Impact of three genetic musculoskeletal diseases: a comparative synthesis of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta

Achondroplasia, Duchenne muscular dystrophy, and osteogenesis imperfecta are among the most frequent rare genetic disorders affecting the musculoskeletal system in children. Rare genetic disorders are severely disabling and can have substantial impacts on families, children, and on healthcare systems. This literature review aims to classify, summarize and compare these non-medical impacts of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.


Introduction
A rare disease is defined as one that affects less than one in 2000 individuals in Europe and one in 1250 in the United States [1]. Most rare diseases are severely disabling genetic disorders that can have substantial impacts on families and children, and on healthcare systems [2,3].
Despite their specific biomedical features, many rare genetic diseases (RGDs) share several non-medical characteristics, in particular, their psychosocial consequences [4]. While it is acknowledged that research on these non-medical common features may benefit from a non-categorical approach, a disease-specific approach remains common. In addition, the literature assessing these issues is sometimes difficult to summarize due to the inconsistent use of terminology. Several terms are commonly used in the literature to examine the impacts of RGDs: burden of care, quality of life, impacts, consequences, meaning of leaving, and coping strategies [5][6][7]. This proliferation of concepts, which depends on research interest and disciplinary tradition (e.g., biomedical, psychological, economic, social and nursing) reflects the complexity of the field, but may also lead to a fragmented version of 'the same reality'. A clear and synthetized conceptualization of the impacts of RGDs with a non-disease-specific approach is warranted. Scoping reviews, an increasingly popular knowledge synthesis approach in health care, can help in such conceptualization [8]. Moreover, scoping reviews can yield a framework for collating and summarizing results that can empower patients and families, raise awareness among health care professionals, identify knowledge gaps and priorities for future research, and advocate for policies to develop support services for families [8,9]. This paper reports a scoping review that describes the literature on non-medical impacts for patients and families. Due to the exploratory nature of the review and to reflect the research areas of our team, we delineated the focus of this review to three common RGDs in the pediatric orthopedic context: achondroplasia, Duchenne muscular dystrophy (DMD) and osteogenesis imperfecta (OI). These three RGDs are single-gene musculoskeletal diseases characterized by physical disability and little or no impairment of mental ability. Table 1 provides their clinical and genetic characteristics.
The three specific objectives of this review research were: i) to categorize the types of non-medical impacts of achondroplasia, DMD and OI; ii) to summarize these impacts; and iii) to discuss findings on these impacts across the three diseases.

Methods
While systematic reviews synthesize the complete nature of a particular field, outlining what approaches are effective and where further research is required, scoping reviews are exploratory projects that map the literature available on a topic, identifying the key concepts, theories, sources of evidence, and gaps in the research [10]. We therefore opted for a scoping review to allow for a quick mapping of the "key concepts underpinning a research area and the main sources and types of evidence available" [11]. We adopted a broad definition of impact that includes consequences of, but also reactions to, a disease. We followed the five stages suggested for a quality scoping review: i) identification of the research question; ii) identification of relevant studies; iii) selection of studies to include in the review; iv) charting of information and data within the included studies; and v) collating, summarizing and reporting results of the review [11].

Identification of relevant publications
From March to June, 2013, we conducted a search of the literature in three electronic databases: Web of Science, CINAHL, and MEDLINE. The following two string combinations of keywords were used: [Impact, burden, quality of life, living with, coping, adjustment, well-being, quality of life, effects, impacts, responses, reactions, psychosocial] AND [Rare genetic disease/disorder, rare childhood disease, osteogenesis imperfecta, brittle bone disease, Duchenne muscular dystrophy, achondroplasia, chronic illness, musculoskeletal system, physical disorders]. We complemented our search for publications with a systematic screening of the table of contents of specific journals dedicated to rare diseases (e.g. Orphanet Journal of Rare Diseases) and a screening of references of relevant publications. Opinions, commentaries, letters, editorials, and publications without an abstract were immediately initially excluded. The initial search yielded the identification of  [81] 845 publications. After removing 8 duplicates, two authors independently selected publications addressing the nonmedical impacts of Achondroplasia, DMD and OI, based on the titles and the abstracts. Publications that addressed a rare genetic disease other than the three retained by the research group were excluded from this review, as were publications focussed on the identification of genes. In the case of disagreement among authors, the full-text publications were reviewed by a third senior author. A total of 65 full-text publications remained at this stage of the review.

