Clinical and genetic characterization of patients with eye diseases included in the Spanish Rare Diseases Patient Registry.

BACKGROUND: The low prevalence of rare diseases poses a significant challenge in advancing their understanding. This study aims to delineate the clinical and genetic characteristics of patients with rare eye diseases (RED) enrolled in the Spanish Rare Diseases Patient Registry. METHODS: A total of 864 patients from the registry database were included. Diseases were categorized into inherited retinal dystrophies (n=688); anterior segment diseases (n=48); congenital malformations (n=27); and syndromic diseases with ocular involvement including muscular (n=46), neurological (n=34), or metabolic (n=13); inflammatory diseases (n=4); and tumors (n=4). Data on visual acuity (VA) and/or visual field (VF), symptoms and signs, concurrent diseases in syndromic cases, age of onset and at diagnosis, affected genes, disability rating, inability to work and dependency grade recognition were collected. RESULTS: A mean diagnostic delay of 7 years from symptom onset was observed. Commonly reported symptoms included photophobia, night blindness, and progressive vision loss (≥57% of patients). Cataract was the most prevalent secondary disease (46%), with pseudophakia being the most common ocular surgery (26%). Hearing loss and cardiovascular diseases were the most prevalent concurrent systemic diseases (≥13%). Certificates of disability, incapacity for work, and dependency were held by 87%, 42%, and 19% of patients, respectively. Among the 719 patients with available VA data, 193 (27%) were blind, and 188 (26%) had moderate to severe visual impairment. Over half of the patients (54%) exhibited VF defects, and 216 (25%) had concentric contraction ≤5° or abolished VF. Most had genetic diseases with autosomal recessive (55%), autosomal dominant (30%), X-linked (9%), and mitochondrial (6%) patterns. One patient had mutations in both recessive USH2A and dominant RHO genes simultaneously. Of the 656 patients (75.7%) who underwent genetic testing, only 461 (70.3%) received a positive result (pathogenic or likely pathogenic mutations explaining the phenotype). We found 62 new gene variants related to RED not previously reported in databases of genetic variants related to specific phenotypes. CONCLUSIONS: This study delineates the clinical and genotypic profiles of RED in Spain. Genetic diseases, particularly retinal disorders, predominate, but a significant proportion of affected patients remain genetically undiagnosed, hindering potential gene therapy endeavors. Despite notable improvements in reducing diagnosis delays, it is still remarkable. RED frequently lead to disability and blindness among young populations.

Psychosocial impact at the time of a rare disease diagnosis.

Over half of all persons with rare diseases (RDs) in Spain experience diagnostic delay (DD) but little is known about its consequences. This study therefore aimed to analyze the psychological impact of obtaining a diagnosis of an RD, and to ascertain what social determinants are influenced and what the personal consequences are, according to whether or not patients experienced DD. Data were obtained from a purpose-designed form completed by persons registered at the Spanish Rare Diseases Patient Registry. The following were performed: a descriptive analysis; a principal component analysis (PCA); and logistic regressions. Results revealed that while searching for a diagnosis, people who experienced DD were more in need of psychological care than those diagnosed in less than one year (36.2% vs 23.2%; p = 0.002; n = 524). The PCA identified three principal components, i.e., psychological effects, social implications, and functional impact. Reducing DD would improve psychological effects, such as irritability (OR 3.6; 95%CI 1.5-8.5), frustration (OR 3.4; 95%CI 1.7-7.1) and concentration on everyday life (OR 3.3; 95%CI 1.4-7.7). The influence of the social implications and functional repercussions of the disease was greater in persons with DD (scores of 22.4 vs 20 and 10.6 vs 9.4, respectively) in terms of the difficulty in explaining symptoms to close friends and family (3.3 vs 2.9), and loss of independence (3.3 vs 2.9). In conclusion, this is the first study to analyze the psychosocial impact of diagnosis of RDs in Spain and one of few to assess it in the patients themselves, based on data drawn from a purpose-designed form from a national registry open to any RD. People affected by RDs who underwent DD experienced greater psychosocial impact than did those who were diagnosed within the space of one year.

