PEDIATRICS Vol. 121 No. 3 March 2008, pp. 540-546 (doi:10.1542/peds.2007-1641)
ARTICLE |
Early Determinants of Fractures in Rett Syndrome
a Centre for Child Health Research, Telethon Institute for Child Health Research, Perth, Australia
b Sydney Children's Hospital and School of Women's and Children's Health, University of New South Wales, Sydney, Australia
c School of Public Health, Curtin University of Technology, Perth, Australia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. The goals were to compare the fracture incidence in Rett syndrome with that in the general population and to investigate the impact of genotype, epilepsy, and early motor skills on subsequent fracture incidence in girls and young women with Rett syndrome.
METHODS. The Australian Rett syndrome study, a population-based study operating since 1993, investigated Australian subjects with Rett syndrome born since 1976. The 234 (81.2%) of 288 verified cases in the Australian Rett syndrome database in 2004 whose families had completed follow-up questionnaires and provided information about fracture history were included in the analyses. The main outcomes were fracture incidence in the Rett syndrome population and fracture risk according to genotype, presence of epilepsy, and early motor profile.
RESULTS. Fracture incidence in this cohort was 43.3 episodes per 1000 person-years, nearly 4 times greater than the population rate. Risk was increased specifically in cases with p.R270X mutations and in cases with p.R168X mutations. Having epilepsy also increased fracture risk, even after adjustment for genotype.
CONCLUSIONS. Girls and young women with Rett syndrome are at increased risk of fracture. Those with mutations found previously to be more severe and those with epilepsy have an increased propensity toward fractures. Improved understanding of the risk factors for fracture could contribute to better targeting of interventions to decrease fracture incidence in this vulnerable population.
Key Words: Rett syndrome • MECP2 • population-based • epilepsy • fractures
Abbreviations: AED—antiepileptic drug • HR—hazard ratio • CI—confidence interval • BMD—bone mineral density
Rett syndrome manifests in early childhood with a sudden or gradual loss of speech and hand function, followed by a slow decrease in acquired gross motor skills.1–3 Rett syndrome is caused by mutations in the X-linked MECP2 gene4 and affects mainly girls, resulting in severe functional dependence.5 There is considerable clinical variability in Rett syndrome, and information that links phenotypes to particular MECP2 mutations is emerging.2,5–7
We reported previously that girls with Rett syndrome were at increased risk of fracture.8 Nearly one third had sustained a fracture by the age of 15 years,8 compared with only 15% of girls and women in the general population by the age of 20 years.9
Bone mineral density (BMD) assessed with densitometry has been shown to be a strong predictor of fracture risk in the general adult population10 and has been associated with forearm fractures in children.11 During childhood, however, low BMD has not been related consistently to the total number of fractures11 or to the occurrence of fractures in prepubertal children.12 Individuals with Rett syndrome were reported to have decreased BMD, compared with age- and gender-matched control subjects,13,14 although their decreased body size might have influenced bone outcome interpretation.15 We previously found decreased cortical bone thickness in subjects with Rett syndrome, compared with age- and gender-matched control subjects,8 and also demonstrated a relationship with fracture incidence.8 In general, children and adults with severe intellectual and physical disabilities may be at risk of having low BMD16,17 and fracture susceptibility.16,18
Factors that influence BMD and fracture risk in the general adult population include genetic predisposition, hormonal factors, weight-bearing exercise, previous fractures, certain medications such as antiepileptic drugs (AEDs), and vitamin D levels. Factors that increase susceptibility to falls include physical inactivity, poor balance, and muscle weakness.15 All of these could potentially affect subjects with Rett syndrome, but research in this area has been fairly limited to date.8,13 For example, subjects with Rett syndrome who were not given AEDs or were ambulatory had higher BMD levels,13 and the same factors had protective effects on the risk of a first fracture.8 In Rett syndrome, many aspects of the phenotype, including the risk of epilepsy19 and the development of scoliosis,20 are influenced by genotype. It is possible that there is also a relationship between genotype and bone strength acquisition, and this needs to be explored.
