Mapping Keratoconus in Italy: Insights from 100 Centers reporting to the Italian National Rare Disease Registry

Mapping Keratoconus in Italy: Insights from 100 Centers reporting to the Italian National Rare Disease Registry | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Mapping Keratoconus in Italy: Insights from 100 Centers reporting to the Italian National Rare Disease Registry Giulio Ferrari, Matteo Pederzolli, Adele Rocchetti, Gianluca Ferrari, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7807408/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Keratoconus (KC) is a progressive ectatic corneal disease classified as rare in Italy. To date, no nationwide incidence data from Italy or southern Europe has been published. Methods: This study analyzes on new reports of KC collected from 2019 to 2021 by the Italian National Rare Disease Registry (NRDR), the first national rare disease registry in Europe. Analyzed data include national and regional report rates, demographic characteristics, geographic distribution, and inter-regional healthcare mobility indexes. Data was expressed using descriptive statistics and standardized rates per 100,000 person-years. Results: A total of 5,280 new KC reports from 100 centers were recorded. The average annual report rate was 2.97 per 100,000 person-years, with male predominance (66.8%); average age at report was 28.06 years. Regional disparities in report rates emerged; two super-regional clusters (in northern and southern Italy) and regions Sardinia and Umbria had higher incidence in the NRDR. Inter-regional healthcare mobility was higher for specific regions and centers. Conclusions: This study is the largest-scale KC incidence analysis in Europe and the first nationwide incidence study in Southern Europe. Findings show a relatively comparable incidence to northern European countries, marked geographic clustering, and highlight healthcare access disparities. Such data may be useful on a local and national level and provide useful information for researchers, public health decision makers and people of Italian descent worldwide. Efforts should be made to expand the use of national rare disease registries and to include subclinical KC cases. Funding: Open access funding provided by GF . Health sciences/Health care/Public health/Epidemiology Health sciences/Diseases/Eye diseases/Corneal diseases Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Keratoconus (KC) is a bilateral and progressive corneal condition, is defined by central or paracentral thinning of the stromal layer and corneal protrusion, and leads to the development of irregular astigmatism, corneal scarring, and varying degrees of vision impairment [1]. Epidemiology data from a recent metanalysis suggest that KC may affect up to 0.29% of the population worldwide, typically in the second decade, and more frequently males, with a global incidence of 4 cases per 100.000 persons [2]. Compared to Africa, Asia, and the USA, Keratoconus has lower prevalence in Europe (36.9/100.000) [2]. In Italy, KC is classified as a rare disease [3]. Rare diseases (RDs), as defined by the European Union (EU), affect fewer than 5 in 10,000 individuals [4]. It is estimated that 29 million people in the EU are affected by up to 8,000 different rare conditions [5]. Consequently, the EU has recommended the creation and use of registries and databases as essential tools to advance clinical research, improve patient care, and inform healthcare planning [5]. Italy has been the first country in Europe to establish a population-based public health registry dedicated to RDs [6]. This study aims to present for the first time epidemiological data on KC from the Italian National Rare Disease Register (NRDR). METHODS AND STATISTICAL ANALYSIS The NRDR is managed by the National Centre for Rare Diseases (Centro Nazionale Malattie Rare, CNMR) of the National Institute of Health (Istituto Superiore di Sanità, ISS), serving as both a scientific and institutional tool, supporting epidemiological surveillance and public healthcare governance [7]. The NRDR registry is fed by the National Rare Disease Network, composed of referral centers (with accredited expertise in RDs prevention, diagnosis, and care) and regional registries. Data flows in three steps: (1) clinicians at referral centers diagnose and enter patient information; (2) regional databases collect these records; (3) aggregated data are transmitted annually to the NRDR. National coverage was progressively achieved, with full completeness reached in 2012. Registered patients are exempt from National Healthcare System (Sistema Sanitario Nazionale, SSN) copays for disease-specific visits and procedures. Our analysis of KC data from the Italian NRDR covers a 3-year period (2019 to 2021, latest available data) and concerns the distribution by gender, descriptive and dispersion indices related to age at diagnosis and age of onset, annual crude report rates, distribution by referral center, region of diagnosis/residence/ birth, and healthcare mobility data. Categorical variables, such as gender, region of diagnosis/residence/birth, were expressed as absolute frequencies and percentages. Continuous variables, such as age, were reported as medians and interquartile ranges. Because not all patients with a KC diagnosis may attend referral centers, we used the term “average yearly report rate” rather than “incidence” to express the number of keratoconus diagnoses registered on average in a year based on the total number of reports collected during the three-year period. The average yearly report rate was estimated using a pooled person-years approach, considering annual case counts and population denominators across the three years, and it was expressed per 100,000 person-years. Active mobility index was calculated as the number of patients certified in a region but residing in other regions, divided by the total certifications in the certification region. Passive mobility index was calculated as the number of residents who migrated to another region for certification, divided by the total certifications for their region of residence. Finally, both indices were standardized against the resident population for a given period. RESULTS The National Rare Diseases Registry collected 5,280 new reports from 100 centers from 20 regions during the 2019–2021 period. There was a moderate decrease in reports from 2019 to 2020, probably due to the Covid-19 pandemic (Fig. 1). The population of reference was represented by all Italian residents with a valid registration with the SSN. The number of Italian residents in 2019, 2020 and 2021 was 59.641.488; 59.236.213, and 59.030.133, respectively. The pooled yearly report rate for KC in Italy was calculated as 2.97 cases per 100,000 person-years (95% CI 2.89 – 3.05). Median age at report was 28.06 years (first quartile 21.10, third quartile 40.03, missing data in 369 records). Due to differences in reporting among different centers, data on age at onset was only available for less than a half of records (2478); based on available data, median age at onset was calculated as 24.09 (first quartile 18.09, third quartile 33.08). Out of the number of complete reports, 33.2% of patients were female, 66.8% were male (432 missing data – Fig. 2). Women showed higher age at report than men (32 versus 26.5 years). Within Italy, we observed differences in report rates from different regions. The number of total records per region in the timeframe considered is reported in Supplementary Fig. A; the highest absolute number was recorded in Veneto and Apulia. Supplementary Tab. A. shows the figures divided per referral center; the center with the highest number of reports was AOU Cons. Policlinico Bari. Fig. 3 and Tab. 1 and 2 display average annual report rates normalized per 100,000 inhabitants per region of residence and region of birth of registered patients, respectively. This representation shows higher report rates in two super-regional clusters (one in the north and one in the south), and in regions Sardinia and Umbria. Lombardy and Latium, where the two biggest Italian metropolitan centers (Milan and Rome) are located, had a high total number of reports, but their resident and native populations had lower-than-average report rates. We observed that substantial