- Email: [email protected]
Female Predominance and Effect of Gender on Unilateral Condylar Hyperplasia: A Review and Meta-Analysis
J Oral Maxillofac Surg 70:e72-e76, 2012
Female Predominance and Effect of Gender on Unilateral Condylar Hyperplasia: A Review and Meta-Analysis Pieter G. Raijmakers, MD, PhD,* Luc H. E. Karssemakers, DDS,† and Dirk B. Tuinzing, DMD, PhD‡ Purpose: The objective of this review and meta-analysis was to determine the existence and extent of
the predominance of women among patients with unilateral condylar hyperplasia (UCH). Furthermore, we examined the laterality of UCH in women and men from international study populations. Materials and Methods: We performed a review using a standardized search strategy and meta-analysis. Results: We included 10 studies in this review, with a total of 275 UCH patients. The meta-analysis showed a clear predominance of female patients in the UCH study populations; the pooled proportion of female patients was 0.64 (95% confidence interval [CI], 0.58-0.70; n ⫽ 275 patients). The pooled percentage of female patients with left-sided UCH was 42% (95% CI, 34%-51%; n ⫽ 138), whereas 45% (95% CI, 33%-57%; n ⫽ 74) of male patients had left-sided UCH (P ⫽ .69 for female patients vs male patients). Conclusions: Female UCH patients outnumber male UCH patients in international study populations; therefore female gender may be considered a risk factor for UCH. We found no evidence of an association between laterality of UCH and gender: male patients and female patients have an almost equal distribution of left- and right-sided UCH. © 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:e72-e76, 2012 Unilateral condylar hyperplasia (UCH) is a disorder with unknown etiology and is characterized by increased or persistent growth of the condyle. Progressive unilateral enlargement of the head and neck of the condyle results in facial asymmetry, malocclusion, and shifting of the midpoint of the chin to the unaffected side. Patients with UCH have asymmetric growth of the mandibular condyle; in such patients,
relative increases in the activity of the affected condyle can be assessed by bone scintigraphy and 18Ffluoride positron emission tomography (PET).1-6 Condylar hyperplasia is also referred to as condylar hyperactivity. Although the etiology of UCH remains unknown, several possible causes for the increase in condylar bone growth have been proposed, including earlier condylar trauma, inflammation, hormonal influence, and hypervascularization. A recent study showed a higher prevalence of UCH in women than in men.7 The study also proposed a gender-based laterality of UCH, whereby women predominantly have right-sided UCH, as compared with men, who more often have left-sided UCH. These observations have implications for future research. A clear predominance in women might shed light on the pathophysiology of condylar hyperplasia, by reflecting, for instance, an X-linked gene that underlies a potential genetic etiology of this syndrome. However, the data on specific study populations might be biased, because sample sizes of such populations have been limited. A meta-analysis considerably improves the sample size by considering many patients and providing highly robust relative frequencies of, for example, gender distribution and potential
Received from the VU University Medical Centre, Amsterdam, The Netherlands. *Nuclear Medicine Physician, Department of Nuclear Medicine & PET Research. †Resident, Department of Oral and Maxillofacial Surgery and Oral Pathology. ‡Oral and Maxillofacial Surgeon, Department of Oral and Maxillofacial Surgery and Oral Pathology. Address correspondence and reprint requests to Dr Raijmakers: Department of Nuclear Medicine & PET Research, VU University Medical Centre, de Boelelaan 1117, 1007 MB Amsterdam, The Netherlands; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons
0278-2391/12/7001-0$36.00/0 doi:10.1016/j.joms.2011.05.026
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Table 1. OVERVIEW OF STUDIES
Author
No. of Patients
Gender (Female/Male)
Right-/Left-Sided UCH
Mean Age (Range) (yr)
Country
Year
Hodder et al6 Chan et al1 Gray et al11 Motamedi12 Slootweg and Muller13 Nitzan et al7 Saridin et al3 Villanueva-Alcojol et al16 Dong et al15 Meng et al14
18 23 20 13 22 61 47 36 15 20
14/4 13/10 15/5 1/12 16/6 46/15 29/18 25/11 8/7 9/11
9/9 — 11/9 12/1 — 39/21 21/26 22/14 — 9/11
20 (13-34) 20 25.8 (15-55) 25.8 (19-37) 24.5 27.9 (11-80) 21.6 22.7 (11-42) 23.0 22.4 (14-34)
United Kingdom Australia United Kingdom Iran The Netherlands Israel The Netherlands Spain China China
2000 2000 1990 1996 1986 2008 2010 2011 2008 2011
Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
differences in laterality between male patients and female patients. The objective of this review and meta-analysis was to determine the existence and extent of the predominance of UCH in women. Furthermore, we examined the laterality of UCH in women and men from international study populations.