The Australian Rett syndrome database was established in 1993 and is a population-based registry of juvenile Rett syndrome cases, with information collected longitudinally from families and clinicians.21 The aims of the present study were to use data from this database (1) to estimate the fracture incidence in this population and to make comparisons with Australian normative data9 and (2) to investigate the role of early determinants, such as early motor development, epilepsy, and genotype, on the subsequent fracture incidence.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Available relevant data from questionnaires administered to caregivers on recruitment to the Australian Rett syndrome database and biennially from 1996 to 2004 (except 1998) and from a 1-year-long calendar study conducted in 2000 were used for this analysis. Ethical approval for the study was provided by the ethics committee of the Women's and Children's Health Services in Western Australia. Information collected included age at occurrence and location of all fractures experienced over the lifespan of the subject with Rett syndrome. A single fracture event was a report of an episode in which
1 bone was fractured and both the location and timing of the event (to the nearest year) were recorded. Midpoints of the year (June) and month (15th day) were used to impute missing information to describe the month and day, respectively, on which the fracture occurred. The censoring date for each subject was the date of return of the most-recently completed questionnaire.
At initial recruitment, the family was asked whether the child had ever walked. Information on mobility at 10 months was coded as walking/crawling, bottom-shuffling, rolling, or not mobile. The presence of epilepsy was a binary variable, with a diagnosis of epilepsy being accepted with parental recording of seizures.19 The number of AEDs used, based on data collected in 200022 or, when data were not available for 2000, from questionnaires administered subsequently, was coded as 0, 1, or 2. A previous analysis showed that, in 2000, carbamazepine, sodium valproate, and lamotrogine were the most commonly used medications, either singly or in combination with another AED.22 The molecular techniques used to identify pathogenic mutations in the MECP2 gene were described previously.23 Cases were categorized according to mutation types, including the p.R106W, p.R133C, p.T158M, p.R168X, p.R255X, p.R270X, p.R294X, p.R306C, C-terminal deletion, early truncating, and large deletion mutations. A final group included all other pathogenic mutations.
Kaplan-Meier survival analysis24 was used to describe the risk of a first fracture episode and the incidence of all fracture episodes. Comparative population data on number of fractures and person-time exposed in the appropriate gender and age group bracket were obtained from a population-based Tasmanian study,9 and the incidence rate ratio was calculated. The effects of potential risk factors on all fracture episodes were assessed by using a proportional-hazards model with a counting-process style of input, and robust SEs were used for recurrent fractures.24 Univariate and multivariate analyses were conducted by using Stata 9 (Stata, College Station, TX).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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A total of 288 case subjects were known to the Australian Rett syndrome database when the 2004 follow-up questionnaire was administered. The families of 240 case subjects had provided
1 follow-up questionnaire since 1996, with 234 families providing information describing the occurrence of fractures. At the time of censoring, the median age of all girls/women was 14.7 years (range: 2–29 years). Genetic testing had been performed in 215 (91.9%) of 234 cases, and a pathogenic mutation had been identified in 164 (76.3%) of the 215 cases tested. The distributions of the potential risk factors under investigation are shown in Table 1.
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Eighty-four subjects (36%) experienced
1 fracture episode, with 32 (38% of those subjects) experiencing >1 episode (Fig 1). The bone fractured most commonly was the femur, and the region affected most commonly was the lower limb, although fractures were reported in all regions, including the face (Table 2). The number of bones fractured during most episodes was 1.
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There was a 38.3% risk of fracture by the age of 15 years (Fig 2). The incidence of any fracture episode was 43.3 episodes per 1000 person years (95% confidence interval [CI]: 36.9–50.8 episodes per 1000 person years). The rate of fracture was nearly 4 times greater (incidence rate ratio: 3.82; 95% CI: 3.2–4.6) than the population rate, as estimated from data for Tasmanian girls <20 years of age.
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Case subjects with a diagnosis of epilepsy had nearly 3 times the risk of fracture, and those receiving
2 AEDs had nearly twice the risk of those who were receiving no medication (Table 3 and Fig 3). Of those who developed epilepsy, 22 (11.4%) sustained a fracture before their diagnosis of epilepsy. There was some protective effect of learning to walk on any fracture (hazard ratio [HR]: 0.66; 95% CI: 0.41–1.05) (Table 3). The risk of any fracture was increased nearly threefold in subjects with the p.R270X mutation and nearly twofold in subjects with the p.R168X mutation (Table 4).
