# Value of rare diseases reference centers: impact on diagnosis and access to specialized care in fibrous dysplasia of bone

M.A. Legrand, F. Bagouet, B. Merle, D. Gensburger, Roland Chapurlat

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M.A. Legrand, F. Bagouet, B. Merle, D. Gensburger, Roland Chapurlat. Value of rare diseases reference centers: impact on diagnosis and access to specialized care in fibrous dysplasia of bone. European Journal of Medical Genetics, 2023, 66 (11), pp.104849. 10.1016/j.ejmg.2023.104849. inserm-05028761

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# Value of rare diseases reference centers: impact on diagnosis and access to specialized care in fibrous dysplasia of bone

M.A. Legrand<sup>a,b,*</sup>, F. Bagouet<sup>a</sup>, B. Merle<sup>b</sup>, D. Gensburger<sup>a,b</sup>, R. Chapurlat<sup>a,b</sup>

<figure><img src="image_3.png" /></figure>

## ARTICLE INFO

Handling Editor: A. Verloes

**Keywords:**

Fibrous dysplasia of bone
Mc Cune Albright syndrome
Fracture
Rare bone disease
Healthcare organization

## ABSTRACT

**Introduction:** Reference Centers and Rare Disease Health Networks aim to improve the management of patients with rare diseases. The French reference center for Fibrous Dysplasia was certified in 2006.

**Objective:** The objective of our study was to assess the effectiveness of our reference center since its constitution.

**Methods:** In a retrospective cohort study, we compared the activity of our center, including the time elapsed between access to the center and the diagnostic delay of patients with Fibrous Dysplasia between two periods, 1994–2006 (before certification) and 2007–2019 (after certification). Data were extracted from patients’ records (Easily®). Wilcoxon and Fisher tests were performed, using R®.

**Results:** Our cohort included 527 patients with Fibrous Dysplasia/Mc Cune Albright syndrome. The activity of the Fibrous Dysplasia center increased from 139 patients in the first period (1994–2006) to an additional 388 patients for the second period (2007–2019). Mean time elapsed to diagnosis of Fibrous Dysplasia was 1.5 years before 2007 and 1.9 years after 2007 (p = 0.12). Diagnosis was made before referral in over 80% of patients. There was a non-significant decrease in the number of patients with delayed diagnosis: 37 patients (44%) in the first period had a diagnostic delay and 94 patients (33%) in the second period (p = 0.07). Patients were referred to our center on average 6.8 years (before 2007) and 7.9 years (after 2007) after their diagnosis (p = 0.77).

**Conclusion:** Healthcare organization with reference centers significantly impacted the management of patients with Fibrous Dysplasia/Mc Cune Albright syndrome, with a substantial increase in the activity of our center, that roughly tripled since certification. This healthcare organization was also associated with a trend toward decreasing diagnostic delay. However, diagnostic delay affected more than a third of patients and the time to access to the center remained extended (≈7–8 years after diagnosis). The current challenge lies in informing primary care providers and patients about education to rare diseases and existence of reference centers for earlier and more effective specialized management.

## 1. Introduction

Rare diseases are often complex, chronic, and cause intellectual and physical disability requiring frequent access to multiple specialist health services. Many have onset in childhood, but diagnostic delays are common (European Organisation for Rare Diseases, 2009). Diagnosis delay could be explained by a limited access to specialized care, a lack of screening tests and a knowledge gap among health providers and limited availability of official guidelines. Also, delayed diagnosis or receiving the wrong diagnosis may lead to inappropriate and potentially harmful treatments. On average, it takes more than five years, eight physicians and two to three misdiagnoses until a rare disease patient receives the

correct diagnosis (Molster et al., 2016).

