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Sandra Darilek, MS,* Catherine Wicklund, MS,† Diane Novy, PhD,‡ Allison Scott, MD,§ Michael Gambello, MD, PhD,* Dennis Johnston, PhD,{ and Jacqueline Hecht, PhD* short stature, blood vessel compression, peripheral nerve Abstract: This study was undertaken to characterize pain in compression, and spinal cord compression.1,3–5 The most individuals with hereditary multiple exostosis (HME). Two hundred severe complication of HME is the malignant transformation ninety-three patients with HME completed a questionnaire designed of an exostosis. Recent studies estimate the lifetime risk of to assess pain as well as its impact on their life. Eighty-four percent of malignant degeneration to be about 2% for individuals with participants reported having pain, indicating that pain is a real HME.2,5 Many individuals with HME undergo surgery as problem in HME. Of those with pain, 55.1% had generalized pain.
a result of HME-related complications, with 66% to 74% of Two factors were found to be associated with pain outcome: HME- individuals undergoing at least one operation for their related complications and surgery. Individuals who had HME-related exostoses and the average number of surgeries being two to complications were five times more likely to have pain, while those who had surgery were 3.8 more likely to have pain. No differences There is little information in the current literature were found between males and females with respect to pain, surgery, concerning pain in individuals with HME. While the presence or HME-related complications. The results of this study indicate that of pain has been documented in HME, its overall severity and the number of individuals with HME who have pain has been effects on individuals have not been thoroughly assessed. This underestimated and that pain is a problem that must be addressed study was undertaken to characterize pain in individuals with when caring for individuals with HME.
HME to determine what proportion of individuals with HME Key Words: hereditary multiple exostosis, pain, exostoses, osteo- have pain, whether the pain is isolated or generalized, whether there are differences in pain between genders and age groups,and to what extent the pain in individuals with HME is associated with surgery for HME-related complications.
Hereditary multiple exostosis (HME) is a skeletal disorder characterized by the presence of numerous bony out- growths (osteochondromas or exostoses) that develop next to the growth plates of all the long bones.1 HME is an autosomal A four-part questionnaire was designed for this study.
dominant condition with a prevalence of approximately 1 in Part 1 was a demographic section. Part 2 addressed the 50,000 individuals.2 It has been estimated that 66% to 90% of participant’s HME-related medical history and was partly individuals with HME have a family history of the condition.1,2 based on the data collection sheet used in the study by The most striking feature of HME is the numerous Wicklund et al.5 Part 3 addressed pain and assessed whether cartilage-capped exostoses, which are associated with the all the participant had pain and if and how pain interferes with his of the skeleton. In addition to having exostoses, individuals or her life, using numeric rating scales and a pain drawing.6–9 with HME can have other skeletal and nonskeletal compli- Part 4 was a family history section. The complete study cations, including limb discrepancy, bony deformities, mild Questionnaires were mailed to 755 individuals with HME, 700 ascertained through the MHE Coalition and 55 From *Department of Pediatrics, University of Texas-Houston Medical through the Shriners Hospital for Children, Houston. For School, Houston, Texas; †Department of Obstetrics, Gynecology, and young children, the questionnaire was completed with the help Reproductive Sciences, University of Texas-Houston Medical School, of a parent or family member. A total of 293 questionnaires Houston, Texas; ‡Department of Anesthesiology, University of Texas-Houston Medical School, Houston, Texas; §Shriners Hospital for were returned (39% response rate). Of the 293 participants, 38 Children, Houston, Texas; and {Department of Biomathematics, (13%) were ascertained through the Shriners Hospital and 255 University of Texas M. D. Anderson Cancer Center, Houston, Texas.
(87%) through the MHE Coalition. All participants included in Study conducted at the University of Texas Health Science Center, Houston, the study indicated that they had a diagnosis of HME and were The MHE Coalition (http://www.mhecoalition.com) provided partial funding known to have multiple exostoses. All information was kept for this study. None of the authors received any additional financial confidential and analyzed using unique identifiers.
Data were analyzed using the SPSS statistical analysis Reprints: Jacqueline T. Hecht, PhD, Department of Pediatrics, University of software program version 10.0 (SPSS Inc, Chicago, IL).
Texas-Houston Medical School, P.O. Box 20708, Houston, TX Frequencies were calculated for all variables and testing for 77225-0708 (e-mail: jacqueline.t.hecht@uth.tmc.edu).