Selection of studies to include in the review
For inclusion in our study, publications had to be i) published between 1980 and 2013; ii) in English or French; iii) about non-medical effects and responses to OI, achondroplasia and DMD; and iv) have a well-defined methodology. Because a scoping review is not intended to assess the quality of studies, emphasis was not placed on methodological rigor of the retained studies. At this second stage, 8 publications were excluded as they examined medical impacts of a treatment or intervention, and 57 publications were retained. Figure 1 displays the study selection flow diagram. We used a data extraction grid to gather the following items: i) general information (e.g., type of study, country, focus); and ii) the relevance of the article to our study and the scientific information such as concepts, theoretical orientation, methodology, and research tradition.
Collating, summarizing and reporting results of the review The 57 retained publications were coded using qualitative structure coding [12] with Nvivo 10 (QSR International) and Endnote X6. From this, we identified main study themes and grouped based on similarity. We iteratively constructed a working framework ( Figure 2) to examine separately the extent, range and research activity for OI, achondroplasia and DMD. The adequacy of the framework to review question was tested independently by two authors (MJD and ED) on 10 selected articles. Disagreements were solved by discussion among these authors or by the adjudication of a senior author (FR).
To ensure consistent mapping and analysis of data, we developed a glossary of codes used to classify the impacts as follows: i) 'scope' refers to whether the article addresses one or several pediatric rare musculoskeletal disorders; ii) 'direction' was used to capture whether the article studied the 'Effect of Disease' (Direction 1) or 'Response to the Disease' (Direction 2); iii) 'target' refers to three distinct groups of focus: 'individuals' such as patients, adults, carers, or siblings; 'groups' such as physicians, caregivers, or school teachers; and 'societies' such as communities or society as a whole; iv) 'timeline' and 'trend' refer to the temporal analysis of impacts; and v) 'type' refers to positive or negative consequences; finally vi) 'domain' refers to the aspect of QOL being studied (psychological, functional and so on) or the research tradition or academic discipline used to study the impacts. Once the 57 publications were categorized, we performed a narrative review of the findings on the impacts separately for each disease, and then critically compared the findings across the three diseases. An overview of the distribution of the publications using the components of our working framework is presented, as well as a summary of the major findings of the publications achondroplasia, DMD and OI. Finally, we discuss how research compares across the three diseases.

Overview of the publications
The majority of the publications (50) were original research focused on a single disease, while 6 publications concerned two diseases (DMD and other diseases), and 1 publication was a literature review.
The target group assessed was spread between the experiences of the individual with the disease (26), the impact of the disease on families (18), the experience of caregivers only (8), or were focused on the impacts of other groups or tool development and reviews of the literature (5; physicians' attitudes, the effects on community).
The direction of the impacts was explicitly stated in 44 of the 57: 31 addressed the effects and impacts of living with achondroplasia, DMD or OI, 13 addressed responses to living with the disease on individuals, groups or society (such as resilience, adjustment, coping strategies and attitudes). In these 44 papers, the occurrence of a RGD was conceptualised as a source of stress to which people react. The direction was either a combination of directions, or not explicitly stated, in the remaining 13 papers. Table 2 outlines the studies according to the scope, target, direction, timeline, trend, and type of impacts.
Papers were also spread over several domains (as defined above), with 15 examining the quality of life (QOL) through a normative and validated measure of function, psychosocial well-being, and perception of health (2 achondroplasia, 7 DMD, and 6 OI). Psychosocial impacts on their own were addressed in 18 publications (14 DMD, 4 OI), and functional status on its own was addressed in 10 publications (1 achondroplasia, 6 DMD, 3 OI). The remaining 14 publications assessed the domains of illness experience, utilisation of healthcare services, palliative care, medical staff reactions to the disease, or newborn screening. Tables 3, 4 and 5 report the general information and major findings of the publications for the domain.

Narrative review
The non-medical impacts of achondroplasia Evidence from the publications on achondroplasia suggests that affected individuals have an impaired QOL when compared to first-degree relatives [14]. The lower QOL could mainly be linked to psychosocial limitations including lower self-esteem and social stigmatization, to the extent that serial lower limb lengthening appeared a good option to patients despite its numerous complications [13,15]. The functional status of patients with achondroplasia was impaired by back pain and pain in the lower extremity, resulting in some cases in complete cessation of work. However, the functional limitation and psychological distress remained unchanged over time [13].

