1. Introduction {#sec1-ijerph-15-01470}
===============

Rare diseases (RD) are complex diseases with a very low prevalence (in the EU, a prevalence of less than 5/10,000 in the general population is considered). These conditions are currently estimated to be as many as 6000--8000 and the International Classification of Diseases codes a very limited number of them. Consequently, hospital health records are often not the appropriate sources to get information on RD. Therefore, knowledge on RD is often based on data collections and registries resulting from academic and commercial interests. ORPHANET censused a total of more than 700 registries and databases on RD \[[@B1-ijerph-15-01470]\] involving European scientists. They address a variety of aims and differ in their organization, quality and database structure, usually monitoring one disease or a group of related diseases \[[@B2-ijerph-15-01470]\]. Moreover, many studies are based on hospital data in regions with a higher prevalence \[[@B3-ijerph-15-01470]\]. This situation results in the difficulty of assessing the burden of RD in the general population and developing appropriate priority policies for the care of RD patients and the planning of health and social care services. To overcome these difficulties and support the development of knowledge on RD, the USA NIH-NCATS launched the Global RD Patient Registry and Data Repository---GRDR \[[@B4-ijerph-15-01470]\], and the EU Council issued a Recommendation urging Member States to support specific disease information networks, registries, and databases \[[@B5-ijerph-15-01470]\]. The EU also supported several initiatives addressing the better exploitation of RD patient data \[[@B6-ijerph-15-01470],[@B7-ijerph-15-01470],[@B8-ijerph-15-01470],[@B9-ijerph-15-01470],[@B10-ijerph-15-01470],[@B11-ijerph-15-01470]\]. All these efforts envisage a system addressed to the registration of many, not to say all, RD and to the improvement of data interoperability. The need for efficient and extensive registries for RDs is also made urgent by international cooperations, such as IRDiRC \[[@B12-ijerph-15-01470]\] and the European Reference Networks \[[@B13-ijerph-15-01470]\], as well as by the establishment of National Registries \[[@B14-ijerph-15-01470]\].

The specificities of RD and the special needs of RD patients were recognized in Italy in 2001 when the National Network of Accredited Centres for the assistance and care of RD patients was established by the Ministerial Decree (MD) 279/2001 \[[@B15-ijerph-15-01470]\]. This Decree mandated the notification of new cases to the National Registry of Rare Diseases (RNMR), through Regional Registries (RR). The RNMR central database was placed in the National Institute of Health and has been managed by the National Centre for Rare Diseases since its establishment. This registry can be of interest to the current efforts of promoting data comparability and data retrieval across registries for many reasons. RNMR is organized as a devolved system of 17 regional registries, two registries of Autonomous Provinces, and one interregional registry (Piemonte and Valle d'Aosta), which cover populations spanning from about 10.0 to 0.3 million residents. They are controlled by regional or provincial authorities, which make independent decisions and have their own peculiar needs and resources regarding the delivery of care. Therefore, RNMR may represent a pilot on the feasibility and use of the cooperation among national registries, which will seemingly be developed by mainly following the needs of different countries. Moreover, the set of data collected in the central repository very closely resembles the mandatory Common Data Set proposed by EPIRARE \[[@B16-ijerph-15-01470]\], which aimed at building synergies among public health authorities, researchers, patients, and the industry for fulfilling their information needs. To this aim, the EPIRARE Common Data Set was devised to support the production of indicators useful for decision-making in public health and research on RD \[[@B6-ijerph-15-01470],[@B16-ijerph-15-01470],[@B17-ijerph-15-01470]\], as well as to fulfill some patients' information needs. A recent publication by a regional registry which contributes to RNMR, provided some indicator data relevant to RD and their care \[[@B18-ijerph-15-01470]\].

After achieving the full coverage of the national territory in 2011 monitoring, individually, 284 RD and, collectively, many more RD distinguished in 47 groups, it is now possible to use the data contained in RNMR. In this paper, we aim to provide a detailed and systematic picture of the epidemiology of RD in Italy, with particular reference to patients requiring RD dedicated assistance and care. The results have been obtained from 247 accredited hospitals, which cover the whole national territory and serve a population of 60.4 million residents. This population is characterized by a sex ratio of 0.94 (males:females), while the youth (0--14 year) and 65+ people make up 13.9% and 21.4%, respectively. In 2017, non-European foreigners were mostly from Western and Northern Africa (1.70% residents), Eastern and Central-Southern Asia (1.66%), and Latin America (0.58), with all other origins accounting for 0.22%. Since this is the first time that an analysis of RNMR data has been published, special attention has been devoted to assessing and describing the validity of the data collected.

2. Materials and Methods {#sec2-ijerph-15-01470}
========================

2.1. Set of Data Communicated to RNMR and Collection Procedures {#sec2dot1-ijerph-15-01470}
---------------------------------------------------------------

The data communicated to RNMR by the RR and used for further elaborations were:Personal identifiers of the patient: name, surname, place and date of birth, sex, and national ID code (represented by the Fiscal Code and by an Encrypted Univocal Patient Code derived from it)Patient place of residenceDisease diagnosed (defined according to the exemption codes listed in MD 279/2001 \[[@B15-ijerph-15-01470]\])Center making the diagnosis, with geographical location (coded according to the National Health Service Information System \[[@B19-ijerph-15-01470]\])Date of disease onsetDate of diagnosis

Data, which referred to the time point when the RD diagnosis is certified by an Accredited Centre, was communicated immediately to its RR by the Accredited Centre itself. This procedure was formally agreed with the regional authorities in 2007 \[[@B20-ijerph-15-01470]\] and ensures that diagnoses are notified based on the most reliable diagnostic protocols and best expert advice. Following this agreement, two slightly different record structures were developed by the centers to better serve their regional health service organization. In some regions, the record reported the centre which ascertained the RD diagnosis for the first time and the Accredited Centre notifying the case, while, in other regions, the record indicated the Accredited Centre entitled to formally certify the diagnosis and notify the case. Correspondingly, the date of diagnosis was reported as the date of the first ascertainment of the diagnosis or as the date on which the diagnosis was formally certified and notified. Piemonte, Valle d'Aosta, and Lombardia communicated both the dates of diagnosis ascertainment and certification, while Sardinia switched from the former to the latter record structure in 2012--2013. The date of diagnosis is a main reference for data selection and elaboration. Therefore, data were kept distinct: records characterized by the diagnosis ascertainment date are indicated as "AD notifications" and the regions using this record structure are referred to as "AD regions". The records characterized by the diagnosis certification date are indicated as "CD notifications" and the related regions as "CD regions". The coexistence of two notification practices had an important bearing on the epidemiological data. Indeed, as it will be shown in more detail in the results section, frequency data of a disease in a regional population were usually a mix of data notified by AD and CD regions, due to the migration of patients from the residence region to another region, which could confirm the RD diagnosis and notified the case. Finally, Friuli-Venezia Giulia (FVG) communicated no personal identifiers in compliance with local personal data protection regulations. Procedures of data collection and communication have been described elsewhere \[[@B21-ijerph-15-01470]\].