Copyright Ó 2005 by Lippincott Williams & Wilkins statistical significance was performed using chi-square J Pediatr Orthop  Volume 25, Number 3, May/June 2005 J Pediatr Orthop  Volume 25, Number 3, May/June 2005 hypothesis testing, t test, and logistic regression. Statistical breathing, bone deformities, and spinal cord compression.
significance was considered at P # 0.05. This study was Twelve individuals (4.1%) reported malignant degeneration of approved by the Institutional Review Board of the University an exostosis, with the most common location being the pelvis of Texas Health Science Center-Houston.
(Table 2). Eight individuals reported having a chondrosarcoma,three had an osteosarcoma, and one had a Ewing sarcoma.
Eighty-four percent of the participants reported having Of the participants, 132 (45.1%) were male and 161 pain (Tables 3 and 4). Of those reporting pain, 55.1% were (54.9%) were female. The mean age was 28.2 years. Seventy- determined to have generalized pain and 44.9% to have six percent of the participants indicated that they were isolated pain. A participant was determined to have members of the MHE Coalition (not all participants generalized pain if he or she described having pain throughout ascertained through the MHE Coalition were members of the body (multiple locations in different parts and sides of the the support group); of those, 12.0% are active on a daily basis, body) and not localized to areas where he or she had exostoses.
19.8% are active on a weekly to monthly basis, 20.3% are Questions about the location of pain and the location of active every few months, 4.6% are active on a yearly basis, and exostoses as well as the pain drawing were used to determine 43.4% are non-active members (Table 1). Activity in the whether an individual has generalized pain. When asked how support group is defined as e-mailing or contacting other frequently they experience pain in an average month, 45.3% members of the support group, visiting the website, and reported having pain daily, 12.2% 20 to 29 days per month, 14.3% 10 to 19 days per month, and 28.2% 1 to 9 days permonth. Twenty participants (0.07%) reported being on disability or unable to work due to pain. For those who were The mean age at first exostosis was 4 years and the mean able to work, the average number of days of work missed in age at diagnosis of HME was 7 years. Eighty percent of a month was 1 day. Eighty-seven percent of participants with participants reported having surgery for their exostoses, witha median of two surgeries (range 0–45). Seventy-four percent of participants reported having complications secondary tohaving exostoses, with most having compression of tendons, muscles, ligaments, or nerves. Thirty-five percent of partic- ipants reported having other complications such as pain when Compression of Tendons, Muscles, Ligaments (n = 293) Frequency of Support Group Participation (n = 218) Malignant Degeneration of an Exostosis (n = 293) *Complications such as pain when breathing due to an exostosis, spinal cord J Pediatr Orthop  Volume 25, Number 3, May/June 2005 (P = 0.008), and age at first exostosis (P , 0.001). Participants with HME-related complications were 3.1 (95% CI 1.4–6.7) times more likely to have surgery. Participants who reported having more severe interference with sleep due to pain were 2.5 (95% CI 1.4–5.0) times more likely to have surgery, while older participants and participants with a younger age at first exostosis were 1.7 (95% CI 1.3–2.5) times and 2.1 (95% CI 1.3–3.2) times more likely to have surgery than other *Data only for individuals with pain.
Two other important findings were observed (Table 6).
Males and females did not differ with respect to pain, surgery, pain have had at least one surgery as a result of having or HME-related complications. Female participants were just exostoses. Seventy-four percent of participants reported taking as likely to report having pain, surgery, or HME-related some type of medication for their pain, with 17% taking complications as male participants. Membership in the support a prescription narcotic, 26% taking non-narcotic prescription group was associated with having surgery, HME-related medication, and 57% taking over-the-counter pain medication.
complications, and pain, with significantly more individuals Appendix B lists the medications taken by participants. Fifteen who were members of the support group having had surgery percent of participants who reported pain had seen a pain (P = 0.044), having HME-related complications (P = 0.035), Chi-square testing was used to determine which variables were associated with pain, and four were found tobe significantly associated: age, HME-related complications,surgery, and support group membership (Table 5). Signifi- cantly fewer individuals under the age of 11 years experienced The goal of this study was to evaluate whether pain in pain (P = 0.003). To adjust for this age effect, all participants HME is a significant problem, as previous natural history under the age of 11 were excluded so that further analysis studies did not examine or identify pain as a significant could be performed on a more homogenous group. Chi-square outcome.2,5 Our results suggest that pain is a significant testing was then repeated on all variables. Significantly more problem, with 84% of the study population reporting that they individuals with pain had HME-related complications (P , experience pain and that pain has a negative impact on their 0.001), specifically compression of tendons, muscles, or lives. Similar pain rates were reported in MHE Coalition ligaments (P , 0.001) and compression of nerves (P , (85%) and Shriners Hospital (80%) participants, which 0.001). A significant association was found for surgery and indicates that pain is a pervasive problem for individuals pain, with more individuals with pain having had surgery (P , who have HME. This is an important observation, as the 0.001). Membership in the MHE Coalition was the fourth participants from the MHE Coalition and the Shriners Hospital significant variable found to be associated with pain (P = represent two different populations of individuals with HME.