Materials and Methods LITERATURE SEARCH AND STUDY SELECTION
We conducted a PubMed search and selected observational studies on patients with UCH. We used a standardized literature search and used the following terms: [condyle or condylar] and [mandible or mandibular] and [hyperplasia or hyperactivity]. We limited our search to observational and diagnostic studies to avoid including the same population from a single institution twice. We augmented this search by reviewing the reference lists of the selected studies. CRITERIA FOR STUDY SELECTION
Potentially relevant studies for inclusion were screened and selected by examining the titles and abstracts. Ultimately, full-length articles were included, without blinding to the journal, authors, or date of publication. We selected studies that were written in English and 1) were observational or diagnostic in nature, 2) included patients with UCH, 3) included at least 10 UCH patients, and 4) reported the data in sufficient detail to determine the distribution of UCH in the study population with regard to gender or laterality. Thus, nonhuman studies, reviews, case reports, and descriptions of small-sized patient groups were excluded.5,8-10 Studies with potentially overlapping populations were not pooled; instead, we selected the largest or most recent population from such studies. Using these inclusion and exclusion criteria, we inde-
pendently selected studies by checking titles and abstracts of individual studies. STATISTICAL ANALYSIS AND META-ANALYSIS
For each study, the proportion of women and men in the patient population and their confidence intervals (CIs) were calculated from the original study data. Similarly, the proportion of left-sided and rightsided UCH patients was calculated for each study, as well for men and women, if such data were available. A meta-analysis was performed for all studies that included populations comprising more than 10 patients. Before we calculated the pooled estimates of the gender distribution and laterality of UCH, we analyzed the heterogeneity of these values by calculating I2 values and performing an 2 test with k – 1 df (where k is the number of studies). The heterogeneity of the results between studies was assessed using the quantity I2, which describes the percentage of total variation across studies and is attributable to heterogeneity rather than chance. I2 ranges between 0% and 100%; a value of 0% indicates no observed heterogeneity, and values greater than 50% can reflect substantial heterogeneity. In the meta-analysis the percentages of female patients per study and patients with left-sided UCH were pooled for male and female subpopulations. The Z test was used to evaluate possible differences in left/ right laterality of UCH between men and women. P ⬍ .05 was considered significant.
Results Our search identified a total of 264 potentially relevant studies that examined UCH patients. Ten studies, comprising a total of 275 patients, met the inclusion criteria and were included in the review.1,3,6,7,11-16 The mean age of the patients was consistent between populations, ranging from 20 to 27.9 years (Table 1).
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GENDER OF UCH PATIENTS
FIGURE 3. Percentage of male patients with left-sided UCH. FIGURE 1. Percentage of female UCH patients. Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
GENDER BIAS IN UCH PATIENTS
Significant heterogeneity was observed in the percentage of women in the 10 studies, generating an I2 value of 70.3% (2 ⫽ 30.3, P ⫽ .0004). The proportion of female patients ranged between 0.08 in an Iranian study to 0.78 in a study from the United Kingdom.6,12 The meta-analysis showed a clear predominance of female patients in the UCH study populations; the pooled proportion of women was 0.64 (95% CI, 0.58-0.70; n ⫽ 275 patients) (Fig 1). LATERALITY OF UCH AND GENDER
Female Patients Six studies provided sufficient data and enabled us to extract gender and laterality findings for women (with a total of 138 female patients).3,6,7,11,14,16 The heterogeneity in the percentage of female patients with left-sided UCH between female subpopulations was insignificant (2 ⫽ 10.3, P ⫽ .066), ranging from 26% to 62%. The pooled percentage of female patients with left-sided UCH was 42% (95% CI, 34%-51%; n ⫽ 138) (Fig 2). Male Patients Seven studies (with a total of 74 male patients) reported on the laterality of UCH, for which there was
Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
near-significant heterogeneity in men (2 ⫽ 12.4, P ⫽ .052).3,6,7,11,12,14,16 The percentage of left-sided UCH in men was 8% to 67%. In the meta-analysis the pooled percentage of left-sided UCH in men was 45% (95% CI, 33%-57%; n ⫽ 74) (Fig 3). The proportion of left-sided UCH did not differ significantly between the genders (P ⫽ .69). In the combined data on women and men (n ⫽ 214), 43% of patients had left-sided UCH (95% CI, 36%-49%) and 57% had right-sided UCH (95% CI, 51%64%) (difference for left- vs right-sided UCH, P ⫽ .0075 [Z test]).