The collected data set and the data flow were established and made mandatory by the supporting MD 279/2001 \[[@B15-ijerph-15-01470]\]. Therefore, no patient consent nor ethical approval was required. Data were processed according to the EU and Italian data protection regulations in all participating structures. Data processing procedures were communicated to the National Authority for Personal Data Protection and their approval was obtained.

2.2. Aims, Procedures and Limitations of Data Curation {#sec2dot2-ijerph-15-01470}
------------------------------------------------------

Data curation aimed at spotting erratic or inconsistent data, at discarding records that referred to cases diagnosed after the end of the reference period (31 December 2014) and at detecting and managing duplicate records. Data communicated by RR were checked upon their reception by the National Centre of Rare Diseases. Regional duplicates (i.e., records sent by the same region, referred to the same national ID code) and records showing data not passing the validation criteria (detailed in [Supplementary File 1](#app1-ijerph-15-01470){ref-type="app"}), were fed back to the experts responsible for pertaining the RR, for them to perform the necessary checks, even with the primary data sources, and to confirm or correct the data. After receiving the data sets resulting from these controls, the residual mistakes and discrepancies were recorded; then, the name, surname, place of birth, and Fiscal Code of the patient were removed by all records and the place of residence of the patient was substituted by her/his region of residence; finally, the regional data sets were merged into a single file. In this file, national duplicates (i.e., records with the same Encrypted Univocal Patient Code) were detected, classified, and managed to obtain the subsets to be used according to the scope of the analyses, as reported in [Supplementary File 1](#app1-ijerph-15-01470){ref-type="app"} ([Table S1](#app1-ijerph-15-01470){ref-type="app"}. Control of duplicate records and curation of demographic data from Friuli-Venezia Giulia (FVG) could not be carried out. Data curation was accomplished by means of an Excel model.

2.3. Symptoms Onset Age and Distribution between Sexes {#sec2dot3-ijerph-15-01470}
------------------------------------------------------

These features have been calculated from the data of Subset 1 for diseases with at least four records with valid data. For these analyses, data of individual diseases identified with their specific denomination were used, including those coded with group codes.

2.4. Birth Prevalence and Incidence of Rare Diseases {#sec2dot4-ijerph-15-01470}
----------------------------------------------------

The data used for the calculation of the incidence rates refer to cases with date of diagnosis ascertainment or certification included in the period from 1 January 2012 to 31 December 2014. The data selected for the assessment of birth prevalence (BP) were limited to cases born between 1 January 2012 and 31 December 2013 and with diagnoses ascertained or certified during the first year of life of the case. In these calculations, the dates of diagnosis ascertainment were only considered in the records from Piemonte, Val d'Aosta, and Lombardia. Records were analysed by codes, so that diseases coded with group codes were not analysed individually.

The calculations of regional incidence and BP rates were carried out as follows. It was assumed that differences in the frequency of each pathology, as resulting from either AD or CD notifications, were mainly due to the different local sensitivities of two notification practices rather than to changes of RD frequencies over time. Therefore, for each pathology and each region, the fraction of AD or CD notifications in their respective reference periods were expressed in percent with respect to the total AD plus CD notifications. The notification practice, which represented at least 90% of total notifications of a region over its reference period, was used to calculate the disease incidence and BP in that region. For those diseases and regions where neither notification system reached 90% total regional notifications, the calculation was not carried out. The assumption was applied considering that the datasets from Piemonte, Valle d'Aosta, and Lombardia, which recorded both dates, showed differences between dates of ascertainment and dates of certification of 4.9 years (95% Confidence Interval: 4.4--5.4 years), 8.5 years (95% CI: 6.1--10.9), and 5.3 years (95% CI: 4.9--5.7), respectively (data not shown).

Mean national incidence and BP rates for the three-year period of 2012--2014 were estimated with the same assumption as above, that the frequency of new cases in the period defined by the diagnosis certification date did not differ significantly from the frequency of new cases in the period defined by the diagnosis ascertainment date. Therefore, AD and CD notifications were merged and their sum was used for national frequency estimates. Regional populations on 31 December 2012, 2013, and 2014 \[[@B22-ijerph-15-01470]\] and regional live births in the two-year period of 2012--2013 \[[@B23-ijerph-15-01470]\] were used to calculate the denominators for regional and national data.

2.5. Internal Consistency of the Incidence and Birth Prevalence Data and Comparison with Literature Data {#sec2dot5-ijerph-15-01470}
--------------------------------------------------------------------------------------------------------

The internal consistency of the RNMR database has been checked by comparing the medians of the regional incidence and BP rates obtained from AD and CD notifications. The comparison with literature data was limited to the diseases which were monitored by RNMR and could be traced with certainty to an ORPHA code. In addition, comparisons of BP data were limited to diseases which showed a median onset age lower than six months. Results from the RNMR database were firstly compared with literature data reported by ORPHANET \[[@B3-ijerph-15-01470],[@B24-ijerph-15-01470]\]. In cases where differences of more than one order of magnitude were observed, a further, dedicated, literature search of incidence and BP estimates in the general population was carried out.

2.6. Statistical Methods {#sec2dot6-ijerph-15-01470}
------------------------

Data were reduced by means of contingency tables using RNMR individual disease and disease group codes for frequency calculations. Specific disease names were used to determine the sex ratio and the age at disease onset. Therefore, these features were determined separately for diseases coded with the same group code. The dispersion of regional notifications was described by means of medians and quartiles to minimize the effects of specific situations of selected regions, such as: unusual low sensitivity or unusually high frequencies due to the notification of cases diagnosed in previous years, which were especially likely in regions which activated a registry or adopted a CD record structure shortly before the observation period. The dispersion of the age at symptoms onset was described by means of median and extreme values due to the skewness of the dispersion of the values. Data of frequency for each disease were reported as the yearly average calculated from the total notifications in the three-year observation period. The use of yearly notifications was not considered due to the enhancement of stochastic effects for most diseases.

