Reducing diagnostic delay is a major healthcare priority, especially for individuals with a rare disease. In this study of adults living with FD/MAS, the median time from potential first symptom to final diagnosis was 2 years with diverse range of clinical specialties involved in the diagnostic odyssey. The longest delay was from first visit to secondary care to final diagnosis.
The vision of the International Rare Diseases Research Consortium is for all known RDs to be diagnosed within a maximum of one year from the date which they come to medical attention4. In Europe, the 2007 EURORDIS patient group survey indicated 25% of patients waited between 5 and 30 years and 40% received another first diagnosis5. A study of all rare disease patients in Spain, demonstrated the diagnostic journey varied by type of rare disease with a shorter diagnostic journey within a year for rare musculoskeletal disorders 5. However, this study did not distinguish between types of rare musculoskeletal disorders. In hypophosphatasia, the mean time taken from initial symptoms to final diagnosis was around 10 years for adults, highlighting the importance of taking a comprehensive medical history at initial presentation11. In sternocostoclavicular hyperostosis (SCCH), a chronic inflammation condition affecting the anterior chest wall, the mean diagnostic delay across 52 patients was 5.6 ± 5.9 years12. The authors highlighted that greater recognition of the clinical characteristics of SCCH was crucial to achieving a more timely diagnosis.
Multiple factors influence the diagnostic delay, including patient, healthcare providers and system factors and disease factors. The diagnostic intervals can be divided into the time from first symptoms, patient appraisal, seeking medical attention in primary care, referral to secondary care and then final diagnosis6,7. The long diagnostic interval we have observed probably reflects the heterogeneity in both symptoms and age of clinical presentation in FD/MAS. This study identified the time from first hospital visit to final diagnosis as the highest attributable delay, highlighting a critical bottleneck in the diagnostic odyssey to address within secondary care. Contributing factors may include non-specific symptoms presenting to secondary care, lack of clinical knowledge, unclear referral pathways to expert centres and limited diagnostic laboratory tests for FD/MAS. The detection of the GNAS p.R201 variants in blood circulating cell free DNA has been shown to be effective for diagnosis of FD/MAS for those with endocrinopathy or high skeletal burden score 8. However, the diagnostic uncertainty is higher in those with monostotic or craniofacial lesions, where this test is less sensitive. In our study, the date of first presentation to the healthcare system was via primary care in all but one case, reflecting the healthcare system of the NHS. While primary care provider can contribute to the diagnostic odyssey with a lack of coordination, information sharing and guidance9, time from GP visit to hospital referral had a smaller contribution to the diagnostic journey in this patient group.
The diagnosis of FD/MAS usually requires musculoskeletal radiologists with clinical experts in rare diseases2. A number of European initiatives, including the European Reference Networks (ERNs), have been resourced to help reduce the diagnostic journey by supporting expert multidisciplinary meetings to shorten the diagnostic odyessey10. However, the BREXIT referendum of 2016 and subsequent withdrawal agreement, has excluded UK based clinicians and researcher from active participation in the ERNs, to the detriment of patient care11, given no equivalent network has since been funded in the UK. Although the publication of recent, evidence-based, best practice guidelines has provided greater clarity over the radiological, histological and extra-skeletal manifestations of FD/MAS14, it is anticipated that patients with FD/MAS will continue to experience diagnostic delay. Indeed, the rarity of the disease, in conjunction with its diverse clinical manifestations and multi-system involvement (requiring multi-specialty care), mean that diagnostic delay is likely. The NHS in the UK is about to institute a Rare Disease Collaborative Network for adults with rare bone diseases that should link every district hospital in England, Wales and Scotland to an adult rare bone disease network. Comparing these findings for individuals diagnosed after the network is functional may demonstrate the value of the network. The observation of a longer diagnostic interval in women and older individuals is consistent with other common and rare conditions12. The reasons behind this diagnostic disparities is likely multi-dimensional. Contributary factors may be related to the perception of symptoms in older patients and gender based differences in health seeking behaviour. These finding highlight the need for healthcare professionals not to overlook symptoms based on patients age alone as some symptoms, such as bone pain are more common in the older individual with FD/MAS13. Further work is needed to understand the short, medium and long term impacts from a longer diagnostic delay for the patient, family and healthcare system perspectives4.
The strengths of this study is patient reported symptom onset is often inconsistently recorded in clinical records and best recorded by patients. Another strength is representation across the subgroups of FD/MAS. A major limitation is the self-reporting of the diagnosis of FD/MAS and uncertainty that the first reported symptom was clinically related to the FD/MAS.
In conclusion, this study has characterised the diagnostic odyssey for adults with FD/MAS and demonstrated significant delay worse in older adults, younger age of first symptoms and in those with adult onset symptoms, in women. These findings provide a basis for researchers, clinicians and patients societies to co-develop interventions to reduce the diagnostic delay in this rare disease.