Discussion In this review and meta-analysis, we found no evidence linking gender and laterality of UCH. This is in contrast to the findings of the study by Nitzan et al, who observed specific associations between rightsided UCH and female gender and between left-sided UCH and male gender.7 The observation of UCH in a mirror pattern in 2 male siblings also contradicts the association between male gender and left-sided UCH.17 In this meta-analysis, women and men had comparable frequencies of left-sided UCH of 42% and 45%, respectively; by combining the data for women and men, we found that the frequency of left-sided UCH was significantly lower than that of right-sided UCH. LATERALITY OF UCH
FIGURE 2. Percentage of female patients with left-sided UCH. Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
There is no clear pathophysiologic basis for the slightly increased incidence of right-sided UCH in women and men; earlier contralateral condylar trauma might explain this phenomenon, leading to decreased blood flow in the bone, reduced bone growth in the contralateral condyle, and asymmetric mandibular growth. This hypothesis is consistent with the findings of our recent 18F-fluoride PET study, in which we observed a greater than 40% decrease in bone activity in the contralateral condyle in UCH patients, when compared with the condylar fluoride
RAIJMAKERS, KARSSEMAKERS, AND TUINZING
uptake in control subjects.2 With 18F-fluoride PET, quantification of absolute 18F-fluoride uptake in the condylar region is possible, in contrast to bone scintigraphy, which assesses the relative activity of both condyles. Bone blood flow measured with PET in the contralateral condyle was approximately 25% lower than the control values, but this difference was insignificant (P ⫽ .066), perhaps because of the limited power of this pilot study that included 7 UCH patients.2 It is possible that the asymmetric mandibular growth in certain UCH patients is associated with reduced bone metabolism and bone blood flow on the contralateral side; however, large-scale studies are necessary to confirm this possibility. These findings implicate local pathology in the contralateral condyle of UCH patients (eg, due to an earlier trauma). However, no causal relation between the presence of UCH and reduced bone metabolism and blood flow on the contralateral side was established, because only a single measurement in a relatively small group of patients was obtained. The observed differences in bone metabolism and flow might also be due to the asymmetry of the mandible (eg, by increased mechanical pressure in the contralateral condyle). Asymmetric condylar activity explains the asymmetric mandibular growth, but the increase in the size of the hyperplastic condyle in UCH patients is not attributable to decreased bone activity or blood flow of the contralateral condyle. Alternatively, noncessation of (normal) condylar growth on the side with UCH with normal, timely cessation on the contralateral side may explain the difference in condylar size. In this meta-analysis, women were significantly predisposed to UCH compared with men (female-male ratio, 2:1); hence, female gender may be considered a risk factor for UCH. Interestingly, the majority of patients who present with pain in the temporomandibular region are women, but this phenomenon is unexplained.18 Several etiologic factors might be associated with the female bias for UCH. UCH might have a genetic origin—for example, an X-linked trait. There is, however, not much evidence for this model; there was considerable and significant variation in the distribution of genders in UCH patients in the study populations, rendering this hypothesis unlikely. Furthermore, the presence of UCH in 2 male siblings argues against it being an X-linked trait.17 Alternatively, hormonal differences, especially estrogen in women, between women and men might explain the differences in incidence. Because nearly all UCH patients were in their reproductive years, it is possible that sex hormones were involved in the abnormal growth of the mandible. Estrogen is a major regulator of bone growth, and estrogen decreases the cartilage thickness of rat mandibular condyles.19 Furthermore, estrogen receptors are expressed in articu-
e75 lar cartilage, the growth plate, and osteoblasts and are known to be regulators of skeletal growth and maturation.20,21 A direct link between sex hormones and condylar growth was found with an experimental study showing an increased mandibular condyle size after ovariectomy.22 Female patients with osteoarthritis of the temporomandibular joint and who carry a specific haplotype for the estrogen receptor have significantly smaller facial axis angles and mandibular body lengths than noncarriers, suggesting a role for estrogen in mandibular growth.20 The local production of estrogen might influence the development of UCH. There is experimental evidence of local synthesis of estrogen in the temporomandibular joint.23,24 Hence, differences in local estrogen production might explain the differences in mandibular growth between the sides in UCH patients. Further studies are necessary regarding the possible interaction of locally produced estrogen and condylar growth, especially in UCH patients, but estrogen might be an important variable in aberrant mandibular growth in UCH patients. Regardless of a possible hormonal cause of UCH, the predominance of women in UCH patient populations suggests that etiologic investigations should consider biologic and/or psychosocial factors that are more common in women than in men. An alternative explanation for the predominance of women in UCH patient populations may be related to a difference in motivation between female and male subjects to seek care for facial asymmetry. Women may be more likely to seek care for clinical evaluation for facial asymmetry, explaining—at least partly—the higher proportion of female patients in clinical study populations. The significant heterogeneity in the prevalence of UCH between genders in the studies that we analyzed may depend on statistical variation with regard to sample size bias and sociocultural differences between populations. Sample size bias is a problem because UCH populations are rather small, making reliable estimates of, for example, gender distribution in the population difficult to obtain. A meta-analysis reduces the risk of statistical variation, and despite our inclusion of a relatively limited number of studies (10), the 2:1 female-male ratio appears to be a reasonable estimate of UCH prevalence between genders. Female UCH patients outnumber male UCH patients in international study populations; therefore female gender may be considered a risk factor for UCH. We found no evidence of an association between laterality of UCH and gender: male patients and female patients have an almost equal distribution of left- and right-sided UCH.