3. Results and Discussion {#sec3-ijerph-15-01470}
=========================

3.1. General Description of the National Database {#sec3dot1-ijerph-15-01470}
-------------------------------------------------

The National Database was made up of records associated with 195,492 notifications. Its Subset 1, which refers to disease occurrences, was made up of 190,622 records, after excluding 4870 Type 2 duplicate records from the National Database. Subset 1 records regarded 275 individually-coded diseases and 47 disease groups. Records with dates of diagnosis ascertainment and certification in the period 2012--2014 were 26,870 and 36,292, respectively. Both the National Database and its Subset 1 contain 6607 Type 3 duplicate records related to cases with multiple diagnoses (3.5% total records of Subset 1). These duplicates may represent cases with multiple diseases, second opinions, and revised or refined diagnoses. Since it was not possible to distinguish among these different possibilities, no selection was applied at this time. Most of these records referred to group-coded pathologies and the differing diagnoses pertained to the same code. In 1855 records, referring to 925 cases, the diagnoses pointed at diseases belonging to different chapters of the ICD9-CM.

3.2. Data Quality: Missing, Inaccurate or Inconsistent Values {#sec3dot2-ijerph-15-01470}
-------------------------------------------------------------

The disease onset date was missing or inaccurate in 26% of records of the National Database. The limited completeness of the onset date prevented the use of this variable to study the incidence of the monitored RD in the whole database, regardless of the notification practice. Due to the importance of this variable, a dedicated analysis was carried out to characterize the incomplete records. The study considered both the notifying region and the disease. [Figure S1](#app1-ijerph-15-01470){ref-type="app"} shows the distribution of the notified diseases in completeness classes of the onset date per notifying region. Data presented also includes the conventional dates for unknown dates and asymptomatic cases. It can be observed that the completeness of this date can be very different, even in regions notifying comparable and large fractions of the monitored diseases. Completeness (including conventional values) for each disease or disease group code was, on average, 81.9% (SD: 17.5%; *n* = 317 codes) for AD regions, while it was 54.2 (SD: 23.6; *n* = 303 codes) for CD regions, with a statistically significant difference among the two groups (*p* \< 0.001). Therefore, it appears that the completeness of this variable depends, to a considerable extent, on the rules for data access and communication associated with CD or AD notification practices. Since it is not expected that these rules introduce a biased selection of the data for a disease, available data were used for the determination of the disease onset age.

The completeness of the variable indicating the centre making the first ascertainment of the diagnosis was only checked in AD records: this indication was missing in 5% of records. The Fiscal Code and other identifiers were missing in all FVG records, which make up about 1.1% of total records, and in an additional 0.2% of records from other regions. Remarks on the other variables affected less than 1% of records. [Table S2 (Supplementary File 1)](#app1-ijerph-15-01470){ref-type="app"} shows detailed remarks regarding the variables of the National Database.

3.3. Data Quality: Selection of the Regions and Reference Period for Frequency Rates Assessment {#sec3dot3-ijerph-15-01470}
-----------------------------------------------------------------------------------------------

[Table S3 (Supplementary File 1)](#app1-ijerph-15-01470){ref-type="app"} shows the overall number of RD occurrences per region of residence of the case. The table provides summary evidence that epidemiological analyses of the available data could not rely on a single AD or CD record structure. Consequently, the analyses were carried out for individual regional populations, using the data from the record structure which dominated for each disease.

The progress of notifications was studied distinguishing AD from CD notifications, to detect possible differences related to the data collection practice, and the results are summarised in [Figure 1](#ijerph-15-01470-f001){ref-type="fig"}. Yearly AD notifications increased from 2001 to 2008 and then remained approximately constant afterwards. The time course of CD notifications showed an increasing trend from 2006 to 2013, when the median of notifications attained the maximum value. The high variance of CD regional notifications is explained by the adoption of the CD record structure by the CD regions at various times till 2011: before 2006, this record structure was only used by Veneto. Moreover, in some regions, the establishment of registries was followed by a peak in the yearly notifications. The variability of the absolute frequencies of regional notifications over time in the periods 2008--2014 and 2012--2014 is presented in [Table S4 (Supplementary File 1)](#app1-ijerph-15-01470){ref-type="app"}. Umbria, accounting for about 1.5% of the national population and adopting the CD record structure in 2011, showed by far the highest variability of yearly regional notifications in the period 2012--2014. This period showed the lower variability of both AD and CD notifications with respect to the period 2008--2014. Therefore, it was selected as the reference period for the assessment of RD frequency rates.

3.4. Symptoms Onset Age and Sex Distribution {#sec3dot4-ijerph-15-01470}
--------------------------------------------

Data of age at disease symptoms onset are reported in [Table 1](#ijerph-15-01470-t001){ref-type="table"} for selected diseases. [Table S5](#app1-ijerph-15-01470){ref-type="app"} reports data for all 414 diseases in which it was determined. In total, 108 diseases set on in all cases notified before 18 years of age and 15 showed all occurrences setting on after 18. The comparison with literature data could be carried out for almost three hundred diseases using data available in the ORPHANET portal, which mostly referred to the main life stages where the first symptoms set on ([Table S5](#app1-ijerph-15-01470){ref-type="app"}). There was a general agreement between RNMR and literature data, but for about 12% of compared diseases.

The sex distribution of diseases unevenly frequent between sexes is presented in [Table 2](#ijerph-15-01470-t002){ref-type="table"}. Eleven diseases occurred with a female:male ratio higher than 9:1. Twelve diseases prevailed in males with a female:male ratio lower than 1:9. Data of sex distribution could be compared with data of 65 diseases reported in the ORPHANET data sheets and further literature as having a predominance in either sex. RNMR results showed a good agreement with literature data, except for three diseases (5% comparisons). [Table S6](#app1-ijerph-15-01470){ref-type="app"} shows the sex distribution of 441 RD reported to RNMR and the comparison with literature data, where available.