Predictors of autism spectrum disorder diagnosis in a spanish sample of preterm children with very low birthweight: A cross-sectional study.

Background and Aims: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a higher likelihood of being diagnosed in preterm populations. Likewise, low birthweight has also been connected with an increased likelihood of ASD. The objectives were to study the frequency and define the relationship between ASD, gestational age, birthweight, and growth percentiles for preterm children. Methods: A sample of preterm children with very low birthweight was selected from the Spanish population at 7-10 years old. Families were contacted from the hospital, and they were offered an appointment to conduct a neuropsychological assessment. The children who showed signs of ASD were referred to the diagnostic unit for differential diagnosis. Results: A total of 57 children completed full assessments, with 4 confirmed ASD diagnoses. The estimated prevalence was 7.02%. There were statistically significant weak correlations between ASD and gestational age (τb = -0.23), and birthweight (τb = -0.25), suggesting there is a higher likelihood of developing ASD for those born smaller or earlier in their gestation. Conclusion: These results could improve ASD detection and outcomes for this vulnerable population while also supporting and enhancing previous findings.

Familial Mediterranean Fever in Spain: Time Trend and Spatial Distribution of the Hospitalizations.

Familial Mediterranean Fever (FMF) is a rare, hereditary, auto-inflammatory disease. The aims of this study were to explore the time trend and geographical distribution of hospitalizations in Spain from 2008 to 2015. We identified hospitalizations of FMF from the Spanish Minimum Basic Data Set at hospital discharge, using ICD-9-CM code 277.31. Age-specific and age-adjusted hospitalization rates were calculated. The time trend and the average percentage change were analyzed using Joinpoint regression. Standardized morbidity ratios were calculated and mapped by province. A total of 960 FMF-related hospitalizations (52% men) were identified across the period 2008-2015, with an increase in hospitalizations of 4.9% per year being detected (p < 0.05). The risk of hospitalization was higher than expected for the national total (SMR > 1) in 13 provinces (5 in the Mediterranean area), and lower (SMR < 1) in 14 provinces (3 in the Mediterranean area). There was an increase in hospitalizations of patients with FMF in Spain throughout the study period, with a risk of hospitalization that was higher, though not exclusively so, in provinces along the Mediterranean coast. These findings contribute to the visibility of FMF and provide useful information for health planning. Further research should take into account new population-based information, in order to continue monitoring this disease.

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry.

BACKGROUND: According to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them. METHODS: Using data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960-2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression. RESULTS: Detailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2-7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07-1.45); in cases with symptom onset at age 30-44 years (OR 1.48; 95% CI 1.19-1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26-7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02-1.88). CONCLUSIONS: This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

Transcultural Validation of a Spanish Version of the Quality of Life in Epidermolysis Bullosa Questionnaire.

INTRODUCTION: Epidermolysis bullosa (EB) is a relatively infrequent genodermatosis for which there is still no cure, and which impacts the quality of life of those that are affected by it. The Quality of Life evaluation in Epidermolysis Bullosa (QoLEB) questionnaire was specifically developed for English-speaking persons with EB. OBJECTIVES: To undertake the transcultural adaptation and analysis of the psychometric properties of a Spanish version of the QoLEB questionnaire. METHOD: We designed an observational study to implement the process of translation and validation of the scale in accordance with World Health Organisation guidelines. We assessed the content validity of the Spanish version with the participation of 33 adult patients who presented with four principal subtypes of EB. The subjects were examined and evaluated using the QoLEB and Short Form-36 (SF-36) questionnaires. RESULTS: The Spanish version of the QoLEB displayed excellent internal consistency and content validity, α = 0.91. Test-retest reliability was likewise excellent (ps = 0.93), as was the reliability among subtypes (range ps = 0.82-0.93). The functional part of the QoLEB correlated well with the SF-36 physical component summary (ps = 0.70). The emotional QoLEB was moderately correlated with the SF-36 mental component summary (ps = 0.49). Significant discriminant validity existed between the global score of the questionnaire (p = 0.033) and the functional scale (p = 0.003). CONCLUSIONS: The Spanish version of the QoLEB questionnaire can be recommended for use in any subsequent studies seeking to assess the efficacy of possible treatments and care programmes in this group.