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References 1. Chan WL, Carolan MG, Fernandes VB, et al: Planar versus SPET imaging in the assessment of condylar growth. Nucl Med Commun 21:285, 2000 2. Saridin CP, Raijmakers PG, Kloet RW, et al: No signs of metabolic hyperactivity in patients with unilateral condylar hyperactivity: An in vivo positron emission tomography study. J Oral Maxillofac Surg 67:576, 2009 3. Saridin CP, Raijmakers PG, Slootweg PJ, et al: Unilateral condylar hyperactivity: A histopathologic analysis of 47 patients. J Oral Maxillofac Surg 68:47, 2010 4. Saridin CP, Raijmakers PG, Tuinzing DB, et al: Comparison of planar bone scintigraphy and single photon emission computed tomography in patients suspected of having unilateral condylar hyperactivity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106:426, 2008 5. Saridin CP, Raijmakers PG, Tuinzing DB, et al: Bone scintigraphy as a diagnostic method in unilateral hyperactivity of the mandibular condyles: A review and meta-analysis of the literature. Int J Oral Maxillofac Surg 40:11, 2011 6. Hodder SC, Rees JI, Oliver TB, et al: SPECT bone scintigraphy in the diagnosis and management of mandibular condylar hyperplasia. Br J Oral Maxillofac Surg 38:87, 2000 7. Nitzan DW, Katsnelson A, Bermanis I, et al: The clinical characteristics of condylar hyperplasia: Experience with 61 patients. J Oral Maxillofac Surg 66:312, 2008 8. Temmerman OP, Raijmakers PG, Berkhof J, et al: Accuracy of diagnostic imaging techniques in the diagnosis of aseptic loosening of the femoral component of a hip prosthesis: A metaanalysis. J Bone Joint Surg Br 87:781, 2005 9. Temmerman OP, Raijmakers PG, Deville WL, et al: The use of plain radiography, subtraction arthrography, nuclear arthrography, and bone scintigraphy in the diagnosis of a loose acetabular component of a total hip prosthesis: A systematic review. J Arthroplasty 22:818, 2007 10. Raijmakers PG, Paul MA, Lips P: Sentinel node detection in patients with thyroid carcinoma: A meta-analysis. World J Surg 32:1961, 2008 11. Gray RJ, Sloan P, Quayle AA, et al: Histopathological and scintigraphic features of condylar hyperplasia. Int J Oral Maxillofac Surg 19:65, 1990
GENDER OF UCH PATIENTS 12. Motamedi MH: Treatment of condylar hyperplasia of the mandible using unilateral ramus osteotomies. J Oral Maxillofac Surg 54:1161, 1996 13. Slootweg PJ, Muller H: Condylar hyperplasia. A clinico-pathological analysis of 22 cases. J Maxillofac Surg 14:209, 1986 14. Meng Q, Long X, Deng M, et al: The expressions of IGF-1, BMP-2 and TGF-1 in cartilage of condylar hyperplasia. J Oral Rehabil 38:34, 2011 15. Dong Y, Wang XM, Wang MQ, et al: Asymmetric muscle function in patients with developmental mandibular asymmetry. J Oral Rehabil 35:27, 2008 16. Villanueva-Alcojol L, Monje F, Gonzalez-Garcia R: Hyperplasia of the mandibular condyle: Clinical, histopathologic, and treatment considerations in a series of 36 patients. J Oral Maxillofac Surg 69:447, 2011 17. Yang J, Lignelli JL, Ruprecht A: Mirror image condylar hyperplasia in two siblings. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97:281, 2004 18. LeResche L: Epidemiology of temporomandibular disorders: Implications for the investigation of etiologic factors. Crit Rev Oral Biol Med 8:291, 1997 19. Talwar RM, Wong BS, Svoboda K, et al: Effects of estrogen on chondrocyte proliferation and collagen synthesis in skeletally mature articular cartilage. J Oral Maxillofac Surg 64:600, 2006 20. Lee DG, Kim TW, Kang SC, et al: Estrogen receptor gene polymorphism and craniofacial morphology in female TMJ osteoarthritis patients. Int J Oral Maxillofac Surg 35:165, 2006 21. Abubaker AO, Raslan WF, Sotereanos GC: Estrogen and progesterone receptors in temporomandibular joint discs of symptomatic and asymptomatic persons: A preliminary study. J Oral Maxillofac Surg 51:1096, 1993 22. Fujita T, Kawata T, Tokimasa C, et al: Breadth of the mandibular condyle affected by disturbances of the sex hormones in ovariectomized and orchiectomized mice. Clin Orthod Res 4:172, 2001 23. Yu S, Xing X, Liang S, et al: Locally synthesized estrogen plays an important role in the development of TMD. Med Hypotheses 72:720, 2009 24. Yu SB, Wang MQ, Zhao W, et al: The effects of age and sex on the expression of aromatase in the rat temporomandibular joint. J Orofac Pain 20:156, 2006
Female Predominance and Effect of Gender on Unilateral Condylar Hyperplasia: A Review and Meta-Analysis Pieter G. Raijmakers, MD, PhD,* Luc H. E. Karssemakers, DDS,† and Dirk B. Tuinzing, DMD, PhD‡ Purpose: The objective of this review and meta-analysis was to determine the existence and extent of