3.5. Incidence in the General Population and Prevalence in Live Births {#sec3dot5-ijerph-15-01470}
----------------------------------------------------------------------

[Table 3](#ijerph-15-01470-t003){ref-type="table"} and [Table 4](#ijerph-15-01470-t004){ref-type="table"} report, respectively, the rates of diseases (and disease groups) most incident in the general population and most prevalent at birth. National and regional incidence and BP rates of all diseases and disease groups notified to RNMR in Italy are reported in [Tables S7 and S8](#app1-ijerph-15-01470){ref-type="app"}. The collection of data of such a wide range of diseases has been made possible thanks to the sustainability of the registration and, since 2011, full coverage of the population residing in the whole Italian territory. Full population coverage relies on the national network for the diagnosis and care of RD, made up of 247 accredited centres belonging to the public health service \[[@B21-ijerph-15-01470]\]. Completeness of case ascertainment relies on mandatory case notification and the possibility for the patients to access RD-specific assistance when their condition is certified by these centres. However, completeness of case ascertainment may depend on the actual need for RD-specific assistance and care. Moreover, the occurrence of diseases and malformations in still births and at termination of pregnancy for foetal anomalies is not recorded. This implies that RNMR data are actually representative of patients requiring care in specialized RD centres.

Median regional incidence and BP rates calculated from CD and from AD collection practices are compared in [Tables S9 and S10](#app1-ijerph-15-01470){ref-type="app"}. Incidence data from the two collection practices showed a Pearson correlation coefficient of 0.78, while the Pearson's correlation coefficient of BP rates was 0.44. The low correlation of BP rates may be related to the limited population monitored and record selection criteria. For both incidence and BP, the rates calculated from the CD collection practice were, on average, higher than those from the AD collection practice. The reason for such a difference may be related to the different time courses shown by CD and AD notifications ([Figure 1](#ijerph-15-01470-f001){ref-type="fig"}), which may involve the certification of cases diagnosed before the adoption of the CD practice.

Incidence data for 34 diseases and BP data for 56 diseases could be compared with data retrieved in the ORPHANET compilations ([Tables S11 and S12](#app1-ijerph-15-01470){ref-type="app"}). Diseases with differences of more than one order of magnitude were subject to a dedicated survey of the literature, which showed that information and data justifying our results were published, except for three and four diseases, respectively, for incidence and BP rates.

4. Conclusions {#sec4-ijerph-15-01470}
==============

This study determined basic features to assess the reliability and internal consistency of RNMR data. Data of the three-year period 2012--2014 provided information on 275 diseases and 47 disease groups. Moreover, the onset age and sex distribution have been determined for more than 400 individual diseases. This data is mostly representative of patients requiring care in specialized RD centres and is especially suitable to assess the burden of assistance and care by RD-dedicated resources of the public health service.

The external validity of the data collected in the RNMR database was studied by comparing the RD national estimates derived from it with the estimates of frequency in the general population available in the literature. Differences bigger than an order of magnitude were found for 7--8% diseases for which comparisons were possible regarding national incidence and BP. A similar level of agreement with literature data was found regarding the age at disease onset and sex distribution. Therefore, RNMR data is rather consistent with information available in the literature. The remarkable consistency of RNMR data with data of some diseases, which can be traced reliably from hospital records, was also shown in a recent publication \[[@B25-ijerph-15-01470]\].

In conclusion, it appears that RNMR results provide basic epidemiological information, which was still lacking for many RD, and overcome the current typical fragmentation of data resulting from the observation of one or a few related diseases in different, selected populations with varied methodologies. In fact, RNMR results compose a unique systematic picture of the occurrence of a wide range of RD in a population as big as about 60 million residents. Although further efforts are still required to achieve the full exploitation of such a complex and extended collection system, this picture represents a novel and sound information basis to improve the assessment of the rare disease burden, and to inform public health policy planning and research prioritization on rare diseases in Italy and beyond.

The authors are gratefully indebted with the following experts, who communicated and cured the data used in this publication: Giuliano LOMBARDI, Giandomenico PALKA (Registro Regionale dell'Abruzzo), Antonella ANGIONE, Domenico TRIPALDI (Registro Regionale della Basilicata), Rosalba BARONE (Registro Regionale della Calabria), Generoso ANDRIA, Roberto della Casa, Simona FECAROTTA, Iris SCALA (Registro Regionale della Campania), Maria VIZIOLI, Matteo VOLTA (Registro Regionale dell'Emilia-Romagna), Bruno BEMBI, Laura DEROMA (Registro Regionale del Friuli-Venezia Giulia), Domenico DI LALLO, Esmeralda CASTRONUOVO, Marco PIGNOCCO (Registro Regionale del Lazio), Mirella ROSSI (Registro Regionale della Liguria), Laura BOTTANELLI, Erica DAINA, Sara GAMBA (Registro Regionale della Lombardia), Orazio GABRIELLI (Registro Regionale delle Marche), Maria Lucia DI NUNZIO (Registro Regionale del Molise), Giuseppina ANNICCHIARICO, Maria MALERBA (Registro Regionale della Puglia), Simone BALDOVINO, Dario ROCCATELLO (Registro Interregionale del Piemonte e della Valle d'Aosta), Antonello ANTONELLI, Paolo MOI, Maria Antonietta PALMAS, Rosanna PORCU (Registro Regionale della Sardegna), Lucia BORSELLINO, Salvatore SCONDOTTO (Registro Regionale della Sicilia), Fabrizio BIANCHI, Anna PIERINI, Federica PIERONI (Registro Regionale della Toscana), Paola CASUCCI, Ombretta CHECCONI, Maria Concetta PATISSO (Registro Regionale dell'Umbria), Paola FACCHIN, Monica MAZZUCATO (Registro Regionale del Veneto), Francesco BENEDICENTI, Carla MELANI, Paola ZUECH (Registro della Provincia Autonoma di Bolzano), Annunziata DI PALMA, Annalisa PEDROLLI (Registro della Provincia Autonoma di Trento).