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After adjustment for the effects of genotype, a diagnosis of epilepsy remained associated with a significantly increased risk of any fracture episode (HR: 2.67; 95% CI: 1.09–6.55), as did receiving
2 medications (HR: 2.11; 95% CI: 1.22–3.67) (Table 3). However, the protective effect of learning to walk on avoiding fractures that was seen in the univariate analysis was not maintained after controlling for genotype. |
DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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This study showed that the risk of fracture in Rett syndrome was considerably greater than that in the general population; fractures occurred most commonly in the lower limb and the single bone that fractured most frequently was the femur. Subjects with p.R270X or p.R168X mutations were at increased risk of fracture. The presence of epilepsy continued to increase the risk of fracture, even after adjustment for genotype. Those who had learned to walk had a decreased likelihood of any fracture but, after adjustment for genotype, this effect was no longer statistically significant.
Study data were sourced from a longstanding population-based registry.5 Therefore, a large proportion of Australian subjects with Rett syndrome born since 1976 were included, which supports the representativeness of the sample. This is in contrast to studies exploring fractures in children with motor disabilities such as cerebral palsy,25,26 spina bifida,27 or neuromuscular disorders,28,29 which have been large but not population-based. In our study, questionnaires were administered over an 8-year period from 1996, which provided the opportunity to assemble longitudinal data on fracture history and to limit missing information attributable to recall errors. Furthermore, mutation data were available for the majority of subjects, making this study the first to investigate the role of genotype in the occurrence of fractures in Rett syndrome.
Information was reported by parents, and we did not have access to radiologic information. Although it is unlikely that false-positive results would be reported, some fractures might have been missed or unreported and it is possible that we underestimated the true fracture incidence. Because of the nature of Rett syndrome (and the fact that subjects cannot self-report), there might have been missing information concerning the description of the injury, and it was not always possible to establish the mechanism of the fracture. A small proportion of girls seemed to have sustained a fracture before their epilepsy diagnosis. Therefore, we acknowledge that the strength of the association between epilepsy and fractures might have been slightly overestimated.
The 38.3% risk of fracture at the age of 15 years was similar to the 42% risk found previously.8 However, we have now demonstrated that the fracture rate is 4 times higher than that of Australian girls of similar age.9 The effects of this high fracture incidence on the quality of life, care needs, and outcomes for this group and their families are likely to be of importance. We recently reported that one of the most strongly negative associations with mother's mental health status was her child having had a fracture during the previous 2 years.30
In the general population of children, fracture occurs most commonly in the upper limb and, in particular, the forearm.31,32 In this study and our previous study,8 the lower limb was the most frequently fractured region of the body and, similar to studies of subjects with cerebral palsy and neuromuscular disorders,25,29 the femur was the most frequently fractured bone. The reason for this pattern is not clear from our data, and additional study of the mechanisms of fracture in Rett syndrome is indicated. We also note that the distribution of most commonly fractured bones varies somewhat among different conditions. For example, fractures of the hand and foot were observed frequently in children and adults with developmental delays,18 and lower limb fractures occurred most frequently in children with acute lymphoblastic leukemia during maintenance therapy.33 Lower limb fractures (femur more than tibia/fibula) predominated in boys with Duchenne muscular dystrophy who were independently mobile or wheelchair dependent, whereas upper limb fractures (humerus more than forearm) were more common if knee-ankle-foot orthoses were worn.28 Although these different conditions may be associated with different mechanisms of injury, it seems that long bones are at particular risk in patients with chronic diseases.
Persons with severe physical and intellectual disabilities often live in protected environments and usually are not subject to fractures resulting from car accidents, childhood games, or sporting activities.18 Therefore, the high fracture rate in our young Rett syndrome population may represent the effects of other risk factors, such as genotype and the presence of epilepsy.
The current study has provided evidence for the first time that the propensity to fracture can be associated with a specific genotype. Individuals with the p.R270X mutations were found to be particularly vulnerable. It is interesting that this mutation in the nuclear localization signal region of the transcription repression domain is the one that was found to be clinically most severe in a number of studies, including our own.7,34 We also found that this mutation was one of those associated with the most severe profile for early development,35 which suggests that its effects were in play from an early period. By combining Australian data with data from the United Kingdom, we also showed that the p.270X mutation seemed to be associated with earlier death, compared with other mutations.36 Given these associations, the relationship we found with fracture risk is perhaps not surprising. Whether the increased risk of fracture is related to the increased general severity and decreased mobility for this mutation or whether this genotype has a specific effect on bone remains to be determined. These remain very important questions, as we attempt to understand more about the downstream effects of MECP2 and the functions of this protein.