0.023). Logistic regression was used to determine which The finding of similar pain rates in both populations indicates factors were associated with pain outcome and to calculate risk that the pain outcome did not result from differential sampling.
ratios for these factors. All variables, including age, were used An important new finding reported by 55% of in this analysis. Only two factors were found: HME-related participants is that they experience generalized pain. Pre- complications (P , 0.001) and surgery (P = 0.001). Indi- viously, pain was associated only with the sites of exostoses viduals with HME-related complications were 5 (95% con- and was considered to be secondary to compression of nerves fidence interval [CI] 2.3–11.2) times more like to have or soft tissues; this study also found that 44% of participants pain, while those who had surgery were 3.8 (95% CI 1.7–8.6) reported isolated pain associated with an exostosis. Our results times more likely to have pain. Logistic regression was also suggest that both localized pain and generalized pain are used to determine which factors were associated with surgical significant problems in HME. This raises the question of outcomes. Four factors were identified: HME-related compli- whether there is an underlying mechanism for generalized pain cations (P , 0.001), interference with sleep (P , 0.001), age *Data only for individuals with pain.
J Pediatr Orthop  Volume 25, Number 3, May/June 2005 pain, and as a result of the complications or the pain is more TABLE 5. Outcome by Presence or Absence of Pain likely to have surgery, and as a result of all of these factors (pain, complications, and surgery) is more likely to seek support from others similarly affected. This study cannot tease apart this relationship; nevertheless, these outcomes are Logistic regression results showed that only HME- related complications and surgery had a significant role in pain outcome. Individuals with HME-related complications were five times more likely to report having pain. Since we did not assess the severity of the disease phenotype in this study, we cannot determine whether these individuals with HME-related complications have a more severe form of the disease. HME individuals reporting surgery were 3.8 times more likely to report having pain, and this result has important implications, as surgical intervention is a common treatment in HME. Two possible explanations may explain why surgery is associated with pain. First, while surgery may initially be undertaken to relieve pain, it could start a pain cycle in which the surgery itself leads to pain, which may lead to more surgery and then more pain. Alternatively, individuals who have surgery may be more severely affected with HME, and it is the more severe phenotype and not the surgery per se that causes pain. The finding that individuals with HME-related complications are 3.1 times more likely to have surgery supports this second possibility but does not rule out the first. The results suggest *Excluding participants under the age of 11 years.
that individuals who have HME-related complications and/orsurgery are at increased risk for pain. These findings alsosuggest that surgery should be avoided or kept to a minimum, Four variables were found to be associated with pain in as it is an important risk factor for pain in HME individuals. At HME in individuals: age, HME-related complications, the very least, this point must be considered before un- surgery, and membership in the support group. Three of these dertaking surgery and when considering repeated surgeries.
factors (HME-related complications, surgery, and support No significant differences were identified between males group membership) may be related. It is possible that a person and females with respect to pain, surgery, or HME-related who has a more severe HME phenotype is more likely to have complications. This is in contrast to two HME studies thatsuggest that males have a more severe HME phenotype thanfemales. Schmale et al found that the females in their studywere more mildly affected than the males and concluded that TABLE 6. Outcomes Based on Support Group Membership their data supported the concept that the genes for HME are expressed more severely in males.2 In support of this finding, Wicklund et al5 found an excess of males undergoing surgical removal of exostoses; this suggested that males with HME are either more severely affected or that they seek medical attention more often than females with HME. However, the results from our study showed that there is no difference between males and females with respect to pain. Gender differences and phenotypic severity warrant additional study.