The following are available online at <http://www.mdpi.com/1660-4601/15/7/1470/s1>: Supplementary File 1: Criteria for data validation; Table S1. Type of national duplicate records and their management; Figure S1. Completeness of disease onset date by notifying region; Table S2. Results of the quality control of data communicated to RNMR; Table S3. Distribution of records by region of residence of the case and validity of diagnosis ascertainment and certification dates; Table S4. Yearly notifications, by region of residence, in different periods of diagnosis ascertainment or confirmation. Table S5: Age at onset of rare diseases reported to RNMR and comparison with literature data. Table S6: Sex distribution of the rare diseases reported to RNMR and comparison with literature data. Table S7: National and regional incidence of rare diseases notified to RNMR during 2012--2014. Table S8: National and regional birth prevalence of rare diseases notified to RNMR (2012--2013). Table S9: Comparison of regional incidence data from AD and CD notifications. Table S10: Comparison of regional birth prevalence data from AD and CD notifications. Table S11: Comparison of national incidence data with literature data. Table S12: Comparison of national birth prevalence data with literature data. References \[[@B26-ijerph-15-01470],[@B27-ijerph-15-01470],[@B28-ijerph-15-01470],[@B29-ijerph-15-01470],[@B30-ijerph-15-01470],[@B31-ijerph-15-01470],[@B32-ijerph-15-01470],[@B33-ijerph-15-01470],[@B34-ijerph-15-01470],[@B35-ijerph-15-01470],[@B36-ijerph-15-01470],[@B37-ijerph-15-01470],[@B38-ijerph-15-01470],[@B39-ijerph-15-01470],[@B40-ijerph-15-01470],[@B41-ijerph-15-01470],[@B42-ijerph-15-01470],[@B43-ijerph-15-01470],[@B44-ijerph-15-01470],[@B45-ijerph-15-01470],[@B46-ijerph-15-01470],[@B47-ijerph-15-01470]\] are cited in Supplementary Materials.

###### 

Click here for additional data file.

Conceptualization, D.T., L.V., A.R., and P.T.; Software, L.F.; Validation, A.R.; Formal Analysis, A.R.; Methodology: L.V.; Resources, D.T.; Data Curation, A.R., P.T.; Writing-Original Draft Preparation, L.V.; Writing-Review & Editing, D.T., L.V., A.R., and P.T.; Visualization, L.V.; Supervision, D.T.

This research received no external funding.

The authors declare no conflict of interest.

![Time course of notifications, by year of diagnosis ascertainment or certification. Dataset: Subset 1; Origin of notifications: Regions using the record structure with the Date of diagnosis Ascertainment (AD) and regions using the record structure with the Date of diagnosis Certification (CD); Selection of records: Records with valid diagnosis ascertainment or certification date; Total records: 115,575 (AD records) and 121,854 (CD records, including those from Lombardia, Piemonte, Sardegna, and Val d'Aosta). Data are expressed as percentage of the total regional notifications (by region of residence) to better compare the progress of AD or CD notifications from regional populations with different dimensions. Absolute numbers of yearly notifications per region of residence are reported in [Table S4](#app1-ijerph-15-01470){ref-type="app"}.](ijerph-15-01470-g001){#ijerph-15-01470-f001}

ijerph-15-01470-t001_Table 1

###### 

Age at symptoms onset of selected rare diseases monitored by RNMR. Dataset: Subset 1; Origin of notifications: all Regions; Record selection: records with diagnosis indicating a specific disease (i.e., excluding disease groups) and at least four records with valid onset date per disease; Total records: 84,859.