migration occurred from specific regions. Fig. 4 shows active and passive mobility by Italian region per 100,000 inhabitants. The three regions with the highest passive mobility index were Friuli-Venezia Giulia, Basilicata, and Molise, whereas Veneto, Friuli-Venezia Giulia, and Molise showed the highest active mobility index. DISCUSSION The analysis of KC epidemiology from the Italian NRDR showed a national average annual report rate for KC—used as a surrogate for incidence, since registration is not compulsory—of 2.97 per 100,000 inhabitants. This figure aligns with the recently reported pooled incidence of 2.66 cases per 100,000 persons in Europe [2] and is lower than the global pooled incidence of 4 per 100,000 person-years [2].However, among published incidence studies [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24], many rely on small datasets, specific subgroups (e.g. younger patients), and estimated reference populations, limiting generalizability. In Italy, a prevalence study conducted in Rome found 2.1% among patients attending a first eye exam [25]. This study reported data from ophthalmology patients referred to a single center between 2021 and 2022. To date, however, no nationwide data exists on KC prevalence, incidence, or regional distribution. In line with several previous reports, we observed that KC appears to affect males more than females [2]. Women had a higher age at diagnosis (32 years) than men (26.5); globally, median age at diagnosis was approximately 28 years, consistent with international data [2]. Since KC development initiates during infancy or puberty, it can be inferred that there is some latency before patients reach a diagnosis or decide to register the disease, which induce health policy stakeholders to consider information campaigns to alert ophthalmologists and patients. Our study shows regional differences in KC reporting. Between 2019 and 2021, the highest numbers of new KC diagnoses were reported in Veneto, Puglia, and Lombardy, while the lowest came from Molise, Calabria, and Abruzzo. When incidence data was normalized by region of birth, a marked geographic variability emerged. Patients born in two areas—Apulia-Basilicata-Campania (southern Italy) and Veneto-Trentino-Alto Adige/Südtirol (Northern Italy)—showed higher than average report rates, as did Umbria and Sardinia. Such a clustering and lack of linear progression with latitude does not align with the hypothesis of sunlight exposure as a driver of KC onset and progression [26], possibly reinforcing the role of genetic predisposition [26, 27, 28]. On this note, it should be remembered that Italy presents a notable internal clustering of genetic signatures, with differences at times exceeding those expected among populations living in different European countries [29, 30].In particular, Sardinia-an island located in the middle of the Mediterranean Sea- is known to have a distinct genomic pool due to genetic isolation, including peculiar genetic variants in inflammatory biomarkers [31, 32]. The term “active mobility” refers to the attraction index of a region, meaning the volume of healthcare services provided to non-residents. In contrast, “passive mobility” represents the outflow index, i.e. the healthcare services that residents of a given region seek elsewhere when they migrate to another area for certification and care. Health migration, or health mobility, mainly concerned specific reference centers or neighboring regions. Residents of Friuli Venezia Giulia (the region with the highest passive mobility index) who move towards Veneto (the region with the highest active mobility index) most frequently refer to the Mestre and the Conegliano Hospitals. Residents of Basilicata mostly move towards Apulia to the AOU Cons. Policlinico Bari. In the case of Molise, residents mostly refer to the Abruzzo hospitals. Such trends for inter-regional healthcare migration may underscore patient-perceived gaps in regional ophthalmology services. We acknowledge that our study has certain limitations. Indeed, the most accurate way to assess KC distribution—including undiagnosed cases—would be population-based screenings using corneal topography/tomography, which is challenging in terms of resources [33]. For this reason, most of the published KC incidence studies rely on insurance databases, registries, monocentric data, which, however, may miss subclinical or undiagnosed cases, underestimate prevalence due to underreporting or assumptions about catchment populations. In addition to the case ascertainment method, there are multiple reasons which explain potential discrepancies among studies reported in the literature: different ethnicities included in the studies, age of the study population (KC incidence is higher in younger subjects), healthcare access and reporting incentives. Specifically, registries that tie registration to benefits (e.g., copay exemption)- as in our case- will have different completeness than systems without incentives. It should also be noted that NRDR data are limited to specific variables: unique identifier, basic demographics, vital status, diagnosis, referral center, dates of onset/diagnosis, and orphan drug use. Moreover, data flow depends on accredited centers and excludes private ophthalmology practices, where mild KC cases may be managed, leading to underrepresentation. Still, as mentioned, copay exemption provides a financial incentive for patients to register, mitigating underreporting. Regional inconsistencies in reporting (e.g., dates of diagnosis vs. certification) and incomplete variables (e.g., gender) remain. Report numbers for 2020 were lowest in the study period, which was probably a consequence of COVID-19 lockdowns. Therefore, it is possible that a higher reporting rate will emerge in the future. Rare disease registries present organizational challenges, because they require: accreditation of reporting centers, physician training on reporting procedures and robust IT infrastructure, together with a clear legal framework to manage privacy issue concerned with data collection and storage. Despite these challenges, however, registries provide essential insights: they support resource allocation at subnational levels, enable large-scale epidemiological studies and clinical trial design, eventually facilitating international collaborations to study genetic and geographic influences on disease onset. CONCLUSIONS This analysis is the largest-scale incidence study for KC in Europe, and it provides the first nationwide yearly report rates in Southern Europe. We found incidence rates comparable to previous estimates for northern European countries and a clear male predominance. The apparent emergence of specific subnational clusters of higher KC incidence should encourage the inclusion of information about local KC distribution in future large-scale epidemiological studies. National rare disease registries, while challenging to implement, are invaluable for public health planning, research, and clinical care. Expanding registry access and certification processes is essential to deliver the population with equitable healthcare services and to increase epidemiologic surveillance accuracy. Our findings will serve to inform health policies at a local and national level and may provide useful information for people of Italian descent, KC researchers and public healthcare policymakers worldwide. Further studies—possibly including early-stage cases and prevalence data— are needed to refine KC epidemiology in Italy and globally and may challenge the often-recurring classification of KC as a rare disease. Declarations ACKNOWLEDGEMENTS Thanks go to the contribution of the regional rare disease registries, which have been feeding the National Rare Disease Registry for years and providing valuable collaboration with the National Center for Rare Diseases. CONTRIBUTIONS GF was responsible for the study conception and design. MP was responsible for writing the manuscript and interpreting results. AR, GLF, and PT were responsible for data collection and interpretation of results. GS, FP, and GT were responsible for data analysis and manuscript revision. MDM and FB supervised study conception and design. All authors contributed to draft manuscript preparation, reviewed the results and approved the final version of the manuscript. References Alió JL. Keratoconus: Recent advances in diagnosis and treatment. Springer International Publishing; 2016. https://books.google.es/books?id=TWWtDAEACAAJ . Sriranganathan A, Chan CC, Dhillon J, Felfeli T. 