Malignant degeneration, a severe sequela of HME, is estimated to occur in 0.9% to 25% of HME individuals.10,11 The higher estimates may relate to differential ascertainment in early study designs, as more recent studies estimate a 2% lifetime risk for malignant degeneration.4,12 Malignant de- generation of an exostosis was reported by 4% of our study population, higher than more recent estimates. It is unknown why a higher frequency was found in this population, and thus this finding should be cautiously interpreted.
Assessment of pain is difficult, as it is subjective and *Complications such as pain when breathing, bone deformities, and spinal cord requires sampling of a large sample set. One of the strengths of this study was the large number of individuals with HME who J Pediatr Orthop  Volume 25, Number 3, May/June 2005 participated. However, although we were sampling a large 7. Jensen MP, Engel JM, McKearnan KA, et al. Validity of pain intensity population, it is possible that individuals with pain were more assessment in persons with cerebral palsy: a comparison of six scales.
J Pain. 2003;4:56–63.
likely to participate, especially in view of the fact that we 8. Lara-Munoz C, DeLeon SP, Feinstein AR, et al. Comparison of three cannot be certain whether those individuals who chose not to rating scales for measuring subjective phenomena in clinical research. I.
participate in the study did so because they do not have pain or Use of experimentally controlled auditory stimuli. Arch Med Res. 2004; due to other unrelated reasons. We found that equal numbers of participants in the MHE Coalition and the Shriners Hospital 9. Turk DC, Melzack R, eds. Handbook of Pain Assessment. New York: populations reported pain, suggesting that we were not 10. Jaffe HL. Hereditary multiple exostosis. Arch Pathol. 1943;36:335–337.
sampling the pain-only group of HME individuals. While 11. Voutsinas S, Wynne-Davies R. The infrequency of malignant disease in both the MHE Coalition and Shriners Hospital populations diaphyseal aclasis and neurofibromatosis. J Med Genet. 1983;20:345– represent populations that have come to medical attention due 12. Salmivirta M, Lidholt K, Lindahl U. Heparan sulfate: a piece of to having HME-related problems or a family member with information. FASEB J. 1996;10:1270–1279.
HME, not all of these individuals have pain, and thus we donot believe that the study was biased toward only individualswith pain. Lastly, pain is subjective and inherently difficult tocharacterize and describe in any population. To overcome thisdifficulty, different means of assessing pain were used, including numeric rating scales, a pain drawing, and multiple-choice questions. The questionnaire used in this study was developed for the study, and thus no validation data for the overall questionnaire are available. The results of the study should be interpreted with this in mind.
Information about pain in HME is important not only to those with HME but also to the physicians who providetreatment and care. This study shows that pain is a significantproblem in HME and affects a large proportion of these individuals. Additional studies are needed to define the causes [ ] Caucasian, non-Hispanic [ ] Black, non-Hispanic and characteristics of pain in HME. For example, it is [ ] Hispanic [ ] Asian/Oriental [ ] Other, please specify important to determine the cause of generalized pain andwhether pain is due to having a more severe HME phenotypeor to personality or psychological factors unique to certain individuals and/or associated with HME. A prospective study of an HME cohort is also needed to better characterize pain in HME and to understand when individuals start to develop pain, if their pain experience changes over the course of theirlifetime, and what the underlying pain process is.
In summary, this study suggests that pain has been underappreciated in HME and should be addressed when 4) What is your current marital status (not applicable for caring for individuals with this condition.
[ ] Single [ ] Married [ ] Divorced [ ] Widowed[ ] Common Law The authors thank the patients at the Shriners Hospital 5) What is your highest level of education? for Children, Houston, Texas, and the members of the MHE [ ] Lower than 8th grade [ ] Associate degree (2 yr) Coalition for their contributions to the study.
[ ] Completed 10th grade [ ] Bachelor’s degree[ ] High School Diploma [ ] Master’s degree or higher[ ] Some College 1. Solomon L. Hereditary multiple exostosis. J Bone Joint Surg [Br]. 1963; 2. Schmale GA, Conrad EU, Raskind WH. The natural history of hereditary 6) How many people live in your home (including you)? multiple exostosis. J Bone Joint Surg [Am]. 1994;76:986–992.
3. Karasick D, Schweitzer ME, Eschelman DJ. Symptomatic osteochon- dromas: Imaging features. AJR Am J Roentgenol. 1997;168:1507–1512.
4. Vanhoenacker FM, Van Hul W, Wuyts W, et al. Hereditary multiple exostosis: from genetics to clinical syndrome and complications. Eur JRadiol. 2001;40:208–217.