Mild hypercalcuria in Rett syndrome has been described, which suggests that bone resorption might contribute to osteopenia in Rett syndrome.37 Motil et al37 speculated that potential mechanisms could be related to increased cortisol excretion or to a regulatory effect of the MECP2 gene on bone. Case study research using bone biopsies showed evidence of decreased bone volume and turnover in 9- to 14-year-old girls.38 In the same publication, the authors discussed additional unpublished data showing osteopenia in 82 of 84 patients with Rett syndrome, with the youngest being <3 years of age.38 Osteopenia at such a young age in this disorder supports the argument for a genetic influence. Furthermore, Haas et al14 found a lower BMD in 20 girls with Rett syndrome, compared with 11 age-matched girls with cerebral palsy with similar ambulatory status. Therefore, the genetic defect in Rett syndrome may have a specific negative effect on skeletal tissue acquisition.
Our findings are consistent with previous research suggesting a positive relationship between the use of AEDs and decreased BMD13 or altered bone morphometric features.8 Additional research is warranted to assess fully the effects of AED prescription patterns over time on fracture risk. However, a meta-analysis of 11 studies on fracture risk and BMD in children and adults with epilepsy found that the risk of fracture was greater than would be expected from the decrease in BMD resulting from the use of AEDs alone.39 Additional contributing factors in the causal pathway to fracture were considered to include the seizures themselves, poor balance and coordination resulting from comorbidity or the use of benzodiazepines, and limited physical activity.39
Individuals with Rett syndrome are prone to falls because of their neurologic dysfunction, which often manifests as poor motor planning, increased muscle tone, poor coordination, and/or limited balance reactions.1,2 Falls are likely to cause some fractures, although we do not know the frequency of this mechanism. Physical activity has a protective effect against fracture in the general population.15,40,41 In this analysis, however, we showed that the effect of ambulation (having learned to walk) was confounded by genotype and had no independent association. People with Rett syndrome can lose mobility skills with increasing age,42 and physical activity levels are represented not only by the achievement of walking at one stage but also by continued participation. This study has not considered how changing mobility levels with age might affect fracture risk, but this could be the subject of future research.
We showed that children and adults with Rett syndrome are at substantially increased risk of fracture. Importantly, we found that the lower limbs, especially the femur, seemed to be particularly susceptible and that patients with the p.R270X genotype were especially vulnerable to fractures. We also found an additional independent effect of epilepsy. In this study, we focused on how factors determined before birth and in the early childhood years affect fracture risk. To guide interventions most effectively, future epidemiologic research needs to consider variables that may change over time, including patterns of AED and hormonal medication use and the effects of changing mobility status. There is also the exciting possibility that progress in molecular research into the functioning of MECP2 may have implications beyond Rett syndrome, for the understanding of bone turnover in general.
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ACKNOWLEDGMENTS |
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We acknowledge the funding of the major aspects of the Australian Rett Syndrome program by the National Institutes of Health (grant 1 R01 HD43100-01A1) and also by the National Medical and Health Research Council, under project grant 303189 for the clinical aspects. Dr Leonard was supported by National Medical and Health Research Council program grant 353514. The Australian Pediatric Surveillance Unit is a unit of the Division of Pediatrics, Royal Australasian College of Physicians, and is funded by the Department of Health and Ageing and the Faculty of Medicine of the University of Sydney.
We acknowledge the molecular work of Linda Weaving and Sarah Williamson (under the guidance of Prof John Christodoulou and Dr Bruce Bennetts) in Sydney and Mark Davis in Perth. We express our sincere gratitude especially to all of the family members who contributed to the study by completing questionnaires, the Australian Pediatric Surveillance Unit, and the Rett Syndrome Association of Australia, which facilitated case ascertainment in Australia.
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FOOTNOTES |
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Accepted Jul 31, 2007.
Address correspondence to Helen Leonard, MBChB, Centre for Child Health Research, University of Western Australia, Telethon Institute for Child Health Research, Perth, Western Australia, 6872. E-mail: hleonard{at}ichr.uwa.edu.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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