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The prevalence of keratoconus in northern poland: A cross-sectional study of patients from a primary healthcare practice. Cont Lens Anterior Eye . 2023;46(4):101846. doi: 10.1016/j.clae.2023.101846 . Tables Table 1 Number of total reports and average yearly report rates per 100,000 inhabitants according to patient residence. Region of residence Total reports Average annual report rate per 100k inhabitants Puglia 756 6,40 Basilicata 98 5,98 Trentino-Alto Adige/Südtirol 184 5,70 Veneto 831 5,69 Umbria 135 5,20 Sardegna 202 4,22 Emilia-Romagna 491 3,68 Friuli-Venezia Giulia 130 3,61 Campania 582 3,43 Marche 106 2,36 Lazio 386 2,24 Molise 19 2,14 Lombardia 590 1,97 Abruzzo 73 1,90 Piemonte 242 1,88 Liguria 83 1,82 Calabria 74 1,32 Sicilia 176 1,21 Toscana 112 1,01 Valle d'Aosta 1 0,27 Abroad 3 - Incomplete/missing 6 - Table 2 Number of average yearly reports and average yearly report rates per 100,000 inhabitants according to patient birthplace. Region of birth Total reports Average yearly report rate per 100k inhabitants Puglia 778 6,59 Basilicata 96 5,86 Veneto 676 4,63 Umbria 107 4,12 Trentino-Alto Adige/Südtirol 133 4,12 Sardegna 197 4,11 Campania 627 3,70 Molise 23 2,59 Emilia-Romagna 337 2,53 Calabria 115 2,05 Friuli-Venezia Giulia 70 1,94 Piemonte 246 1,92 Marche 83 1,85 Liguria 71 1,56 Lombardia 466 1,56 Sicilia 221 1,52 Abruzzo 41 1,06 Toscana 83 0,75 Lazio 40 0,23 Valle d'Aosta 0 0,00 Abroad 396 - Incomplete/missing 474 - Table 3 – Incidence rates among the selected recent different epidemiologic studies. Methodology differed among studies. When possible, median rather than mean age was preferred. Authors Country Years of study Number of cases Incidence (per 100,000) % of male sex Age at diagnosis Reference population Kennedy et al. [ 8 ] U.S.A. 1935–1982 64 2 54.7% 25 Multicentric estimated catchment population Ihalainen [ 9 ] Finland 1964–1984 75 1.44 62.7% 26.5 (M) 30.6 (F) Monocentric catchment population (est. 260,000) Pearson et al. [ 10 ] United Kingdom 1989–1998 271 19.6 (asian) 4.5 (caucasian) 60% (asian) 65% (caucasian) 22.3 (asian) 26.5 (caucasian) 10 to 44-year-olds from single center estimated catchment population Georgiou et al. [ 11 ] United Kingdom 1994–2000 74 25 (asian) 3.33 (caucasian) 72% 21.5 (asian) 26.4 (caucasian) Single center estimated catchment population Cozma et al. [ 12 ] United Kingdom 1997–2001 197 32.3 (asian) 3.5 (caucasian) 53.07% (asian) 73.1% (caucasian) 23 (asian) 27.8 (caucasian) Single center estimated catchment population Assiri et al. [ 13 ] Saudi Arabia 2001–2002 125 20 40.8% 18.5 5 to 29-year-olds from multicentric catchment population Nielsen et al. [ 14 ] Denmark 1995–2005 - 1.3 - - All residents Ziaei et al. [ 15 ] Iran 2008–2009 (1 year) 221 22.3 52.7% 25.7 Multicentric regional reporting system (990,818) Moon et al. [ 16 ] South Korea 2004–2013 1552 3.84 45.7 (based on prevalence) - 1,025,340 subjects covered by National Health Insurance Service Hwang et al. [ 17 ] South Korea 2010–2014 17931 5.56 49.6% 29 National insurance database (all citizens) Godefrooij et al. [ 18 ] Netherlands 2014 218 13.3 60.6% 28.3 10 to 40-year-olds registered with largest health insurer (may include other corneal dystrophies) Lee et al. [ 19 ] South Korea 2002–2015 575 4.47 51.3% 31.1 1,025,340 subjects covered by National Health Insurance Service Bak-Nielsen et al. [ 20 ] Denmark 2003–2015 1008 (after 2011) 3.6 (after 2011) 2.89 (after 2011, considering only native population) - 25 All residents (5,707,251) Ng et al. [ 21 ] Taiwan 2000–2018 7075 1.56 59.5% - All residents (27,540,589) Kristianslund et al. [ 22 ] Norway 2010–2018 9832 19.76 73.4% (based on prevalence) 37.5 Residents < 40 years old Mejia-Salgado et al. [ 23 ] Colombia 2015–2019 18419 10.36 52.6% - Residents covered by National Healthcare System (97.78% of general population) 50,372,424 Alzahrani et al. [ 24 ] Saudi Arabia 2019–2020 - 28.47 67.9% (based on prevalence) 26.45 9- to 29-year-olds from estimated multicentric catchment population Present study Italy 2019–2021 5280 2.97 66.8% 28.1 (age at report) 24.1 (age at diagnosis) All residents (av. 59,302,611) Additional Declarations There is no conflict of interest Supplementary Files SupplementaryFigureA.tif Supplementary figure 1 - Total number of keratoconus reports according to region of reporting centers. SupplementaryTableA.docx Supplementary table 1 – Centers that reported at least one case in the 2019-2021 period. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 13 Feb, 2026 Review # 2 received at journal 09 Feb, 2026 Reviewer # 2 agreed at journal 28 Jan, 2026 Review # 1 received at journal 24 Nov, 2025 Reviewer # 1 agreed at journal 10 Nov, 2025 Reviewers invited by journal 06 Nov, 2025 Editor assigned by journal 17 Oct, 2025 Submission checks completed at journal 08 Oct, 2025 First submitted to journal 08 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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10:25:02","extension":"html","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109432,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/7c199113f0a32ce3aa801ac6.html"},{"id":96074843,"identity":"bb26e148-0313-43d5-9514-e61529977b68","added_by":"auto","created_at":"2025-11-17 10:25:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38156,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of total reports per year.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/c7b49a26f9ba07adff9a5e4a.png"},{"id":96074837,"identity":"fd578802-381f-4acf-a702-08301dad00ba","added_by":"auto","created_at":"2025-11-17 10:25:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78741,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of gender among patients diagnosed with keratoconus in the 2019–2021 period.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/6fe3c153866bf270cdc00be7.png"},{"id":96074839,"identity":"e03767dc-e179-4e4c-a482-74624c363a7e","added_by":"auto","created_at":"2025-11-17 10:25:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":149933,"visible":true,"origin":"","legend":"\u003cp\u003eAverage annual report rates per 100k inhabitants per region of residence (A) and region of birth (B)\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/616dbdc0027605362317bccf.png"},{"id":96246260,"identity":"3181dbe6-4efc-40aa-89dc-b96d4550a844","added_by":"auto","created_at":"2025-11-19 07:25:13","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":110935,"visible":true,"origin":"","legend":"\u003cp\u003eActive and passive mobility indexes for each region per 100.000 inhabitants. The autonomous provinces of Trento and Bolzano (Trentino-Alto Adige/Südtirol region) are represented separately.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/8cef1ef24d04644ca682dc85.png"},{"id":96256100,"identity":"d88d39f6-8991-42c5-a4d5-d8aacd057c6f","added_by":"auto","created_at":"2025-11-19 07:49:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1182109,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/8962527e-e040-47a1-a82f-d8487c798479.pdf"},{"id":96074853,"identity":"39c1a2a8-7e8d-4b6d-8734-45137c2f9de0","added_by":"auto","created_at":"2025-11-17 10:25:02","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":97970,"visible":true,"origin":"","legend":"Supplementary figure 1 - Total number of keratoconus reports according to region of reporting centers.","description":"","filename":"SupplementaryFigureA.tif","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/f923f74e4a9757db1ea6fa18.tif"},{"id":96247643,"identity":"faf86592-6e60-4d03-9abb-31e260f5cc63","added_by":"auto","created_at":"2025-11-19 07:27:39","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":24714,"visible":true,"origin":"","legend":"Supplementary table 1 \u0026#x2013; Centers that reported at least one case in the 2019-2021 period.","description":"","filename":"SupplementaryTableA.docx","url":"https://assets-eu.researchsquare.com/files/rs-7807408/v1/9c10fcc5f2c97fda7baf4b23.docx"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Mapping Keratoconus in Italy: Insights from 100 Centers reporting to the Italian National Rare Disease Registry","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eKeratoconus (KC) is a bilateral and progressive corneal condition, is defined by central or paracentral thinning of the stromal layer and corneal protrusion, and leads to the development of irregular astigmatism, corneal scarring, and varying degrees of vision impairment [1].