5. Wicklund CL, Pauli RM, Johnston D, et al. Natural history study of 7) What best describes your approximate yearly household hereditary multiple exostosis. Am J Med Genet. 1995;55:43–46.
6. Jensen MP. The validity and reliability of pain measures in adults with income before taxes (the income of all family members who are working and currently living at home with you)? J Pediatr Orthop  Volume 25, Number 3, May/June 2005 (To be answered by parent or guardian if you are under If yes, please specify where on the body the compression is [ ] Less than $10,000 [ ] $50,000–$74,999 [ ] $10,000–$24,999 [ ] $75,000–$100,000 [ ] $25,000–$49,999 [ ] More than $100,000 [ ] NoIf yes, please specify where on the body the compression isor was: 8) What type of health insurance are you covered by? Mark e) Have any exostoses undergone malignant changes all that apply. (To be answered by parent or guardian if you [ ] Health Maintenance Organization (HMO) [ ] Preferred Provider Organization (PPO) If yes, please specify the type of cancer (chondrosarcoma, osteosarcoma, other) and where on the body the cancer(s) f) Other complications (example: spinal cord compres- 9) At what age was your first exostosis noticed (age in years)? 10) How old were you when you were diagnosed with 13) In an average month (30 days) how often do you have 11) Have you had any HME-related surgeries (example: removal of exostosis, limb lengthening, stapling, limb 14) In an average month, how would you rate your average c) At what age did you have the surgery, where was the pain when you have pain? (Mark both scales) surgery (example: knee, hip) and what type ofprocedure was it (example: exostosis removed, limblengthening)? (If you need more space please use theextra sheet provided at the end of the questionnaire.) Age: [ ] Location: Procedure:Age: [ ] Location: Procedure:Age: [ ] Location: Procedure:Age: [ ] Location: Procedure:Age: [ ] Location: Procedure:Age: [ ] Location: Procedure: 15) How would you rate your pain right now? (Mark both 12) Have you had any other medical problems due to the b) Compression or irritation of tendons, muscles, or [ ] Yes[ ] NoIf yes, please specify where on the body the compression isor was: J Pediatr Orthop  Volume 25, Number 3, May/June 2005 22) How would you describe your pain over the past month? a) All the time (constantly throughout the day)? b) On and off throughout the day (intermittently)? c) At specific times or with specific activities during the day (example: when I wake up, when I walk)? 23) In an average month, how many days or partial days of [ ] NoIf yes please specify when during the day or whatactivities: 24) Do you receive any special accommodations or assisted technology at work or school? (example: At work, doemployers excuse you from tasks that would trigger pain,such as heavy lifting, carrying heavy objects, etc.? Atschool, do you have an Individual Education Plan (IEP) or 17) Where do you have pain? (Please mark all parts of the 25) If yes, please explain: In an average week, how much does pain interfere with your general activity? 26) In an average week, how much does pain interfere with 27) In an average week, how much does pain change how you 18) Do you have pain where you have exostoses (bony 28) In an average week, how much does pain affect your 19) If you have had exostoses removed, do you have pain 20) Do you have pain as a result of other HME-related 29) Have you experienced depression as a result of chronic surgeries (example: leg lengthening, stapling, etc.)? b) If yes, what caused the pain (example: nerve damage, 30) What kinds of things make your pain feel worse (example: 21) Do you have pain in parts of your body where there are no 31) What kinds of things make your pain feel better (example: J Pediatr Orthop  Volume 25, Number 3, May/June 2005 32) Do you have any other medical condition(s) that causes Part 4 - Family History – If you do not have a family pain (example: Arthritis, Reflex Sympathetic Dystrophy history of HME do not fill out this section. (If you need more room please use the extra sheet at the end of the questionnaire.) 33) What do you think is the cause of your pain? a) My pain is due to hereditary multiple exostosis.
b) My pain is due to treatment I have received (for c) My pain is due to another medical condition.
34) Do you take any medication(s) for pain? b) If yes, what medication(s), how often do you take them, 35) Are you receiving any other treatments for pain (ex: physical therapy, occupational therapy, chiropractic treat-ments, orthotics and/or braces, etc.)? b) If yes, what treatments and how often? 36) Are you satisfied with the treatment you are receiving for 37) Have you ever seen a pain specialist? 38) Are you a member of the MHE Coalition? b) If yes, how often do you participate in the support group [ ] Daily [ ] Weekly [ ] Monthly [ ] Every few months

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