Since the 1990s, rare diseases have become a public health priority. In the two past decades, to face the challenge of rare diseases, international and national health strategies and organizations emerged to reach these unmet needs. These organizations act to disseminate the information and knowledge, improve access to care and coordinate research on rare disease. The USA developed different organizations, as the National Organization for Rare Diseases (NORD) (National Organization for Rare Disorders, https://rarediseases.org). Similarly, Europe has founded the European Organization for Rare Diseases (EURORDIS) in 1997 (Eurordis, https://www.eurordis.org/). Another result of the European initiative on rare disease was the creation of the Orphanet web

<footnote><sup>a</sup> French Reference Center for Fibrous Dysplasia, Rheumatology Department, Hôpital E.Herriot, Lyon, France</footnote>

<footnote><sup>b</sup> INSERM UMR 1033, Université Lyon 1, Hôpital E Herriot, Lyon, France</footnote>

<footnote>* Corresponding author. French Reference Center for Fibrous Dysplasia, Rheumatology Department, Hôpital E.Herriot, Lyon, France.
E-mail address: melanie.legrand@chu-lyon.fr (M.A. Legrand).</footnote>
database (Orphanet, https://www.orpha.net/). In 2017, twenty-four European Reference Networks (ERNs) were recognized, including the ERN BOND providing specialized healthcare for rare diseases and spreading knowledge about these diseases (Vandevelde, 2020; Publications office of the European Union, https://op.europa.eu/en/home; Héon-Klin, 2017; ERN Bond, https://ernbond.eu/). In France, a national plan for rare diseases (French National Plan for Rare Diseases, 2005–2008) has been published in 2004 and it has resulted in the certification of numerous rare disease reference centers by the “Haute Autorité de Santé” (Haute Autorité de Santé, https://www.has-sante.fr/).

The impact of national health policies and reference centers, however, has not been assessed. Our center was certified in 2006, as national reference center for Fibrous Dysplasia/McCune-Albright syndrome (FD/MAS) where we provide diagnosis, treatment and care for a growing cohort of FD/MAS patients (Benhamou et al., 2016). We have tried to apply official guidelines to manage these patients (Bousson et al., 2014; Protocole national de soins, 2012) but we still do not know whether this approach has improved patients outcomes.

Therefore, we have conducted this “before/after” study, comparing the characteristics and the management of patients with FD/MAS seen for the first time in our reference center before or after certification (2006).

## 2. Methods

### 2.1. Study design

In a retrospective cohort study, we have compared the activity of our center, including the time elapsed between diagnosis and access to the center and the diagnostic delay (defined as a time to diagnosis >6 months) of patients with FD/MAS between two periods, 1994–2006 (before certification) and 2007–2019 (after certification). The 1994 date was chosen in order to compare periods of similar duration, and corresponds to the beginning of FD activity in our center, after starting to manage FD/MAS patients at the end of the 1980s (Liens et al., 1994; Chapurlat et al., 1997).

### 2.2. Patients

We have included children and adults with FD/MAS who visited our center at least once (outpatients and hospitalized patients). Patients were included in the “before” or the “after” groups depending on the date of their first visit in the center (respectively before or in 2006 and in 2007 and thereafter).

The diagnosis of FD/MAS was established or confirmed by an expert rheumatologist of the center, based on a combination of clinical, biological, imaging (including conventional radiographs, computed tomography and magnetic resonance imaging) and/or histological arguments (Protocole national de soins, 2012; Chapurlat and Orcel, 2008). The absence of detectable bone lesion was the sole non-inclusion criteria.

All patients were informed of the study and had the possibility to oppose the use of their anonymized data. The study has obtained approval from the “Commission Nationale de l’Informatique et des Libertés” and was approved by the French ethics committee of the “Hospices Civils de Lyon” (reference number 22_370).

The study is registered under the ClinicalTrials.gov NCT05422833.

### 2.3. Data collection

Data were retrospectively extracted from patient records, using Easily® software. The following data were collected: baseline demographic features (gender, age at diagnosis, age at first symptoms/discovery of bone lesion, age at first visit in the center), initial presenting symptoms, affected bone sites (monostotic or polyostotic form),

endocrine complications, “café au lait” macules, Mazabraud syndrome, renal phosphate wasting, optic nerve compression, fracture, pain (quantified by the visual analogue scale – VAS), disease severity score (defined as VAS>3 and/or presence of at least one fracture), bone specific treatment, especially bisphosphonate and surgery.

### 2.4. Objective

The main objective was to compare the activity of the center with the number of patients with FD/MAS visiting the center for the first time - over two periods of time: 1994–2006 (before certification) and 2007–2019 (after certification).