\u003c/p\u003e\n\u003cp\u003eEpidemiology data from a recent metanalysis suggest that KC may affect up to 0.29% of the population worldwide, typically in the second decade, and more frequently males, with a global incidence of 4 cases per 100.000 persons [2]. Compared to Africa, Asia, and the USA, Keratoconus has lower prevalence in Europe (36.9/100.000) [2].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn Italy, KC is classified as a rare disease [3]. Rare diseases (RDs), as defined by the European Union (EU), affect fewer than 5 in 10,000 individuals [4]. It is estimated that 29 million people in the EU are affected by up to 8,000 different rare conditions [5]. Consequently, the EU has recommended the creation and use of registries and databases as essential tools to advance clinical research, improve patient care, and inform healthcare planning [5]. Italy has been the first country in Europe to establish a population-based public health registry dedicated to RDs [6]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study aims to present for the first time epidemiological data on KC from the Italian National Rare Disease Register (NRDR).\u003c/p\u003e"},{"header":"METHODS AND STATISTICAL ANALYSIS","content":"\u003cp\u003eThe NRDR is managed by the National Centre for Rare Diseases (Centro Nazionale Malattie Rare, CNMR) of the National Institute of Health (Istituto Superiore di Sanità, ISS), serving as both a scientific and institutional tool, supporting epidemiological surveillance and public healthcare governance [7].\u003c/p\u003e\n\u003cp\u003eThe NRDR registry is fed by the National Rare Disease Network, composed of referral centers (with accredited expertise in RDs prevention, diagnosis, and care) and regional registries. Data flows in three steps: (1) clinicians at referral centers diagnose and enter patient information; (2) regional databases collect these records; (3) aggregated data are transmitted annually to the NRDR. National coverage was progressively achieved, with full completeness reached in 2012.\u0026nbsp;Registered patients are exempt from National Healthcare System (Sistema Sanitario Nazionale, SSN) copays for disease-specific visits and procedures.\u003c/p\u003e\n\u003cp\u003eOur analysis of KC data from the Italian NRDR covers a 3-year period (2019 to 2021, latest available data) and concerns the distribution by gender, descriptive and dispersion indices related to age at diagnosis and age of onset, annual crude report rates, distribution by referral center, region of diagnosis/residence/ birth, and healthcare mobility data.\u003c/p\u003e\n\u003cp\u003eCategorical variables, such as gender, region of diagnosis/residence/birth, were expressed as absolute frequencies and percentages. Continuous variables, such as age, were reported as medians and interquartile ranges.\u003c/p\u003e\n\u003cp\u003eBecause not all patients with a KC diagnosis may\u0026nbsp;attend referral centers,\u0026nbsp;we used the term “average yearly report rate” rather than “incidence” to express the number of keratoconus diagnoses registered on average in a year based on the total number of reports collected during the three-year period. The average yearly report rate was estimated using a pooled person-years approach, considering annual case counts and population denominators across the three years, and it was expressed per 100,000 person-years.\u003c/p\u003e\n\u003cp\u003eActive mobility index was calculated as the number of patients certified in a region but residing in other regions, divided by the total certifications in the certification region. Passive mobility index was calculated as the number of residents who migrated to another region for certification, divided by the total certifications for their region of residence. Finally, both indices were standardized against the resident population for a given period.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe National Rare Diseases Registry collected 5,280 new reports from 100 centers from 20 regions during the 2019–2021 period. There was a moderate decrease in reports from 2019 to 2020, probably due to the Covid-19 pandemic (Fig. 1).\u003c/p\u003e\n\u003cp\u003eThe population of reference was represented by all Italian residents with a valid registration with the SSN. The number of Italian residents in 2019, 2020 and 2021 was 59.641.488; 59.236.213, and 59.030.133, respectively.\u003c/p\u003e\n\u003cp\u003eThe pooled yearly report rate for KC in Italy was calculated as 2.97 cases per 100,000 person-years (95% CI 2.89 – 3.05).\u003c/p\u003e\n\u003cp\u003eMedian age at report was 28.06 years (first quartile 21.10, third quartile 40.03, missing data in 369 records). Due to differences in reporting among different centers, data on age at onset was only available for less than a half of records (2478); based on available data, median age at onset was calculated as 24.09 (first quartile 18.09, third quartile 33.08).\u003c/p\u003e\n\u003cp\u003eOut of the number of complete reports, 33.2% of patients were female, 66.8% were male (432 missing data – Fig. 2). \u0026nbsp; Women showed higher age at report than men (32 versus 26.5 years). \u0026nbsp; Within Italy, we observed differences in report rates from different regions. The number of\u0026nbsp;total records per region in the timeframe considered is reported in Supplementary Fig. A; the highest absolute number was recorded in Veneto and Apulia. Supplementary Tab. A. shows the figures divided per referral center; the center with the highest number of reports was AOU Cons. Policlinico Bari.\u0026nbsp;Fig. 3 and Tab. 1 and 2 display average annual report rates normalized per 100,000 inhabitants per region of residence and region of birth of registered patients, respectively. This representation shows higher report rates in two super-regional clusters (one in the north and one in the south), and in regions Sardinia and Umbria. Lombardy and Latium, where the two biggest Italian metropolitan centers (Milan and Rome) are located, had a high total number of reports, but their resident and native populations had lower-than-average report rates.\u003c/p\u003e\n\u003cp\u003eWe observed that substantial migration occurred from specific regions. Fig. 4 shows active and passive mobility by Italian region per 100,000 inhabitants. The three regions with the highest passive mobility index were Friuli-Venezia Giulia, Basilicata, and Molise, whereas Veneto, Friuli-Venezia Giulia, and Molise showed the highest active mobility index.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe analysis of KC epidemiology from the Italian NRDR showed a national average annual report rate for KC—used as a surrogate for incidence, since registration is not compulsory—of 2.97 per 100,000 inhabitants. This figure aligns with the recently reported pooled incidence of 2.66 cases per 100,000 persons in Europe [2] and is lower than the global pooled incidence of 4 per 100,000 person-years [2].However, among published incidence studies [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24], many rely on small datasets, specific subgroups (e.g. younger patients), and estimated reference populations, limiting generalizability.\u003c/p\u003e\n\u003cp\u003eIn Italy, a prevalence study conducted in Rome found 2.1% among patients attending a first eye exam [25]. This study reported data from ophthalmology patients referred to a single center between 2021 and 2022. To date, however, no nationwide data exists on KC prevalence, incidence, or regional distribution.\u003c/p\u003e\n\u003cp\u003eIn line with several previous reports, we observed that KC appears to affect males more than females [2]. Women had a higher age at diagnosis (32 years) than men (26.5); globally, median age at diagnosis was approximately 28 years, consistent with international data [2]. Since KC development initiates during infancy or puberty, it can be inferred that there is some latency before patients reach a diagnosis or decide to register the disease, which induce health policy stakeholders to consider information campaigns to alert ophthalmologists and patients.