  RNMR Code   ORPHA Code   Disease                                       Records (*N*)   Median Onset Age (Years)   Life Stages Reported by ORPHANET \[[@B24-ijerph-15-01470]\]
  ----------- ------------ --------------------------------------------- --------------- -------------------------- -------------------------------------------------------------
  RNG040      1791         Frontofacionasal dysplasia                    7               −0.28                      Neonatal
  RN0490      3447         Weaver syndrome                               7               −0.23                      Neonatal, Antenatal
  RNG030      87           Apert syndrome                                13              −0.18                      Antenatal, Neonatal
  RNG040      2108         Hallermann-Streiff syndrome                   9               −0.17                      Neonatal, Infancy
  RP0040      1915         Fetal alcohol syndrome                        56              −0.14                      Antenatal, Neonatal
  RNG070      313          Lamellar ichthyosis                           60              −0.11                      Neonatal
  RN0400      1540         Jackson-Weiss syndrome                        12              −0.10                      Neonatal
  RNG040      207          Crouzon disease                               43              −0.09                      Infancy, Neonatal
  RN1150      1340         Cardiofaciocutaneous syndrome                 54              −0.06                      Antenatal, Neonatal
  RN0640      1114         Aplasia cutis congenita                       14              −0.06                      Antenatal, Neonatal
  RFG010      141          Canavan disease                               6               −0.06                      Neonatal, infancy (severe form); childhood (mild form)
  RNG040      1452         Cleidocranial dysostosis                      7               −0.05                      Neonatal
  RCG060      352          Galactosemia                                  58              −0.05                      Infancy, Neonatal, Childhood
  RN0130      35,737       Morning glory syndrome                        10              −0.05                      Childhood
  RNG050      429          Hypochondroplasia                             7               −0.05                      Childhood
  RP0010      290          Congenital rubella syndrome                   31              −0.05                      Antenatal, Neonatal
  RN0390      380          Greig cephalopolysyndactyly syndrome          15              −0.04                      Neonatal
  RDG020      326          Factor V deficiency                           24              −0.04                      All ages
  RN0100      708          Peters anomaly                                12              −0.04                      Infancy, Neonatal
  RCG040      238,583      Hyperphenylalaninemia                         673             −0.04                      Neonatal, Infancy
  RN1040      710          Pfeiffer syndrome                             10              −0.03                      Antenatal, Neonatal
  RN1530      500          LEOPARD syndrome                              37              −0.03                      Childhood
  RCG040      407          Non-ketotic hyperglycinemia                   6               −0.03                      Infancy, Neonatal
  RCG060      348          Fructose-1,6-bisphosphatase deficiency        4               −0.03                      All ages
  RN0510      464          Incontinentia pigmenti                        74              −0.03                      Neonatal
  RN1640      1466         COFS syndrome                                 6               −0.03                      Neonatal, Antenatal
  RN1760      912          Zellweger syndrome                            13              −0.02                      Neonatal
  RNG070      461          Recessive X-linked ichthyosis                 60              −0.02                      Neonatal
  RP0060      415,286      Bilirubin encephalopathy                      7               −0.02                      Neonatal
  RCG050      23           Argininosuccinatelyase deficiency             12              −0.02                      Neonatal, All ages
  RN0910      374          Goldenhar syndrome                            187             −0.02                      Neonatal, Antenatal
  RN0600      312          Epidermolytic ichthyosis                      32              −0.02                      Neonatal
  RDG020      327          Factor VII deficiency                         98              −0.02                      All ages
  RN0990      570          Moebius syndrome                              52              −0.02                      Neonatal
  RN0320      2368         Gastroschisis                                 57              −0.02                      Neonatal, Antenatal
  RDG020      328          Factor X deficiency                           9               −0.02                      All ages
  RN0700      280          Wolf-Hirschhorn syndrome                      64              −0.02                      Neonatal, Antenatal
  RN1080      813          Silver-Russell syndrome                       85              −0.02                      Neonatal, Antenatal
  RN0180      1203         Duodenal atresia                              75              −0.02                      Antenatal, Neonatal, Infancy, Childhood
  RN0540      1556         Cutis marmorata telangiectatica congenita     21              −0.02                      Neonatal
  RCG040      511          Maple syrup urine disease                     26              −0.02                      Infancy, Neonatal, Childhood
  RNG070      634          Netherton syndrome                            17              −0.01                      Infancy, Neonatal
  RN1100      808          Seckel syndrome                               11              −0.01                      Neonatal, Antenatal
  RN1310      739          Prader-Willi syndrome                         388             −0.01                      Neonatal, Antenatal
  RCG040      35           Propionic acidemia                            4               −0.01                      Infancy, Neonatal
  RN0080      1764         Familial dysautonomia                         6               −0.01                      Neonatal, Antenatal
  RDG020      331          Factor XIII deficiency                        5               −0.01                      All ages
  RN0850      138          CHARGE syndrome                               116             −0.01                      Neonatal
  RCG040      293,355      Methylmalonic acidemia                        11              −0.01                      All ages
  RN1170      744          Proteus syndrome                              19              −0.01                      Infancy
  RN0170      1201         Atresia of small intestine                    77              −0.01                      Neonatal
  RN1140      107          Branchio-oto-renal syndrome                   35              −0.01                      All ages
  RN1250      887          VACTERL/VATER association                     80              −0.01                      Neonatal
  RN1410      199          Cornelia de Lange syndrome                    74              −0.01                      Neonatal, Antenatal
  RN0930      392          Holt-Oram syndrome                            23              −0.01                      Neonatal
  RDG020      98,878       Hemophilia A                                  1209            −0.01                      Infancy, Neonatal
  RDG020      98,879       Hemophilia B                                  202             0.00                       Infancy, Neonatal
  RN1740      899          Walker-Warburg syndrome                       6               0.00                       Infancy, Neonatal
  RN1010      648          Noonan syndrome                               459             0.00                       Neonatal
  RN0430      2911         Poland syndrome                               299             0.00                       Infancy, Neonatal
  RDG020      745          Protein C deficiency                          233             0.00                       Childhood
  RN0200      388          Hirschsprung disease                          244             0.00                       Infancy, Neonatal
  RN0060      2162         Holoprosencephaly                             46              0.00                       Neonatal, Antenatal
  RN1240      857          Townes-Brocks syndrome                        8               0.00                       All ages
  RN1130      1297         Branchio-oculo-facial syndrome                7               0.00                       Neonatal
  RNG060      1522         Craniometaphyseal dysplasia                   11              0.00                       Childhood
  RN1210      819          Smith-Magenis syndrome                        45              0.00                       Infancy, Neonatal
  RN0890      2053         Freeman-Sheldon syndrome                      9               0.00                       Neonatal
  RCG050      187          Citrullinemia                                 10              0.00                       Neonatal, Adult
  RN0360      1465         Coffin-Siris syndrome                         13              0.00                       Neonatal
  RN0410      2311         Jarcho-Levin syndrome                         11              0.00                       Neonatal, Antenatal
  RN0280      950          Acrodysostosis                                12              0.00                       Neonatal, Antenatal
  RN1660      35,125       Epidermal nevus syndrome                      15              0.00                       Childhood, Adolescent, Adult
  RNG040      861          Treacher-Collins syndrome                     16              0.00                       Neonatal
  RN1450      94,068       Congenital spondyloepiphyseal dysplasia       14              0.00                       Neonatal
  RNG060      289          Ellis-Van Creveld syndrome                    8               0.00                       Neonatal, Antenatal
  RN1590      884          Pallister-Killian syndrome                    16              0.00                       Neonatal, Antenatal
  RN0670      281          Cri du chat syndrome                          46              0.00                       Neonatal
  RN0790      915          Aarskog-Scott syndrome                        28              0.00                       Childhood
  RN0940      2322         Kabuki make-up syndrome                       112             0.00                       Infancy, Neonatal
  RN0040      475          Joubert syndrome                              96              0.00                       Neonatal, Antenatal
  RN1270      904          Williams syndrome                             316             0.00                       Neonatal, Antenatal
  RCG160      567          Di George syndrome                            359             0.00                       Neonatal
  RN1620      783          Rubinstein-Taybi syndrome                     63              0.00                       All ages
  RN1380      110          Bardet-Biedl syndrome                         51              0.00                       Infancy, Neonatal, Antenatal
  RN0660      870          Down syndrome                                 2283            0.00                       Antenatal, Neonatal
  RN0680      881          Turner syndrome                               947             0.00                       Infancy, Neonatal, Antenatal, Childhood
  RN0770      3205         Sturge-Weber syndrome                         134             0.00                       Infancy, Neonatal, Childhood, Adolescent
  RN1330      908          Fragile X syndrome                            288             0.00                       Neonatal, Infancy, Childhood
  RN1510      90,308       Klippel-Trénaunay syndrome                    170             0.00                       Infancy, Childhood, Adolescent
  RN0110      77           Aniridia                                      69              0.00                       Infancy, Neonatal
  RFG050      83,330       Werdnig-Hoffman disease                       13              0.00                       Infancy, Neonatal
  RCG040      26           Methylmalonic acidemia with homocystinuria    16              0.00                       All ages
  RN0860      3157         De Morsier syndrome                           46              0.00                       Infancy, Neonatal
  RN1400      191          Cockayne syndrome                             6               0.01                       All ages
  RN1430      220          Denys-Drash syndrome                          5               0.02                       Infancy, Neonatal
  RN0240      2138         True hermaphroditism                          17              0.02                       Infancy, Neonatal
  RN1190      2614         Nail-patella syndrome                         33              0.02                       Neonatal, Infancy, Childhood
  RN0340      974          Adams-Oliver syndrome                         11              0.02                       Neonatal
  RDG020      903          Von Willebrand disease                        800             0.02                       All ages
  RC0180      205          Crigler-Najjar syndrome                       27              0.04                       Neonatal
  RN1730      893          WAGR syndrome                                 8               0.07                       Neonatal
  RN0950      98,861       Primary ciliary dyskinesia, Kartagener type   345             0.08                       Neonatal, infancy

Note: This table reports pathologies ordered by increasing median age at onset. The number of records is indicated with the only aim of allowing a better assessment of the statistical data presented and cannot be used as an indication of the disease or exemption code frequency.

ijerph-15-01470-t002_Table 2

###### 

Sex distribution of rare diseases monitored by RNMR with the highest relative frequencies in males or females. Dataset: Subset 1; Origin of notifications: all regions; Record selection: records with diagnosis indicating a specific disease (i.e., excluding disease groups) and at least four records per disease; Total records: 119,762.