Other objectives included the comparison between these two periods of:

- The time elapsed to diagnosis, defined by the time elapsed between first symptoms or discovery of bone lesions and the diagnosis of FD/MAS

- The time to access to the center, defined by the time elapsed between diagnosis (when patients were diagnosed before their first visit) and the first visit to the reference center

- The diagnosis delay - defined as the time to diagnosis ≥6 months according to our previous study (Benhamou et al., 2016).

We also examined the main patient characteristics and the possible change in medical and surgical approaches.

### 2.5. Statistical analysis

We have compared variables “before” and “after” using Wilcoxon and Fisher tests, as appropriate. Analysis regarding fractures were adjusted for age at the first visit and FD type (mono/polyostotic). All statistics were performed, using R software, v4.0.2.

## 3. Results

We have recruited 527 patients, including 139 in the “before” period and 388 in the “after” period (Fig. 1 and Table 1). Thus, the activity of the center has increased substantially by 2.8 fold since the certification, peaking in the last 2 years: +8.9% in 2018 and + 6.8% in 2019 (Fig. 2). Approximately two thirds of patients were women. The mean age at the first visit was 29.7 years in the “before” group and 33.2 years in the

<figure><img src="image_4.png" /><figcaption>Fig. 1. Flow-chart.</figcaption></figure>
<table><caption>**Table 1**
Patients characteristics.</caption><thead><tr><th></th><th>Before</th><th>After</th></tr></thead><tbody><tr><td>First visit in the center, years</td><td>1994–2006</td><td>2007–2019</td></tr><tr><td>Number of patients, n</td><td>139</td><td>388</td></tr><tr><td>Sex female, % (n)</td><td>63.3 (88)</td><td>66.8 (259)</td></tr><tr><td>Age at the first visit, mean ± SD (N)</td><td>29.7 ± 15.8</td><td>33.2 ± 16.1*</td></tr><tr><td>FD type, % (n, N)</td><td></td><td></td></tr><tr><td>- monostotic</td><td>55 (77/139)</td><td>60.2 (233/387)</td></tr><tr><td>- polyostotic</td><td>45 (62/139)</td><td>39.8 (154/387)</td></tr><tr><td>- McCune-Albright Syndrome</td><td>10.7 (15/139)</td><td>12.8 (49/384)</td></tr><tr><td>Café-au-lait spots, % (n, N)</td><td>6.6 (9/136)</td><td>7 (27/386)</td></tr><tr><td>Endocrinopathy, % (n, N)</td><td></td><td></td></tr><tr><td>- Precocious puberty</td><td>10 (14/139)</td><td>9.6 (37/386)</td></tr><tr><td>- GH excess</td><td>0 (0/139)</td><td>1.3 (5/386)</td></tr><tr><td>- Hyperthyroidism</td><td>1.4 (2/139)</td><td>1 (4/386)</td></tr><tr><td>- Hypercortisolism</td><td>0 (0/139)</td><td>0.8 (3/386)</td></tr><tr><td>- Renal phosphate wasting</td><td>12.2 (17/139)</td><td>4.2 (16/384)**</td></tr><tr><td>Optic nerve compression</td><td>9.6 (13/135)</td><td>9.6 (33/342)</td></tr><tr><td>Pain (VAS°), mean ± SD (N)</td><td>1.8 ± 2.0 (127)</td><td>2.3 ± 2.4 (347)</td></tr><tr><td>Severity (VAS>3 and/or fracture), % (n, N)</td><td>50.4 (65/129)</td><td>50.0 (178/356)</td></tr><tr><td>Patients with fractures, % (n, N)</td><td>37.8 (51/136)</td><td>21.4 (82/385)**<sup>a</sup></td></tr><tr><td>Bisphosphonate treatment, % (n, N)</td><td>85.1 (114/134)</td><td>57.3 (200/349)***</td></tr><tr><td>Surgical treatment, % (n, N)</td><td>46.6 (62/133)</td><td>32.3 (120/372) **</td></tr><tr><td>- Osteosynthesis</td><td>31.8 (42/132)</td><td>23.1 (86/372)</td></tr><tr><td>- Prosthesis</td><td>2.2 (3/133)</td><td>1.6 (6/372)</td></tr><tr><td>- Plastic surgery</td><td>2.2 (3/133)</td><td>0.8 (3/372)</td></tr><tr><td>- Curettage, resection and/or graft</td><td>14.3 (19/133)</td><td>9.4 (35/372)</td></tr></tbody></table>

Values are Mean ± SD or percentage % (n,N), n being the number of patients with variable and N the total number of patients during the period.