\u003c/p\u003e\n\u003cp\u003eOur study shows regional differences in KC reporting. Between 2019 and 2021, the highest numbers of new KC diagnoses were reported in Veneto, Puglia, and Lombardy, while the lowest came from Molise, Calabria, and Abruzzo. When incidence data was normalized by region of birth, a marked geographic variability emerged. Patients born in two areas—Apulia-Basilicata-Campania (southern Italy) and Veneto-Trentino-Alto Adige/Südtirol (Northern Italy)—showed higher than average report rates, as did Umbria and Sardinia. Such a clustering and lack of linear progression with latitude does not align with the hypothesis of sunlight exposure as a driver of KC onset and progression [26], possibly reinforcing the role of genetic predisposition [26, 27, 28]. On this note, it should be remembered that Italy presents a notable internal clustering of genetic signatures, with differences at times exceeding those expected among populations living in different European countries [29, 30].In particular, Sardinia-an island located in the middle of the Mediterranean Sea- is known to have a distinct genomic pool due to genetic isolation, including peculiar genetic variants in inflammatory biomarkers [31, 32].\u003c/p\u003e\n\u003cp\u003eThe term “active mobility” refers to the attraction index of a region, meaning the volume of healthcare services provided to non-residents. In contrast, “passive mobility” represents the outflow index, i.e. the healthcare services that residents of a given region seek elsewhere when they migrate to another area for certification and care. Health migration, or health mobility, mainly concerned specific reference centers or neighboring regions. Residents of Friuli Venezia Giulia (the region with the highest passive mobility index) who move towards Veneto (the region with the highest active mobility index) most frequently refer to the Mestre and the Conegliano Hospitals. Residents of Basilicata mostly move towards Apulia to the AOU Cons. Policlinico Bari. In the case of Molise, residents mostly refer to the Abruzzo hospitals. Such trends for inter-regional healthcare migration may underscore patient-perceived gaps in regional ophthalmology services.\u003c/p\u003e\n\u003cp\u003eWe acknowledge that our study has certain limitations. Indeed, the most accurate way to assess KC distribution—including undiagnosed cases—would be population-based screenings using corneal topography/tomography, which is challenging in terms of resources [33]. For this reason, most of the published KC incidence studies rely on insurance databases, registries, monocentric data, which, however, may miss subclinical or undiagnosed cases, underestimate prevalence due to underreporting or assumptions about catchment populations. In addition to the case ascertainment method, there are multiple reasons which explain potential discrepancies among studies reported in the literature: different ethnicities included in the studies, age of the study population (KC incidence is higher in younger subjects), healthcare access and reporting incentives. Specifically, registries that tie registration to benefits (e.g., copay exemption)- as in our case- will have different completeness than systems without incentives.\u003c/p\u003e\n\u003cp\u003eIt should also be noted that NRDR data are limited to specific variables: unique identifier, basic demographics, vital status, diagnosis, referral center, dates of onset/diagnosis, and orphan drug use. Moreover, data flow depends on accredited centers and excludes private ophthalmology practices, where mild KC cases may be managed, leading to underrepresentation. Still, as mentioned, copay exemption provides a financial incentive for patients to register, mitigating underreporting. Regional inconsistencies in reporting (e.g., dates of diagnosis vs. certification) and incomplete variables (e.g., gender) remain. Report numbers for 2020 were lowest in the study period, which was probably a consequence of COVID-19 lockdowns. Therefore, it is possible that a higher reporting rate will emerge in the future.\u003c/p\u003e\n\u003cp\u003eRare disease registries present organizational challenges, because they require: accreditation of reporting centers, physician training on reporting procedures and robust IT infrastructure, together with a clear legal framework to manage privacy issue concerned with data collection and storage. Despite these challenges, however, registries provide essential insights: they support resource allocation at subnational levels, enable large-scale epidemiological studies and clinical trial design, eventually facilitating international collaborations to study genetic and geographic influences on disease onset.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis analysis is the largest-scale incidence study for KC in Europe, and it provides the first nationwide yearly report rates in Southern Europe. We found incidence rates comparable to previous estimates for northern European countries and a clear male predominance. The apparent emergence of specific subnational clusters of higher KC incidence should encourage the inclusion of information about local KC distribution in future large-scale epidemiological studies.\u003c/p\u003e\n\u003cp\u003eNational rare disease registries, while challenging to implement, are invaluable for public health planning, research, and clinical care. Expanding registry access and certification processes is essential to deliver the population with equitable healthcare services and to increase epidemiologic surveillance accuracy.\u003c/p\u003e\n\u003cp\u003eOur findings will serve to inform health policies at a local and national level and may provide useful information for people of Italian descent, KC researchers and public healthcare policymakers worldwide.\u003c/p\u003e\n\u003cp\u003eFurther studies—possibly including early-stage cases and prevalence data— are needed to refine KC epidemiology in Italy and globally and may challenge the often-recurring classification of KC as a rare disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThanks go to the contribution of the regional rare disease registries, which have been feeding the National Rare Disease Registry for years and providing valuable collaboration with the National Center for Rare Diseases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGF was responsible for the study conception and design. MP was responsible for writing the manuscript and interpreting results. AR, GLF, and PT were responsible for data collection and interpretation of results. GS, FP, and GT were responsible for data analysis and manuscript revision. MDM and FB supervised study conception and design. All authors contributed to draft manuscript preparation, reviewed the results and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAli\u0026oacute; JL. \u003cem\u003eKeratoconus: Recent advances in diagnosis and treatment.\u003c/em\u003e Springer International Publishing; 2016. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://books.google.es/books?id=TWWtDAEACAAJ\u003c/span\u003e\u003cspan address=\"https://books.google.es/books?id=TWWtDAEACAAJ\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSriranganathan A, Chan CC, Dhillon J, Felfeli T. 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Keratoconus: The local manifestation of a systemic disease? \u003cem\u003eJ Clin Med\u003c/em\u003e. 2025;14(13):4587. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm14134587\u003c/span\u003e\u003cspan address=\"10.3390/jcm14134587\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. doi: 10.3390/jcm14134587.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBartolomeo N, Pederzolli M, Palombella S, et al. The effects of vitamin D on keratoconus progression. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. 2025;276:235\u0026ndash;251. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajo.2025.04.009\u003c/span\u003e\u003cspan address=\"10.1016/j.ajo.2025.04.