  ORPHA Code   Disease                                                         Records (*N*)   Females (%)   Males (%)   F:M Ratio and Other Literature Information Reported in ORPHANET Data Sheets \[[@B24-ijerph-15-01470]\]
  ------------ --------------------------------------------------------------- --------------- ------------- ----------- --------------------------------------------------------------------------------------------------------
  1791         Frontofacionasal dysplasia                                      7               100           0           \-
  209,981      Iron refractory iron deficiency anemia                          4               100           0           \-
  881          Turner syndrome                                                 1754            99            1           Almost exclusively in F
  778          Rett syndrome                                                   603             97            3           Predominant in F
  538          Lymphangioleiomyomatosis                                        180             97            3           Almost exclusively in F
  464          Incontinentia pigmenti                                          95              97            3           20:1
  37,202       Interstitial cystitis                                           1192            95            5           9:1
  \-           Storage pool deficiency                                         11              91            9           \-
  816          Sjögren-Larsson syndrome                                        93              90            9           \-
  \-           Thrombocytopenic thrombotic purpura-hemolytic-uremic syndrome   10              90            10          \-
  559          Marinesco-Sjögren syndrome                                      30              90            10          \-
  169,615      Idiopathic central precocious puberty                           3686            89            11          10:1
  98,973       Posterior polymorphous corneal dystrophy                        8               88            13          \-
  79,473       Porphyria variegata                                             8               88            13          Predominant in F
  1297         Branchio-oculo-facial syndrome                                  8               88            13          \-
  3143         Schmidt syndrome                                                72              86            14          \-
  1452         Cleidocranial dysostosis                                        7               86            14          \-
  429          Hypochondroplasia                                               7               86            14          \-
  809          Mixed connective tissue disease                                 1092            86            14          10:1
  3287         Takayasu arteritis                                              346             85            14          Predominant in F
  2483         Melkersson-Rosenthal syndrome                                   25              84            16          \-
  317          Erythrokeratodermia variabilis                                  6               83            17          \-
  98,958       Droplet cornea                                                  17              82            18          \-
  436          Hypophosphatasia                                                11              82            18          \-
  \-           Secretion deficiency thrombocytopathy                           11              82            18          \-
  125          Bloom syndrome                                                  5               80            20          \-
  79,273       Hereditary coproporphyria                                       5               80            20          Predominant in F
  98,974       Fuchs endothelial dystrophy                                     30              80            20          3--4:1
  581          Mucopolysaccharidosis type 3                                    5               80            20          \-
  2059         Fryns syndrome                                                  5               80            20          \-
  65,684       Hirayama disease                                                5               20            80          1:20
  3447         Weaver syndrome                                                 10              20            80          \-
  98,895       Becker muscular dystrophy                                       221             19            81          Predominant in M
  379          Chronic granulomatous disease                                   87              18            82          \-
  221,117      Gerstmann syndrome                                              6               17            83          \-
  97,360       Robinow syndrome                                                6               17            83          \-
  478          Kallmann syndrome                                               509             16            84          1:5
  101,330      Porphyria cutanea tarda                                         53              15            85          Predominant in M
  \-           Opitz syndrome                                                  20              15            85          \-
  1466         COFS syndrome                                                   7               14            86          \-
  \-           Simpson-Golabi-Behmel syndrome                                  7               14            86          \-
  2796         Pachydermoperiostosis                                           15              13            87          1:7
  481          Kennedy disease                                                 51              12            88          \-
  98,879       Hemophilia B                                                    271             11            89          Predominant in M
  223          Nephrogenic diabetes insipidus                                  66              11            89          \-
  915          Aarskog-Scott syndrome                                          38              8             92          Predominant in M
  98,878       Hemophilia A                                                    1577            7             93          Predominant in M
  98,896       Duchenne muscular dystrophy                                     258             5             95          Predominant in M
  461          Recessive X-linked ichthyosis                                   65              3             97          Almost exclusively in M
  \-           Klinefelter syndrome                                            2071            0             100         \-
  330          Factor XII deficiency                                           4               0             100         \-
  425          Familial hypoalphalipoproteinemia                               4               0             100         \-
  510          Lesch-Nyhan disease                                             12              0             100         Severe form predominant in M
  534          Lowe syndrome                                                   5               0             100         Almost exclusively in M
  649          Norrie disease                                                  5               0             100         Almost exclusively in M
  580          Mucopolysaccharidosis type 2                                    27              0             100         Almost exclusively in M
  245          Nager syndrome                                                  4               0             100         \-

Note: The number of records is indicated with the only aim of allowing a better assessment of the statistical data presented and cannot be used as an indication of the disease or exemption code frequency. Where the percentages in males and females sum to less than 100, the difference represents records with missing sex data.

ijerph-15-01470-t003_Table 3

###### 

National Incidence rates of most incident rare diseases and rare disease groups monitored by RNMR in the Italian population. Yearly average in the three-year period 2012--2014.