° Visual Analogue Scale (VAS).

ª adjusted for age at the first visit and FD type (mono/polyostotic).

**: p < 0.001; **: p < 0.01; *: p < 0.05.

“after” group (p = 0.03). More than half of the patients had a monostotic form: 55% in the “before” group and 60% in the “after” group (p = 0.53). All patient characteristics are displayed in Table 1.

We observed that diagnostic circumstances were roughly similar during the two periods - Fig. 3. The most common revealing situation was bone pain (43–44%), followed by incidental discovery (18–24%).

The mean age at first symptoms was 20.5 years in the “before” group and 23.6 years in the “after” group, p = 0.15 (Fig. 4). For asymptomatic patients, the mean age at incidental finding (on imaging) was 23.4 years in the “before” group and 31.4 years in the “after” group, p = 0.24.

The mean pain, assessed by VAS (mean ± sd) was not different

between the “before period” (1.8 ± 2.0) and the “after period” (2.3 ± 2.4), p = 0.14. Moderate pain defined by pain >3/10 on VAS concerned 25 patients (21.4%) in the “before period” and 123 (35.4%) in after period, p < 0.01 (Table 1).

The mean age at diagnosis was 23.2 years in the “before” group and 26.4 years in the “after” group, p = 0.08 (Table 2 and Fig. 4). Most patients had a diagnosis of FD prior to evaluation at the reference center: 99 patients (77%) in the “before” period and 316 patients (87%) had a pre-referral diagnosis. Among patients diagnosed prior their first venue, there was no significant change in time to diagnosis between the two periods - respectively 1.5 years in the “before period” and 1.9 years in

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** First-time patient activity
Number of patients visiting for the first time the center each year before (□) and after certification (■).</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Diagnostic circumstances</figcaption></figure>

Seven circumstances of discovery of the DF were reported and expressed in percentage of patients. There was no significant difference in all diagnostic circumstances between the two periods.

The most common circumstance was bone pain (44 and 43% respectively), followed by incidental discovery (18 and 24% respectively).

the “after period”, p = 0.12. Regarding patients with no diagnosis prior their first visit to the center, diagnosis was made on average 6.6 months in the “before period” (0; 47 months) and 5.1 months (0; 57 months) in the “after period”, p = 0.37.

Overall, the diagnostic delay - defined as time to diagnosis greater than 6 months -tended to decrease: in the “before period”, 37 patients (44%) had a diagnostic delay and 94 (33%) in the “after period”, p = 0.07.

There was no significant difference in time to access to the center, i. e., 6.9 years in the “before” period and 7.9 years in the “after period”, p = 0.77 (Table 2).

In the “before” group, 51 patients (37.8%) had fractures before/ during the management at the center (Table 1), compared to 82 patients (21.3%) in the “after” group. This difference was statistically significant, with p < 0.001, after adjustment for age at the first visit and the monostotic/polyostotic character.

The medical treatment approach changed over time (Table 1), with a reduced use of bisphosphonates: 85.1% of patients had received bisphosphonates in the “before” and 57.3% in the “after” periods, p < 0.0001. Bisphosphonates treatment was initiated by the reference center in 61% of patients in the “before period”, and in 55% of patients in the “after period”, p = 0.34.

Similarly, surgery techniques evolved over time, with a significant decrease in the proportion of patients receiving a surgical treatment in the “after” period in comparison with the “before” period (respectively 47% and 32.3%, p < 0.005). There were fewer patients with osteosynthesis in the “after” period than in the “before” period (respectively 23.1% and 31.8%), but the difference was not significant (p = 0.21). Fewer patients had curettage/resection and/or graft surgery for their bone lesions in the after group (9.4%) in comparison with the “before” group (14.3%, p = 0.56).

## 4. Discussion

Healthcare organization with reference centers has resulted in a significant increase – 2.8fold – in the number of patients treated in our center, since certification. This significant increase in the size of the cohort, suggests a better identification of patients with FD by primary and secondary care providers.