the predominance of women among patients with unilateral condylar hyperplasia (UCH). Furthermore, we examined the laterality of UCH in women and men from international study populations. Materials and Methods: We performed a review using a standardized search strategy and meta-analysis. Results: We included 10 studies in this review, with a total of 275 UCH patients. The meta-analysis showed a clear predominance of female patients in the UCH study populations; the pooled proportion of female patients was 0.64 (95% confidence interval [CI], 0.58-0.70; n ⫽ 275 patients). The pooled percentage of female patients with left-sided UCH was 42% (95% CI, 34%-51%; n ⫽ 138), whereas 45% (95% CI, 33%-57%; n ⫽ 74) of male patients had left-sided UCH (P ⫽ .69 for female patients vs male patients). Conclusions: Female UCH patients outnumber male UCH patients in international study populations; therefore female gender may be considered a risk factor for UCH. We found no evidence of an association between laterality of UCH and gender: male patients and female patients have an almost equal distribution of left- and right-sided UCH. © 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:e72-e76, 2012 Unilateral condylar hyperplasia (UCH) is a disorder with unknown etiology and is characterized by increased or persistent growth of the condyle. Progressive unilateral enlargement of the head and neck of the condyle results in facial asymmetry, malocclusion, and shifting of the midpoint of the chin to the unaffected side. Patients with UCH have asymmetric growth of the mandibular condyle; in such patients,
relative increases in the activity of the affected condyle can be assessed by bone scintigraphy and 18Ffluoride positron emission tomography (PET).1-6 Condylar hyperplasia is also referred to as condylar hyperactivity. Although the etiology of UCH remains unknown, several possible causes for the increase in condylar bone growth have been proposed, including earlier condylar trauma, inflammation, hormonal influence, and hypervascularization. A recent study showed a higher prevalence of UCH in women than in men.7 The study also proposed a gender-based laterality of UCH, whereby women predominantly have right-sided UCH, as compared with men, who more often have left-sided UCH. These observations have implications for future research. A clear predominance in women might shed light on the pathophysiology of condylar hyperplasia, by reflecting, for instance, an X-linked gene that underlies a potential genetic etiology of this syndrome. However, the data on specific study populations might be biased, because sample sizes of such populations have been limited. A meta-analysis considerably improves the sample size by considering many patients and providing highly robust relative frequencies of, for example, gender distribution and potential
Received from the VU University Medical Centre, Amsterdam, The Netherlands. *Nuclear Medicine Physician, Department of Nuclear Medicine & PET Research. †Resident, Department of Oral and Maxillofacial Surgery and Oral Pathology. ‡Oral and Maxillofacial Surgeon, Department of Oral and Maxillofacial Surgery and Oral Pathology. Address correspondence and reprint requests to Dr Raijmakers: Department of Nuclear Medicine & PET Research, VU University Medical Centre, de Boelelaan 1117, 1007 MB Amsterdam, The Netherlands; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons
0278-2391/12/7001-0$36.00/0 doi:10.1016/j.joms.2011.05.026
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RAIJMAKERS, KARSSEMAKERS, AND TUINZING
Table 1. OVERVIEW OF STUDIES
Author
No. of Patients
Gender (Female/Male)
Right-/Left-Sided UCH
Mean Age (Range) (yr)
Country
Year
Hodder et al6 Chan et al1 Gray et al11 Motamedi12 Slootweg and Muller13 Nitzan et al7 Saridin et al3 Villanueva-Alcojol et al16 Dong et al15 Meng et al14
18 23 20 13 22 61 47 36 15 20
14/4 13/10 15/5 1/12 16/6 46/15 29/18 25/11 8/7 9/11
9/9 — 11/9 12/1 — 39/21 21/26 22/14 — 9/11
20 (13-34) 20 25.8 (15-55) 25.8 (19-37) 24.5 27.9 (11-80) 21.6 22.7 (11-42) 23.0 22.4 (14-34)
United Kingdom Australia United Kingdom Iran The Netherlands Israel The Netherlands Spain China China
2000 2000 1990 1996 1986 2008 2010 2011 2008 2011
Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
differences in laterality between male patients and female patients. The objective of this review and meta-analysis was to determine the existence and extent of the predominance of UCH in women. Furthermore, we examined the laterality of UCH in women and men from international study populations.