The non-medical impacts of DMD
The overall QOL of parents and their children who are affected with DMD was reported to be lower than in the general population, particularly due to impairments in physical functioning [19,42]. Boys with DMD reported significantly lower QOL than healthy peers in physical and psychosocial domains. Physical limitations increased with age as respiratory problems and muscle weaknesses occurred. However, despite the progressive course of the disease, the psychosocial QOL tended to be higher in adolescents with DMD than in their younger counterparts, suggesting the development of effective coping strategies over time [41,50,52]. For parents, the psychosocial impacts were reported to be great, and quality of life decreased even more around the period of patient transition to wheelchair [22,23]. Finally, parental reports of QOL did not consistently match that of their children, with many underestimating their child's QOL [23].
The 14 studies that solely examined the psychological impacts of DMD reported higher levels of anxiety, depression, and guilt in parents, particularly in mothers [25,26,46]. However, early diagnosis and family hardiness (the energy resources of the family such as commitment, challenge, and control) were reported to positively influence parental psychological adjustments, the patients' level of resilience and the reactions of siblings [20,24,26,29,34,43,48,49,51,53].
In addition to the psychological impacts, parents, particularly mothers, reported caring for their children with DMD to be burdensome (help for bathing, toileting), costly in terms of time, and contributing to increased social isolation [44]. Altogether, participation in daily activities and social life was reduced for patients. Siblings of adolescents with DMD seemed more negatively affected than siblings of healthier counterparts.

The non-medical impacts of OI
There was little difference in the overall QOL of those diagnosed with OI as compared to the general population. Functional limitations were more important in patients with severe forms of OI, and higher life satisfaction, resilience, low depression and higher social achievements were common [55,64,68]. Parents reported several accusations of child abuse, lack of information on the disease, disruptions of family activities due to the occurrence of fractures, and social isolation [56][57][58].

Other findings
Besides these psychosocial impacts of achondroplasia, DMD and OI on families, the impacts on groups and the society were broached in few studies. Two publications examined the attitudes of medical staff about a condition or related treatments options [17,40]. These publications concluded that physicians could promote some experimental treatment options provided that there was a shareddecision making with families. The medical staffs were also found to support newborn and prenatal screening whenever available. Finally, it should be noted that the impacts on the use of health services and economic factors were not assessed in the papers included in this review.

Discussion
The impacts of achondroplasia, DMD and OI on families reported in this review are derived from in-depth qualitative analysis of subjective illness experiences or objective normative measures of QOL. These methodological specificities resulted in variations in the impacts between and within similar categories of publications that may limit the comparison across the three diseases. However, caring for children particularly with DMD and OI was burdensome because of daily practical problems (bathing, toileting), increased time costs and social isolation, as reported in studies on other RGDs [70][71][72]. Consequently, carers reported lower QOL particularly in critical periods of loss of ambulation in boys with DMD and during the occurrence of fractures in OI as recently confirmed [73]. As for the QOL in patients with these three diseases, findings seem contradictory with some publications reporting higher QOL and other reporting lower QOL when compared to healthier unaffected controls [20,22]. The severity of functional and physical impairments follow the severity of the disease, and could be seen as increasing from small functional impairment, such as back pain in achondroplasia, to restricted ambulation from bone deformities and numerous fractures in OI, to progressively reduced ambulation and confinement to a wheelchair in DMD [22]. On the contrary and strikingly, the psychological aspect of QOL in patients did not parallel the severity of the disease. For example, DMD is lifethreatening and its psychosocial impacts are expected to be more severe than for achondroplasia and OI; however, patients with OI did not seem to experience less psychological distress than those with DMD [41,69]. As for the course of the disease, the stable (unchanged) level of psychological distress in patients with achondroplasia reflects the non-progressive course of the disease [13]. The "up and down" pattern of psychological distress in patients with severe OI also confirms the occurrence of fractures as critical periods over the chronic course of OI [73]. While functional limitations increased, the self-reported psychosocial QOL of boys with DMD did not decrease with age. They may have developed effective coping strategies that ought to have been better documented [52]. This finding was confirmed in previous studies. Indeed the level of impact on family including psychological stress was high for families who had children affected by rare genetic metabolic conditions even when the child's function was not impaired and the disease was not severe [5].
Some practical implications emerged from this review that can benefit families and caregivers. The correlation between improved parental coping strategies and early diagnosis, better emotional functioning of the child and siblings suggests that there have been efforts to obtaining an early diagnosis and promoting family hardiness for people living with these diseases [74,75]. To that end, interprofessional teams of geneticists, psychologists and social workers in reference centers for these rare diseases could be effective by offering newborn screening, familycentered and life-span psychosocial support whenever possible [76]. Besides, informal support from family and friends but also institutional health and social support   Marini, Lorusso et al. [43] The DMD group demonstrated reduced abilities in language processing and cognition, specifically visual attention, but not in receptive or expressive lexical abilities. As well, the narrative speech in subjects with DMD was reduced compared to controls, with shorter sentences.  Parents with a son with DMD were more likely to have an episode of major depression and to have consulted a mental health professional during the last year, and to demonstrate lower self-esteem, than parents in a control group.  [26] There were significant correlations between age at diagnosis and family function, with better outcomes associated with a younger age at diagnosis. As well, the level of the child's disability was not associated with family function. However, parents did report poorer overall health and an increase in anxiety, depression, and pain and disability, compared to the general population.  Table 4 Summary of the findings of publications on non-medical impacts of DMD (Continued) Firth, Gardnermedwin et al. [30] Parents reported problems in three main categories: service, practical, and emotional. Parents were also in favour of prenatal screening and early support, as well as an increase in availability of information. Communication within the family about the disease and implications was also reported as a large area of concern.
Illness experiences Guided interviews developed by the authors 56 affected boys, 53 families of boys with DMD USA Pangalila, van den Bos et al. 2012 [44] Parents reported that there was substantial burden as caregivers to adults with DMD, specifically surrounding received support, tracheotomy, active coping, and anxiety.

