-Feb 2012 CLINICAL PRACTICE DIAGNOSTIC CHALLENGE ative family history alone cannot dismiss appropriate diagnostic testing such as blood hereditary gingival enlargement from the differ- testing or biopsy must be considered. Patients ential diagnosis completely. Gingival enlarge- with gingival enlargement should undergo ment has been associated rarely with a number appropriate laboratory testing to ensure that of syndromes such as inclusion-cell disease any underlying disorders are diagnosed and (mucolipidosis II), acanthosis nigricans, Borrone treated at the earliest possible time. ■ di Rocco Crovato syndrome, Cantu syndrome 21 When this article was written, Dr. Pette was a second-year resi- and Winchester syndrome. In this patient, dent