  ORPHA Code   Disease Name                                         National Incidence (/Million)
  ------------ ---------------------------------------------------- -------------------------------
  156,071      Keratoconus                                          25.53
  803          Amyotrophic lateral sclerosis                        19.15
  870          Down syndrome                                        7.76
  169,615      Idiopathic central precocious puberty                7.33
  \-           Lichen sclerosus                                     5.92
  \-           Bullous pemphigoid                                   4.88
  930          Idiopathic achalasia                                 4.63
  117          Behçet disease                                       4.57
  \-           Arnold-Chiari malformation                           4.19
  2932         Chronic inflammatory demyelinating polyneuropathy    3.77
  \-           Pemphigus vulgaris                                   3.75
  \-           Klinefelter syndrome                                 3.75
  397          Giant cell arteritis                                 3.73
  399          Huntington disease                                   3.38
  37,202       Interstitial cystitis                                3.19
  881          Turner syndrome                                      2.53
  98,249       Ehlers-Danlos syndrome                               2.43
  774          Hereditary hemorrhagic telangiectasia                2.36
  2331         Kawasaki disease                                     2.08
  732          Polymyositis                                         1.95
  733          Familial adenomatous polyposis                       1.90
  183          Churg-Strauss syndrome                               1.88
  221          Dermatomyositis                                      1.87
  809          Mixed connective tissue disease                      1.80
  558          Marfan syndrome                                      1.79
  900          Wegener granulomatosis                               1.77
  \-           Mixed cryoglobulinemia                               1.75
  \-           Idiopathic torsion dystonia                          1.46
  \-           Rheumatic endocarditis                               1.36
  761          Henoch-Schönlein purpura                             1.35
  648          Noonan syndrome                                      1.30
  805          Tuberous sclerosis                                   1.18
  908          Fragile X syndrome                                   1.15
  2911         Poland syndrome                                      1.14
  727          Microscopic polyangiitis                             1.14
  171          Primary sclerosing cholangitis                       1.03
  904          Williams syndrome                                    0.98
  2073         Narcolepsy                                           0.97
  478          Kallmann syndrome                                    0.94
  96,346       Anorectal malformation                               0.93
  388          Hirschsprung disease                                 0.88
  790          Retinoblastoma                                       0.83
  91,378       Hereditary angioedema                                0.81
  104          Leber hereditary optic neuropathy                    0.79
  739          Prader-Willi syndrome                                0.78
  70,590       Infantile apnea                                      0.78
  116          Beckwith-Wiedemann syndrome                          0.76
  550          MELAS                                                0.73
  49,041       Retroperitoneal fibrosis                             0.72
  3451         West syndrome                                        0.70
               **Disease Group Name**                               
  \-           Hereditary coagulation defects                       25.16
  \-           Undifferentiated connective tissue syndromes         17.75
  \-           Hereditary retinic dystrophies                       17.60
  \-           Hereditary anemias                                   15.04
  \-           Neurofibromatoses                                    10.08
  \-           Muscular dystrophies                                 8.12
  \-           Congenital alterations of iron metabolism            8.04
  \-           Disturbances of aminoacid transport and metabolism   7.92
  \-           Chromosomal duplication/deficiency syndromes         7.82
  \-           Hereditary neuropathies                              6.61

ijerph-15-01470-t004_Table 4

###### 

National BP Rates of most birth-prevalent rare diseases and rare disease groups monitored by RNMR in the Italian population. Rates in live births of the two-year period 2012--2013.

  ORPHA Code   Disease Name                                                                        Birth Prevalence (/100,000)
  ------------ ----------------------------------------------------------------------------------- -----------------------------
  870          Down syndrome                                                                       35.00
  \-           Esophageal atresia and/or Isolated tracheo-esophageal fistula                       6.67
  96,346       Anorectal malformation                                                              6.37
  3451         West syndrome                                                                       5.69
  388          Hirschsprung disease                                                                4.22
  739          Prader-Willi syndrome                                                               3.63
  \-           Biliary atresia                                                                     3.14
  805          Tuberous sclerosis                                                                  2.84
  116          Beckwith-Wiedemann syndrome                                                         2.65
  648          Noonan syndrome                                                                     2.45
  881          Turner syndrome                                                                     1.96
  1203         Duodenal atresia                                                                    1.86
  374          Goldenhar syndrome                                                                  1.67
  1201         Atresia of small intestine                                                          1.67
  290          Congenital rubella syndrome                                                         1.47
  904          Williams syndrome                                                                   1.47
  \-           Epidermolysis bullosa                                                               1.37
  2911         Poland syndrome                                                                     1.27
  2368         Gastroschisis                                                                       1.18
  138          CHARGE syndrome                                                                     1.18
  \-           Lissencephaly                                                                       1.08
  98,861       Primary ciliary dyskinesia, Kartagener type                                         1.08
  464          Incontinentia pigmenti                                                              0.78
  887          VACTERL/VATER association                                                           0.78
  \-           Congenital colobomatous optic disc                                                  0.69
  3205         Sturge-Weber syndrome                                                               0.69
  \-           Alagille syndrome                                                                   0.69
  2162         Holoprosencephaly                                                                   0.59
  1896         EEC syndrome                                                                        0.59
  205          Crigler-Najjar syndrome                                                             0.59
  77           Aniridia                                                                            0.49
  70,590       Infantile apnea                                                                     0.49
  1915         Fetal alcohol syndrome                                                              0.39
  199          Cornelia de Lange syndrome                                                          0.39
  908          Fragile X syndrome                                                                  0.39
  90,308       Klippel-Trénaunay syndrome                                                          0.39
  912          Zellweger syndrome                                                                  0.29
  570          Moebius syndrome                                                                    0.29
  199,642      Microcephaly                                                                        0.29
  281          Cri du chat syndrome                                                                0.29
  783          Rubinstein-Taybi syndrome                                                           0.29
  380          Greig cephalopolysyndactyly syndrome                                                0.20
  280          Wolf-Hirschhorn syndrome                                                            0.20
  813          Silver-Russell syndrome                                                             0.20
  475          Joubert syndrome                                                                    0.20
  884          Pallister-Killian syndrome                                                          0.20
  3157         De Morsier syndrome                                                                 0.20
  974          Adams-Oliver syndrome                                                               0.20
  726          Alpers syndrome                                                                     0.20
  435          Ito hypomelanosis                                                                   0.20
               **Disease Group Name**                                                              
  \-           Disturbances of aminoacid transport and metabolism                                  30.10
  \-           Congenital craniofacial anomalies                                                   21.57
  \-           Chromosomal duplication/deficiency syndromes                                        8.73
  \-           Disturbances of carbohydrate transport and metabolism, excluded diabetes mellitus   5.39
  \-           Neurofibromatoses                                                                   3.92
  \-           Congenital chondrodystrophies                                                       3.53
  \-           Congenital ichthyoses                                                               2.94
  \-           Other congenital anomalies with intellectual disability                             2.84
  \-           Chromosomal aneuploidy syndromes                                                    2.55
  \-           Urea cycle disturbances                                                             1.18