Materials and Methods LITERATURE SEARCH AND STUDY SELECTION
We conducted a PubMed search and selected observational studies on patients with UCH. We used a standardized literature search and used the following terms: [condyle or condylar] and [mandible or mandibular] and [hyperplasia or hyperactivity]. We limited our search to observational and diagnostic studies to avoid including the same population from a single institution twice. We augmented this search by reviewing the reference lists of the selected studies. CRITERIA FOR STUDY SELECTION
Potentially relevant studies for inclusion were screened and selected by examining the titles and abstracts. Ultimately, full-length articles were included, without blinding to the journal, authors, or date of publication. We selected studies that were written in English and 1) were observational or diagnostic in nature, 2) included patients with UCH, 3) included at least 10 UCH patients, and 4) reported the data in sufficient detail to determine the distribution of UCH in the study population with regard to gender or laterality. Thus, nonhuman studies, reviews, case reports, and descriptions of small-sized patient groups were excluded.5,8-10 Studies with potentially overlapping populations were not pooled; instead, we selected the largest or most recent population from such studies. Using these inclusion and exclusion criteria, we inde-
pendently selected studies by checking titles and abstracts of individual studies. STATISTICAL ANALYSIS AND META-ANALYSIS
For each study, the proportion of women and men in the patient population and their confidence intervals (CIs) were calculated from the original study data. Similarly, the proportion of left-sided and rightsided UCH patients was calculated for each study, as well for men and women, if such data were available. A meta-analysis was performed for all studies that included populations comprising more than 10 patients. Before we calculated the pooled estimates of the gender distribution and laterality of UCH, we analyzed the heterogeneity of these values by calculating I2 values and performing an 2 test with k – 1 df (where k is the number of studies). The heterogeneity of the results between studies was assessed using the quantity I2, which describes the percentage of total variation across studies and is attributable to heterogeneity rather than chance. I2 ranges between 0% and 100%; a value of 0% indicates no observed heterogeneity, and values greater than 50% can reflect substantial heterogeneity. In the meta-analysis the percentages of female patients per study and patients with left-sided UCH were pooled for male and female subpopulations. The Z test was used to evaluate possible differences in left/ right laterality of UCH between men and women. P ⬍ .05 was considered significant.
Results Our search identified a total of 264 potentially relevant studies that examined UCH patients. Ten studies, comprising a total of 275 patients, met the inclusion criteria and were included in the review.1,3,6,7,11-16 The mean age of the patients was consistent between populations, ranging from 20 to 27.9 years (Table 1).
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GENDER OF UCH PATIENTS
FIGURE 3. Percentage of male patients with left-sided UCH. FIGURE 1. Percentage of female UCH patients. Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
GENDER BIAS IN UCH PATIENTS
Significant heterogeneity was observed in the percentage of women in the 10 studies, generating an I2 value of 70.3% (2 ⫽ 30.3, P ⫽ .0004). The proportion of female patients ranged between 0.08 in an Iranian study to 0.78 in a study from the United Kingdom.6,12 The meta-analysis showed a clear predominance of female patients in the UCH study populations; the pooled proportion of women was 0.64 (95% CI, 0.58-0.70; n ⫽ 275 patients) (Fig 1). LATERALITY OF UCH AND GENDER
Female Patients Six studies provided sufficient data and enabled us to extract gender and laterality findings for women (with a total of 138 female patients).3,6,7,11,14,16 The heterogeneity in the percentage of female patients with left-sided UCH between female subpopulations was insignificant (2 ⫽ 10.3, P ⫽ .066), ranging from 26% to 62%. The pooled percentage of female patients with left-sided UCH was 42% (95% CI, 34%-51%; n ⫽ 138) (Fig 2). Male Patients Seven studies (with a total of 74 male patients) reported on the laterality of UCH, for which there was
Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
near-significant heterogeneity in men (2 ⫽ 12.4, P ⫽ .052).3,6,7,11,12,14,16 The percentage of left-sided UCH in men was 8% to 67%. In the meta-analysis the pooled percentage of left-sided UCH in men was 45% (95% CI, 33%-57%; n ⫽ 74) (Fig 3). The proportion of left-sided UCH did not differ significantly between the genders (P ⫽ .69). In the combined data on women and men (n ⫽ 214), 43% of patients had left-sided UCH (95% CI, 36%-49%) and 57% had right-sided UCH (95% CI, 51%64%) (difference for left- vs right-sided UCH, P ⫽ .0075 [Z test]).
Discussion In this review and meta-analysis, we found no evidence linking gender and laterality of UCH. This is in contrast to the findings of the study by Nitzan et al, who observed specific associations between rightsided UCH and female gender and between left-sided UCH and male gender.7 The observation of UCH in a mirror pattern in 2 male siblings also contradicts the association between male gender and left-sided UCH.17 In this meta-analysis, women and men had comparable frequencies of left-sided UCH of 42% and 45%, respectively; by combining the data for women and men, we found that the frequency of left-sided UCH was significantly lower than that of right-sided UCH. LATERALITY OF UCH
FIGURE 2. Percentage of female patients with left-sided UCH. Raijmakers, Karssemakers, and Tuinzing. Gender of UCH Patients. J Oral Maxillofac Surg 2012.