This study underlines the importance of primary care effectors and GP in the diagnosis of rare bone disease, with pre-referral diagnosis of

FD/MAS in over 80% of patients.

The certification of our center was not associated with a significant improvement in time to diagnosis, which was respectively 1.5 years and 1.9 years in the “before period” and in the “after period”, p = 0.12. However, there was a trend toward a decrease of the number of patients with delayed diagnosis – defined as time to diagnosis greater than 6 months. Indeed, 44% of patients in the “before” period had a diagnostic delay versus 33% in the “after” period, p = 0.07. This trend could be indirectly associated with reference center’s action. Indeed, through the publication of guidelines and the dissemination of knowledge about the disease by the reference center, it could result in improvement in the education of pre-referral physicians and in diagnostic performance. This kind of knowledge dissemination is required by our Health Authorities.

In our study, the number of patients with delayed diagnosis was high, but we may have chosen a too stringent criteria. We have chosen a diagnostic delay defined by diagnostic lag time greater than 6 months, to be consistent with our previous work (Benhamou et al., 2016), to be able to make meaningful comparisons. Other authors, however, have arbitrarily defined the diagnostic delay at one year (Boffin et al., 2018). We chose to include asymptomatic patients in the outcomes “time to diagnosis” and “diagnostic delay, because about 20% of patients in our cohort had no symptoms and their disease was incidentally revealed on imagery. This may have increased the time to diagnosis and the diagnostic delay in our study.

The time to access to the center was long in the two periods: patients were referred to our center on average 7–8 years after their diagnosis of FD. This study highlights a limited and delayed access to expert care for patients with rare diseases. This dearth of expert care cannot stem from financial limitations because this type of health care is fully reimbursed in France, including the travel to distant centers. Perhaps, the number of reference centers is too limited and their geographical distribution is inconvenient (Stoller, 2018; Griggs et al., 2009). Another explanation is a lack of coordination and information of primary care providers. General practitioners (GP) have a major role in diagnosis, management and coordination of care for patients with rare diseases. In a recent study (Byrne et al., 2020), assessing the role of GPs in the management of rare diseases in Ireland, 19% of patients were diagnosed by their GP. While GP had access to public information resources, only 35.5% of them were aware of Orphanet and 12.9% used it. In a Belgian survey (Boffin et al., 2018), 35.8% of patients were diagnosed for their rare disease by their GP and only 16% of GP used Orphanet as source of information for their
A.

<figure><img src="image_7.png" /></figure>

B.

<figure><img src="image_8.png" /><figcaption>**Fig. 4.** Age at diagnosis, age at the discovery of the disease and age at the first visit in the center</figcaption></figure>

**4A:** Mean (± SD) of the age of the patients at their first visit in our center, age at the first symptoms or age of fortuitous discovery and age at diagnosis between the two periods i.e. before □ (1994–2006) and after certification ■ (2007–2019).

**4B:** Box-plot of median age of the patients at first visit in the center, age at first symptoms or fortuitous discovery and age at diagnosis between the two periods i.e. before □ (1994–2006) and after certification ■ (2007–2019).

<table><caption>**Table 2**
Time to diagnosis, diagnostic delay and time to access to the center.</caption><thead><tr><th></th><th>Before</th><th>After</th></tr></thead><tbody><tr><td>Number of patients (n)</td><td>139</td><td>388</td></tr><tr><td>Age at diagnosis, years (mean ± SD)</td><td>23.2 ± 14.2</td><td>26.4 ± 16.2</td></tr><tr><td>Diagnostic delay >6months % (n. N)</td><td>44.6 (37/83)</td><td>33.1 (94/284)</td></tr><tr><td>Time to diagnosis, years (mean ± SD)</td><td>1.5 ± 2.5</td><td>1.9 ± 4.9</td></tr><tr><td>Time to access to the center, years (mean ± SD)</td><td>6.9 ± 8.7</td><td>7.9 ± 10.2</td></tr></tbody></table>

Values are mean ± SD or percentage % (n. N), n being the total number of patients and N the number patients during the period.

