Italy’s rare disease registry exposes a steep north-south divide in diagnostic activity
Italy’s national rare disease registry captured 263,817 rare disease diagnoses between 2017 and 2023, offering one of the clearest recent views of how rare conditions are being recognized and recorded across the country. The analysis does more than count cases. It maps where diagnoses are concentrated, how reporting changed over time, which disease groups dominated the registry, and how often patients crossed regional borders for care.
The pattern is uneven from the start. Northern Italy recorded far more diagnoses per capita than the South and the Islands, and the gap was large enough to raise questions about access, diagnostic capacity, and how effectively rare disease networks are functioning across the national system.
Registry volume rose and fell with the pandemic-era disruption
Annual reporting rates were not static. The highest rate occurred in 2018, when the registry recorded 7.7 diagnoses per 10,000 inhabitants. The lowest rate came in 2020, falling to 5.0 per 10,000. The drop is consistent with a health system under strain, when routine pathways for specialist review, testing, and formal registration were likely harder to sustain.
Those shifts matter because rare disease surveillance depends on more than disease biology. It depends on whether patients can reach the right clinician, whether the condition is recognized, and whether the diagnosis is entered into a registry that is complete enough to support planning. A fall in recording does not necessarily mean the diseases became less common. It may simply mean they became harder to detect and document.
Sex was documented as male in 42.7% of records and female in 47.4%, with missing sex data in 9.9%. Even that level of missingness is a reminder that registry-based surveillance is only as strong as the completeness of its underlying data. For public health planning, incomplete fields can weaken comparisons across regions and over time.
Neurologic and developmental disorders dominated the case mix
The largest nosological group was rare neurologic diseases, which accounted for 17.7% of diagnoses. Rare developmental defects during embryogenesis followed at 12.0%, and rare systemic or rheumatologic diseases made up 10.8%. These three categories alone account for a substantial share of the registry, which suggests that neurologic, congenital, and multisystem disorders continue to drive a large portion of specialist rare disease activity in Italy.
Age distribution clustered most heavily in adults aged 35 to 64 years, although the pattern varied by disease group. Some rare disorders are recognized early in life, while others emerge later or remain unrecognized until symptoms accumulate over years. The broad adult concentration likely reflects both true epidemiology and the long diagnostic pathways that many rare disease patients face.
One diagnosis delayed is one diagnosis miscounted.
That point is central to how the registry should be read. These are reporting rates, not direct incidence or prevalence estimates. The numbers capture clinical activity and diagnostic capture, not the full burden of disease in the population. In rare diseases, underdiagnosis can be as important as disease frequency itself.
Regional reporting gaps suggest unequal access to specialized pathways
The clearest finding is the geographic gradient. Population-weighted cumulative reporting rates reached 54.8 diagnoses per 10,000 inhabitants in Northern Italy and 51.7 per 10,000 in Central Italy, but only 26.7 per 10,000 in Southern Italy and the Islands. This is not a trivial difference. It points to a system in which rare disease recognition appears much more concentrated in some parts of the country than others.
Several explanations are plausible from a health-system perspective. Regions with denser specialist networks, better access to reference centers, more mature diagnostic pathways, or stronger registry integration may be more likely to identify and report cases. Regions with fewer specialized services may miss diagnoses, delay confirmation, or transfer patients elsewhere before the case is formally captured.
The registry also documented substantial interregional healthcare mobility. In rare disease care, mobility can reflect both necessity and fragmentation. Some patients travel because highly specialized expertise is concentrated in selected centers. Others move because their home region cannot provide timely access to testing, multidisciplinary assessment, or long-term follow-up. Either way, mobility signals pressure points in the system.
Why reporting rates matter for public health planning
The practical value of the registry lies in its ability to support surveillance and resource allocation. Rare diseases are individually uncommon, but collectively they represent a major clinical and organizational burden. A registry that tracks diagnoses across time and space can help health authorities anticipate demand for genetics, neurology, rheumatology, pediatrics, rehabilitation, and other specialist services.
The study also shows why crude counts are not enough. A high number of diagnoses in one area may mean better detection rather than a higher underlying burden. A low number may indicate limited access, delayed recognition, or weak data capture. Pairing reporting rates with demographic and mobility indicators gives a fuller picture of where the system is functioning and where it is losing patients along the diagnostic path.
For clinicians, the message is equally concrete: rare disease recognition remains deeply dependent on local infrastructure. A patient’s chance of being counted in a national registry can still hinge on geography, referral patterns, and the availability of experts who know what to look for.
Data completeness and ORPHAcodes remain the next bottlenecks
The analysis closes with a clear operational agenda. Better data completeness, stronger harmonization, improved interoperability, and broader implementation of ORPHAcodes would make the registry more useful for surveillance and for European collaboration. These are not abstract administrative improvements. They determine whether registry data can be compared across centers, linked to services, and used to guide planning.
Without harmonized coding, rare disease registries risk becoming collections of partial stories rather than a unified national picture. Without interoperable systems, clinicians may record diagnoses in one setting while planners cannot easily assemble the full burden across regions. And without complete demographic fields, the registry cannot fully describe who is being missed.
The study provides a broad national snapshot, but its most important contribution may be its exposure of structural inequality in diagnosis. Italy’s rare disease burden is not evenly distributed in the registry, and that unevenness likely reflects the shape of the health system as much as the biology of the conditions themselves. For policy makers, the unresolved issue is not only how many rare disease diagnoses occur, but where they are being found, where they are being lost, and which regions still lack the diagnostic capacity to capture them reliably.