There is no clear pathophysiologic basis for the slightly increased incidence of right-sided UCH in women and men; earlier contralateral condylar trauma might explain this phenomenon, leading to decreased blood flow in the bone, reduced bone growth in the contralateral condyle, and asymmetric mandibular growth. This hypothesis is consistent with the findings of our recent 18F-fluoride PET study, in which we observed a greater than 40% decrease in bone activity in the contralateral condyle in UCH patients, when compared with the condylar fluoride
RAIJMAKERS, KARSSEMAKERS, AND TUINZING
uptake in control subjects.2 With 18F-fluoride PET, quantification of absolute 18F-fluoride uptake in the condylar region is possible, in contrast to bone scintigraphy, which assesses the relative activity of both condyles. Bone blood flow measured with PET in the contralateral condyle was approximately 25% lower than the control values, but this difference was insignificant (P ⫽ .066), perhaps because of the limited power of this pilot study that included 7 UCH patients.2 It is possible that the asymmetric mandibular growth in certain UCH patients is associated with reduced bone metabolism and bone blood flow on the contralateral side; however, large-scale studies are necessary to confirm this possibility. These findings implicate local pathology in the contralateral condyle of UCH patients (eg, due to an earlier trauma). However, no causal relation between the presence of UCH and reduced bone metabolism and blood flow on the contralateral side was established, because only a single measurement in a relatively small group of patients was obtained. The observed differences in bone metabolism and flow might also be due to the asymmetry of the mandible (eg, by increased mechanical pressure in the contralateral condyle). Asymmetric condylar activity explains the asymmetric mandibular growth, but the increase in the size of the hyperplastic condyle in UCH patients is not attributable to decreased bone activity or blood flow of the contralateral condyle. Alternatively, noncessation of (normal) condylar growth on the side with UCH with normal, timely cessation on the contralateral side may explain the difference in condylar size. In this meta-analysis, women were significantly predisposed to UCH compared with men (female-male ratio, 2:1); hence, female gender may be considered a risk factor for UCH. Interestingly, the majority of patients who present with pain in the temporomandibular region are women, but this phenomenon is unexplained.18 Several etiologic factors might be associated with the female bias for UCH. UCH might have a genetic origin—for example, an X-linked trait. There is, however, not much evidence for this model; there was considerable and significant variation in the distribution of genders in UCH patients in the study populations, rendering this hypothesis unlikely. Furthermore, the presence of UCH in 2 male siblings argues against it being an X-linked trait.17 Alternatively, hormonal differences, especially estrogen in women, between women and men might explain the differences in incidence. Because nearly all UCH patients were in their reproductive years, it is possible that sex hormones were involved in the abnormal growth of the mandible. Estrogen is a major regulator of bone growth, and estrogen decreases the cartilage thickness of rat mandibular condyles.19 Furthermore, estrogen receptors are expressed in articu-
e75 lar cartilage, the growth plate, and osteoblasts and are known to be regulators of skeletal growth and maturation.20,21 A direct link between sex hormones and condylar growth was found with an experimental study showing an increased mandibular condyle size after ovariectomy.22 Female patients with osteoarthritis of the temporomandibular joint and who carry a specific haplotype for the estrogen receptor have significantly smaller facial axis angles and mandibular body lengths than noncarriers, suggesting a role for estrogen in mandibular growth.20 The local production of estrogen might influence the development of UCH. There is experimental evidence of local synthesis of estrogen in the temporomandibular joint.23,24 Hence, differences in local estrogen production might explain the differences in mandibular growth between the sides in UCH patients. Further studies are necessary regarding the possible interaction of locally produced estrogen and condylar growth, especially in UCH patients, but estrogen might be an important variable in aberrant mandibular growth in UCH patients. Regardless of a possible hormonal cause of UCH, the predominance of women in UCH patient populations suggests that etiologic investigations should consider biologic and/or psychosocial factors that are more common in women than in men. An alternative explanation for the predominance of women in UCH patient populations may be related to a difference in motivation between female and male subjects to seek care for facial asymmetry. Women may be more likely to seek care for clinical evaluation for facial asymmetry, explaining—at least partly—the higher proportion of female patients in clinical study populations. The significant heterogeneity in the prevalence of UCH between genders in the studies that we analyzed may depend on statistical variation with regard to sample size bias and sociocultural differences between populations. Sample size bias is a problem because UCH populations are rather small, making reliable estimates of, for example, gender distribution in the population difficult to obtain. A meta-analysis reduces the risk of statistical variation, and despite our inclusion of a relatively limited number of studies (10), the 2:1 female-male ratio appears to be a reasonable estimate of UCH prevalence between genders. Female UCH patients outnumber male UCH patients in international study populations; therefore female gender may be considered a risk factor for UCH. We found no evidence of an association between laterality of UCH and gender: male patients and female patients have an almost equal distribution of left- and right-sided UCH.