Comparison of the two groups for these outcomes (age at diagnosis, diagnostic delay, time to diagnosis and time to access to the center) showed no significant difference but a trend toward decreasing diagnostic delay (p = 0.07).

patient conditions. Therefore, one of the current challenges for rare diseases is to enhance the education and the information to GPs and improve the coordination of primary care providers with specialists.

We have been able to observe that treatment approach has evolved over time. Thus, the proportion of patients receiving bisphosphonates has declined. This attitude may stem from the results of studies on bisphosphonates - made by reference centers-in the treatment of FD/MAS, that led to refinement of clinical guidelines (Javaid et al., 2019). Currently, we propose IV bisphosphonates only for patients with bone pain, whereas their use was wider in the past, including to try to diminish osteolytic lesions (Chapurlat and Legrand, 2021).

Regarding the surgical approach, there was a significant reduction in the number of patients who had surgical treatment (47% in the “before” versus 32% in the “after” period, p < 0.005) and a decreasing trend in the number of patients with osteosynthesis (32% in the “before” and 23% in the “after” period, p = 0.21). Approximately 10–15% of patients still have a curettage, resection and/or graft surgery for their bone lesions, despite the fact that the recommended attitude is to perform nailing whenever possible (Javaid et al., 2019; Stanton, 2006).

We believe that the changes observed in the treatment approach (both pharmacological and surgical) is due to the evolution of clinical guidelines, but these are established by reference centers. Based on finding of their clinical and research activities, the mission of reference centers is to establish guidelines and to disseminate their results.

We observed that fewer patients sustained fractures in the second period. These results were age-adjusted, making it unlikely that this was due to alterations in the age structure of the cohort. Similarly, the gender distribution and the main predictor for fracture, that is the proportion of the polyostotic form, did not change. Therefore, an important variation in the recruitment does not appear probable. We analyzed the timing of fracture occurrences and in the “after cohort” approximately 3/4 of the patients experienced their fractures before their first visit to our center. Thus, we cannot conclude about these findings. The decrease in fractures could simply be explained by a change in the epidemiology of the disease.

Our study has strength and limitations. Our study included a large cohort for this rare bone disease. However, the data analysis was retrospective, which might have introduced undetectable biases and confounding factors. Another limitation is that, due to the retrospective design, we could not assess quality of life, which is an important parameter in evaluation of efficiency of management. As it has been suggested, the use of patient reported outcome measures (PROMs) in rare diseases could improve patient care and clinical outcomes (Slade et al., 2018).

## 5. Conclusion

Healthcare organization with reference centers significantly impacted the management of FD/MAS patients, with a better identification of patients and a substantial increase in the activity of our center, that roughly tripled since certification.

Additionally, this healthcare organization has also resulted in a decreasing trend in terms of diagnostic delay.

However, diagnostic delay still affected more than a third of patients and the time to access to the center remained extended (≈7–8 years after diagnosis).

This study underscores the key role of GP and primary/secondary care providers in diagnosing rare bone diseases - with a pre-referral diagnosis occurring in over 80% of patients - and in referral to reference center.

The current challenge lies in enhancing the education of primary/secondary care physicians to reduce diagnostic delays, while also informing physicians and patients about rare disease health networks and centers, for earlier and more effective specialized management of rare diseases.

## Ethics approval and consent to participate

All patients were informed of the study and had the possibility to
oppose the use of their anonymized data. The study has obtained approval from the “Commission Nationale de l’Informatique et des Libertés” and was approved by the French ethics committee of the “Hospices Civils de Lyon” (reference number 22_370).

## Consent for publication

Not applicable.

## Availability of data and material

Data sharing is not available due to ethical restrictions.

## Funding

We thank ERN Bond for funding the publication.

## CRediT authorship contribution statement

M.A. Legrand: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. F. Bagouet: Conceptualization, Data curation, Writing – review & editing. B. Merle: Data curation, Formal analysis, Writing – review & editing. D. Gensburger: Conceptualization, Writing – review & editing. R. Chapurlat: Conceptualization, Writing – original draft, Writing – review & editing.

## Declaration of competing interest

All authors state that they have no conflicts of interest.

## Data availability

No data was used for the research described in the article.

## Acknowledgements

We thank ERN Bond for funding the publication

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