Diagnostic Process in Rare Diseases: Determinants Associated with Diagnostic Delay.

Many people living with rare disease (RD) report a difficult diagnostic process from the symptom onset until they obtain the definitive diagnosis. The aim of this study was thus to ascertain the diagnostic process in RDs, and explore the determinants related with having to wait for more than one year in this process (defined as "diagnostic delay"). We conducted a case-control study, using a purpose-designed form from the Spanish Rare Diseases Patient Registry for data-collection purposes. A descriptive analysis was performed and multivariate backward logistic regression models fitted. Based on data on 1216 patients living with RDs, we identified a series of determinants associated with experiencing diagnostic delay. These included: having to travel to see a specialist other than that usually consulted in the patient's home province (OR 2.1; 95%CI 1.6-2.9); visiting more than 10 specialists (OR 2.6; 95%CI 1.7-4.0); being diagnosed in a region other than that of the patient's residence at the date of symptom onset (OR 2.3; 95%CI 1.5-3.6); suffering from a RD of the nervous system (OR 1.4; 95%CI 1.0-1.8). In terms of time taken to see a specialist, waiting more than 6 months to be referred from the first medical visit was the period of time which most contributed to diagnostic delay (PAR 30.2%). In conclusion, this is the first paper to use a collaborative study based on a nationwide registry to address the diagnostic process of patients living with RDs. While the evidence shows that the diagnostic process experienced by these persons is complex, more studies are needed to determine the implications that this has for their lives and those of their families at a social, educational, occupational, psychological, and financial level.

The impact of toxic oil syndrome on physical and psychological health status using the HAQ and the PHQ-9 questionnaires.

BACKGROUND: Toxic oil syndrome (TOS) is a multisystemic disease due to a massive intoxication. To evaluate physical and mental health of TOS patients, we used the Health Assessment Questionnaire (HAQ) and the Patient Health Questionnaire-9 (PHQ-9). Additionally, we correlated both questionnaires with the results of the Short Form-36v2 (SF-36v2) Health Survey obtained in the same patients' sample. METHODS: 895 TOS patients who participated in the prior SF-36v2 study were invited to participate. We described patients' demographic and clinical characteristics, HAQ and PHQ-9 results. HAQ and PHQ-9 scores were correlated to the standardised SF-36v2 results obtained in our previous study. RESULTS: In total, 828 (92.5%) TOS annual follow-up and HAQ and 810 (90.5%) PHQ-9 valid questionnaires were analysed. Participants' average age was 65.4 (Standard Deviation (SD): 13.4), 521 (62.9%) were women, 725 (87.6%) reported having at least other chronic disease and 789 (95.3%) an additional TOS-related health problem. Average scores were 0.91 (SD: 0.83) for HAQ, 35.8 (SD: 10.1) for PCS and 37.8 (SD: 11.6) for MCS. Overall, 467 (57.7%) participants had moderate/severe depression (PHQ-9 ≥ 10), but only 229 (49.6%) of them reported having a depression diagnosis. Correlation between questionnaires was very strong for HAQ and physical function SF-36v2 dimension and moderate/fair for the rest of combinations. CONCLUSIONS: TOS cohort presented low/very low health status measured with SF-36v2, moderate difficulties in performing daily activities according to HAQ, and a high prevalence of major depression measured with PHQ-9. High proportion of undiagnosed depression was detected, proving PHQ-9 useful in terms of detecting and promoting depression diagnosis in the cohort.

Determinants of satisfaction with the detection process of autism in Europe: Results from the ASDEU study.