Illness experiences
Caregiver Strain Index (CSI), Self Rated Burden Scale, The EuroQoL-5D, Hospital Anxiety and Depression Scale (HADS), Utrecht Coping List (UCL). General Self-Efficacy Scale The adolescents interviewed did not identify themselves through their diagnosis, and did not see their diagnosis as a crisis. Spirituality and longing was explored as a means to build relationships and connect with others.

Illness experiences
Interview using Manen's Phenomenological method 9 adolescent boys with DMD USA Beresford and Sloper 2003 [21] Participants recognized that they themselves may lack communication skills. The degree of rapport between adolescents and their doctors was influenced by age and gender.

Illness experiences
Semi-structured interviews and group discussion meetings. 2005 [17] Most physicians support diagnostic genetic testing of high-risk children but are less supportive of expanding newborn screening. Willingness to expand newborn screening does not correlate with professional characteristics but rather with personal interest in testing of their own children.
Other, attitudes of staff  Table 4 Summary of the findings of publications on non-medical impacts of DMD (Continued) Kinali, Manzur et al. 2006 [40] The survey on the attitudes and practices of UK physicians demonstrated that physicians accept and implement NIV to DMD patients. As well most physicians reported that they promoted shared decision making with DMD patients with respect to NIV. There was also a lack in uniformity of opinion concerning long-term respiratory follow-up for DMD.
Other, attitudes of staff  These studies showed a correlation between the severity of the phenotypic expression of OI and QOL indicators tested. Reduced pain, besides being by itself an advantageous outcome, allows effective physical therapy and weight bearing, both benefits that help further strengthen bone. We speculate that improvement in pain resulted in a better sense of well-being and subsequently better self-care scores.  As a predictor of ability to walk in a household, type of OI is the best, along with severity of the collagen defect, and the presence of dentinogenesis imperfecta. Intramedullary rods in the lower extremities have a worse prognosis for walking. From the limited number of publications on the impacts of DMD, achondroplasia and OI, we have learned that research about non-medical impacts of achondroplasia, DMD and OI on healthcare systems and society seems very limited and could be further addressed. However, the selection of the keywords used in the searching strategy in this review might have resulted in the exclusion of some publications. For example, challenges in providing adequate updating training to clinicians and staff on these rare diseases as acknowledged in other RGDs could be examined. In addition, research on healthcare-related impacts might compare the use of healthcare resources according to the severity of the disease. Efficient care delivery models organised around primary care whereby family physicians can help to achieve a smooth transition to adult care institutions must also be investigated [56,77,78]. In addition more theoretical understanding is needed about the complex and non-linear interrelationships between two aspects of QOL: the available quality of care and the family functioning and economic status [79][80][81]. Such understanding will help to acknowledge the relative impacts of these determinants on overall QOL and will help to prioritize adequate interventions.
We acknowledge that methodological limitations could have compromised the inclusion of publications reviewed here. Thus, further longitudinal studies combining normative approaches with qualitative in-depth investigations and comparing several diseases could enhance the understanding of patients' effective coping strategies. Simultaneous use of parent-report and patient-report questionnaires could provide increased insights [22]. Furthermore, our inhouse working framework that guided our organization and analysis of the scoping review could aid others in mapping and organizing the literature during a scoping review; however, to extend its use beyond this would require further validation.

Conclusion
In general, DMD and OI negatively impacted carers. Some events seem particularly critical such as occurrence of fractures or loss of ambulation in patients. As for patients, functional limitations seemed to follow the severity of the disease, but psychological distress did not, which calls for a better understanding of effective coping strategies. This conclusion is supported by the reported higher life satisfaction in very severely affected patients at different stages of the progressing course of DMD, and the reported resilience characteristic of adolescents with OI. In face of the great difficulties presented to families, life span and family-centered psychological support must be developed in a timely fashion to aid patients, carers, and siblings.

Competing interests
Authors declare no competing interests.
Authors' contributions MJD conceived the study, performed the literature review, drafted the initial manuscript and approved this version as submitted. FR conceived the study, critically revised the manuscript and approved this version as submitted. ED performed the literature review and approved this version as submitted. CB critically revised the manuscript and approved this version as submitted.