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFiorito G, Di Gaetano C, Guarrera S, et al. The italian genome reflects the history of europe and the mediterranean basin. \u003cem\u003eEur J Hum Genet\u003c/em\u003e. 2016;24(7):1056\u0026ndash;1062. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/ejhg.2015.233\u003c/span\u003e\u003cspan address=\"10.1038/ejhg.2015.233\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaveane R, Aneli A, Montinaro M, et al. Population structure of modern-day italians reveals patterns of ancient and archaic ancestries in southern europe. \u003cem\u003eSci Adv\u003c/em\u003e. 2019;5(9):eaaw3492. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1126/sciadv.aaw3492\u003c/span\u003e\u003cspan address=\"10.1126/sciadv.aaw3492\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. doi: 10.1126/sciadv.aaw3492.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChiang CWK, Marcus JH, Sidore C, et al. Genomic history of the sardinian population. \u003cem\u003eNat Genet\u003c/em\u003e. 2018;50(10):1426\u0026ndash;1434. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41588-018-0215-8\u003c/span\u003e\u003cspan address=\"10.1038/s41588-018-0215-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSidore C, Busonero F, Maschio A, et al. Genome sequencing elucidates sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. \u003cem\u003eNat Genet\u003c/em\u003e. 2015;47(11):1272\u0026ndash;1281. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/ng.3368\u003c/span\u003e\u003cspan address=\"10.1038/ng.3368\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKanclerz P, Przewł\u0026oacute;cka K, Toprak I, Alio J. The prevalence of keratoconus in northern poland: A cross-sectional study of patients from a primary healthcare practice. \u003cem\u003eCont Lens Anterior Eye\u003c/em\u003e. 2023;46(4):101846. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.clae.2023.101846\u003c/span\u003e\u003cspan address=\"10.1016/j.clae.2023.101846\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNumber of total reports and average yearly report rates per 100,000 inhabitants according to patient residence.\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eRegion of residence\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTotal reports\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAverage annual report rate per 100k inhabitants\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePuglia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e756\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e6,40\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eBasilicata\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e98\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5,98\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTrentino-Alto Adige/S\u0026uuml;dtirol\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e184\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5,70\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eVeneto\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e831\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5,69\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUmbria\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e135\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5,20\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSardegna\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e202\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4,22\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eEmilia-Romagna\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e491\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3,68\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFriuli-Venezia Giulia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e130\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3,61\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCampania\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e582\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3,43\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMarche\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e106\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2,36\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLazio\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e386\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2,24\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMolise\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e19\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2,14\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLombardia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e590\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,97\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAbruzzo\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e73\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,90\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePiemonte\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e242\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,88\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLiguria\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e83\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,82\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCalabria\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e74\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,32\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSicilia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e176\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,21\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eToscana\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e112\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,01\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eValle d\u0026apos;Aosta\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0,27\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAbroad\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIncomplete/missing\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e6\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNumber of average yearly reports and average yearly report rates per 100,000 inhabitants according to patient birthplace.\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eRegion of birth\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTotal reports\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAverage yearly report rate per 100k inhabitants\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePuglia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e778\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e6,59\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eBasilicata\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e96\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5,86\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eVeneto\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e676\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4,63\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUmbria\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e107\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4,12\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTrentino-Alto Adige/S\u0026uuml;dtirol\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e133\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4,12\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSardegna\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e197\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4,11\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCampania\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e627\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3,70\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMolise\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e23\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2,59\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eEmilia-Romagna\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e337\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2,53\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCalabria\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e115\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2,05\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFriuli-Venezia