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References 1. Chan WL, Carolan MG, Fernandes VB, et al: Planar versus SPET imaging in the assessment of condylar growth. Nucl Med Commun 21:285, 2000 2. Saridin CP, Raijmakers PG, Kloet RW, et al: No signs of metabolic hyperactivity in patients with unilateral condylar hyperactivity: An in vivo positron emission tomography study. J Oral Maxillofac Surg 67:576, 2009 3. Saridin CP, Raijmakers PG, Slootweg PJ, et al: Unilateral condylar hyperactivity: A histopathologic analysis of 47 patients. J Oral Maxillofac Surg 68:47, 2010 4. Saridin CP, Raijmakers PG, Tuinzing DB, et al: Comparison of planar bone scintigraphy and single photon emission computed tomography in patients suspected of having unilateral condylar hyperactivity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106:426, 2008 5. Saridin CP, Raijmakers PG, Tuinzing DB, et al: Bone scintigraphy as a diagnostic method in unilateral hyperactivity of the mandibular condyles: A review and meta-analysis of the literature. Int J Oral Maxillofac Surg 40:11, 2011 6. Hodder SC, Rees JI, Oliver TB, et al: SPECT bone scintigraphy in the diagnosis and management of mandibular condylar hyperplasia. Br J Oral Maxillofac Surg 38:87, 2000 7. Nitzan DW, Katsnelson A, Bermanis I, et al: The clinical characteristics of condylar hyperplasia: Experience with 61 patients. J Oral Maxillofac Surg 66:312, 2008 8. Temmerman OP, Raijmakers PG, Berkhof J, et al: Accuracy of diagnostic imaging techniques in the diagnosis of aseptic loosening of the femoral component of a hip prosthesis: A metaanalysis. J Bone Joint Surg Br 87:781, 2005 9. Temmerman OP, Raijmakers PG, Deville WL, et al: The use of plain radiography, subtraction arthrography, nuclear arthrography, and bone scintigraphy in the diagnosis of a loose acetabular component of a total hip prosthesis: A systematic review. J Arthroplasty 22:818, 2007 10. Raijmakers PG, Paul MA, Lips P: Sentinel node detection in patients with thyroid carcinoma: A meta-analysis. World J Surg 32:1961, 2008 11. Gray RJ, Sloan P, Quayle AA, et al: Histopathological and scintigraphic features of condylar hyperplasia. Int J Oral Maxillofac Surg 19:65, 1990
GENDER OF UCH PATIENTS 12. Motamedi MH: Treatment of condylar hyperplasia of the mandible using unilateral ramus osteotomies. J Oral Maxillofac Surg 54:1161, 1996 13. Slootweg PJ, Muller H: Condylar hyperplasia. A clinico-pathological analysis of 22 cases. J Maxillofac Surg 14:209, 1986 14. Meng Q, Long X, Deng M, et al: The expressions of IGF-1, BMP-2 and TGF-1 in cartilage of condylar hyperplasia. J Oral Rehabil 38:34, 2011 15. Dong Y, Wang XM, Wang MQ, et al: Asymmetric muscle function in patients with developmental mandibular asymmetry. J Oral Rehabil 35:27, 2008 16. Villanueva-Alcojol L, Monje F, Gonzalez-Garcia R: Hyperplasia of the mandibular condyle: Clinical, histopathologic, and treatment considerations in a series of 36 patients. J Oral Maxillofac Surg 69:447, 2011 17. Yang J, Lignelli JL, Ruprecht A: Mirror image condylar hyperplasia in two siblings. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97:281, 2004 18. LeResche L: Epidemiology of temporomandibular disorders: Implications for the investigation of etiologic factors. Crit Rev Oral Biol Med 8:291, 1997 19. Talwar RM, Wong BS, Svoboda K, et al: Effects of estrogen on chondrocyte proliferation and collagen synthesis in skeletally mature articular cartilage. J Oral Maxillofac Surg 64:600, 2006 20. Lee DG, Kim TW, Kang SC, et al: Estrogen receptor gene polymorphism and craniofacial morphology in female TMJ osteoarthritis patients. Int J Oral Maxillofac Surg 35:165, 2006 21. Abubaker AO, Raslan WF, Sotereanos GC: Estrogen and progesterone receptors in temporomandibular joint discs of symptomatic and asymptomatic persons: A preliminary study. J Oral Maxillofac Surg 51:1096, 1993 22. Fujita T, Kawata T, Tokimasa C, et al: Breadth of the mandibular condyle affected by disturbances of the sex hormones in ovariectomized and orchiectomized mice. Clin Orthod Res 4:172, 2001 23. Yu S, Xing X, Liang S, et al: Locally synthesized estrogen plays an important role in the development of TMD. Med Hypotheses 72:720, 2009 24. Yu SB, Wang MQ, Zhao W, et al: The effects of age and sex on the expression of aromatase in the rat temporomandibular joint. J Orofac Pain 20:156, 2006