Giulia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e70\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,94\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePiemonte\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e246\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,92\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMarche\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e83\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,85\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLiguria\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e71\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,56\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLombardia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e466\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,56\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSicilia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e221\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,52\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAbruzzo\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e41\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,06\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eToscana\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e83\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0,75\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLazio\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e40\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0,23\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eValle d\u0026apos;Aosta\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0,00\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAbroad\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e396\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIncomplete/missing\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e474\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e\u0026ndash;\u003c/span\u003e Incidence rates among the selected recent different epidemiologic studies. Methodology differed among studies. When possible, median rather than mean age was preferred.\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAuthors\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCountry\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eYears of study\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNumber of cases\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIncidence (per 100,000)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e% of male sex\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAge at diagnosis\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eReference population\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eKennedy et al. [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eU.S.A.\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1935\u0026ndash;1982\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e64\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e2\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e54.7%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e25\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMulticentric estimated catchment population\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIhalainen [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFinland\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1964\u0026ndash;1984\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e75\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e1.44\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e62.7%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e26.5 (M)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e30.6 (F)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMonocentric catchment population (est. 260,000)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePearson et al. [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnited Kingdom\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1989\u0026ndash;1998\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e271\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e19.6 (asian)\u003c/span\u003e\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e4.5 (caucasian)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e60% (asian)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e65% (caucasian)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e22.3 (asian)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e26.5 (caucasian)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e10 to 44-year-olds from single center estimated catchment population\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGeorgiou et al. [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnited Kingdom\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1994\u0026ndash;2000\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e74\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e25 (asian)\u003c/span\u003e\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e3.33 (caucasian)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e72%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e21.5 (asian)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e26.4 (caucasian)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSingle center estimated catchment population\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCozma et al. [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnited Kingdom\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1997\u0026ndash;2001\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e197\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e32.3 (asian)\u003c/span\u003e\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e3.5 (caucasian)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e53.07% (asian)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e73.1% (caucasian)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e23 (asian)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e27.8 (caucasian)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSingle center estimated catchment population\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAssiri et al. [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSaudi Arabia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2001\u0026ndash;2002\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e125\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e20\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e40.8%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e18.5\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5 to 29-year-olds from multicentric catchment population\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNielsen et al. [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eDenmark\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1995\u0026ndash;2005\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e1.3\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAll residents\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eZiaei et al. [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eIran\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2008\u0026ndash;2009 (1 year)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e221\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e22.3\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e52.7%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e25.7\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMulticentric regional reporting system (990,818)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMoon et al. [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSouth Korea\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2004\u0026ndash;2013\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1552\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e3.84\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e45.7 (based on prevalence)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,025,340 subjects covered by National Health Insurance Service\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eHwang et al. [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSouth Korea\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2010\u0026ndash;2014\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e17931\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e5.56\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e49.6%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e29\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNational insurance database (all citizens)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGodefrooij et al. [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNetherlands\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2014\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e218\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e13.3\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e60.6%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e28.3\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e10 to 40-year-olds registered with largest health insurer (may include other corneal dystrophies)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLee et al. [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSouth Korea\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2002\u0026ndash;2015\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e575\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e4.47\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e51.3%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e31.1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1,025,340 subjects covered by National Health Insurance Service\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eBak-Nielsen et al. [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eDenmark\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2003\u0026ndash;2015\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1008 (after 2011)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e3.6 (after 2011)\u003c/span\u003e\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e2.89 (after 2011, considering only native population)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e25\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAll residents (5,707,251)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNg et al. [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTaiwan\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2000\u0026ndash;2018\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e7075\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e1.56\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e59.5%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAll residents (27,540,589)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eKristianslund et al. [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNorway\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2010\u0026ndash;2018\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e9832\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e19.76\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e73.4% (based on prevalence)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e37.5\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eResidents\u0026thinsp;\u0026lt;\u0026thinsp;40 years old\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMejia-Salgado et al. [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eColombia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2015\u0026ndash;2019\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e18419\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e10.36\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e52.6%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eResidents covered by National Healthcare System (97.78% of general population)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e50,372,424\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAlzahrani et al. [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSaudi Arabia\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2019\u0026ndash;2020\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e28.47\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e67.9% (based on prevalence)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e26.45\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e9- to 29-year-olds from estimated multicentric catchment population\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003ePresent study\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eItaly\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e2019\u0026ndash;2021\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e5280\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e2.97\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e66.8%\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e28.1 (age at report)\u003c/span\u003e\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e24.1 (age at diagnosis)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eAll residents (av. 59,302,611)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7807408/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7807408/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eKeratoconus (KC) is a progressive ectatic corneal disease classified as rare in Italy. To date, no nationwide incidence data from Italy or southern Europe has been published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eThis study analyzes on new reports of KC collected from 2019 to 2021 by the Italian National Rare Disease Registry (NRDR), the first national rare disease registry in Europe. Analyzed data include national and regional report rates, demographic characteristics, geographic distribution, and inter-regional healthcare mobility indexes. Data was expressed using descriptive statistics and standardized rates per 100,000 person-years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 5,280 new KC reports from 100 centers were recorded. The average annual report rate was 2.97 per 100,000 person-years, with male predominance (66.8%); average age at report was 28.06 years. Regional disparities in report rates emerged; two super-regional clusters (in northern and southern Italy) and regions Sardinia and Umbria had higher incidence in the NRDR. Inter-regional healthcare mobility was higher for specific regions and centers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003eThis study is the largest-scale KC incidence analysis in Europe and the first nationwide incidence study in Southern Europe. Findings show a relatively comparable incidence to northern European countries, marked geographic clustering, and highlight healthcare access disparities. Such data may be useful on a local and national level and provide useful information for researchers, public health decision makers and people of Italian descent worldwide. Efforts should be made to expand the use of national rare disease registries and to include subclinical KC cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: \u003c/strong\u003eOpen access funding provided by GF\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","manuscriptTitle":"Mapping Keratoconus in Italy: Insights from 100 Centers reporting to the Italian National Rare Disease Registry","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 10:24:56","doi":"10.21203/rs.3.rs-7807408/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-02-13T10:52:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-09T19:25:58+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-01-28T16:40:22+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-11-24T16:10:23+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-11-10T08:11:33+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-11-06T07:52:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-17T15:41:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-08T14:33:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Eye","date":"2025-10-08T11:20:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e3c05098-2e9e-4dd6-a611-7d5b2456345b","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":57531162,"name":"Health sciences/Health care/Public health/Epidemiology"},{"id":57531163,"name":"Health sciences/Diseases/Eye diseases/Corneal diseases"}],"tags":[],"updatedAt":"2026-03-02T08:45:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 10:24:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7807408","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7807408","identity":"rs-7807408","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}