LAY ABSTRACT: Professional guidance and support in response to first concerns appears to be an important predictor of the level of satisfaction with the detection process of autism in young children. In this study, we analyzed the views of 1342 family members, including 1278 parents, who completed an online survey form collecting information about their experience and satisfaction with the early detection of autism in their child. Specifically, we were interested in how specific experiences with the detection process relate to the satisfaction with it and whether we could identify important predictors of satisfaction. The detection process is an emotionally charged period for parents, often described as painful, chaotic, and lengthy. A better understanding of their experiences is important to take appropriate action to improve the detection process. In our sample, the level of satisfaction with the detection process varied greatly from one respondent to another. Among the different experiences we considered, whether or not respondents received professional guidance and support in response to first concerns explained most of this variation. We also found that difficulty finding information about detection services, lack of professional guidance and support in response to first concerns, having to find a diagnostic service on one's own, and longer delays between confirmation of concerns and first appointment with a specialist were experiences associated with a greater likelihood of being unsatisfied. The findings of this study highlight the importance of the parent-professional relationship in the detection process and have important practical implications for health administrations to improve the detection process.

A population-based study of mortality due to muscular dystrophies across a 36-year period in Spain.

Muscular dystrophies (MD) are a group of rare hereditary degenerative diseases. Our aim was to analyze the mortality pattern in Spain from 1981 to 2016 to assess the temporal trend and discern possible geographic differences using population-based data. Annual deaths related to MD were obtained from the National Statistics Institute with codes 359.1 of the ICD-9 (1981-1998) and G71.0 of the ICD-10 (1999-2016). Age-adjusted mortality rates were calculated and changes in mortality trends were identified. The standardized mortality ratios (SMR) and their respective 95% confidence intervals were calculated by district for 1999-2016. Smoothed SMRs and posterior probability were also assessed and then mapped to look for patterns or geographic distribution. All rates were expressed per 1,000,000 inhabitants. A total of 2,512 deaths (73.8% men) were identified. The age-adjusted mortality rates varied from 0.63 (95% CI 0.40-0.95) in 1981 to 1.51 (95% CI 1.17-1.93) in 2016. MD mortality showed a significant increase of 8.81% per year (95% CI 5.0-12.7) from 1981 to 1990, remaining stable afterwards. Areas with risk of death higher than expected for Spain as a whole were identified, not showing a specific regional pattern. In conclusion, the rising trend in MD mortality might be attributable to advanced improvements in diagnostic techniques leading to a rise in prevalence. Further research on the districts with the highest mortality would be necessary.

The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

Effect of a Focused Social and Communication Intervention on Preterm Children with ASD: A Pilot Study.

While advances in intensive neonatal care have greatly improved survival rates among preterm infants, incidence of neurodevelopmental disorders in this group is still high, with autism spectrum disorder (ASD) being one of the most frequent. To this end, we conducted a social-communication intervention aimed at investigating efficacy in social-communicative skills. Eighteen children (preterm and full-term with ASD and preterm children) aged 18 through 20 months participated in the study. Our findings indicate that most participants in the intervention groups registered significant improvements in terms of socio-communicative skills, cognitive development, and language. Accordingly, these pilot data underscore the need for further research and implementation of early interventions in young preterm children with ASD.

Toxic oil syndrome: health-related quality-of-life assessment using the SF-36 Health Survey.

BACKGROUND: Toxic oil syndrome (TOS) is a multisystemic disease due to a massive intoxication that occurred in Spain in 1981 affecting >20 000 persons. This study aims to evaluate the quality of life of the survivors' cohort after 38 years of follow-up using the Short Form 36 (SF-36) Health Survey. METHODS: One thousand patients were selected among the 14 084 alive TOS cohort members in 2018 using a stratified random sampling method. Stratification was performed by the 2017 self-rated health status reported by patients. SF-36 results were compared directly and as standardized (T scores) with the Spanish-population reference values. Relationship between self-rated health status and SF-36 results was assessed. RESULTS: Overall, 900 cohort members participated and 895 valid responses were included in the study. Participants' average age was 65.2 (standard deviation: 13.8) years and 563 (62.9%) participants were women. Participants' distribution by self-rated health status was: 219 (24.5%) good/very good, 415 (46.4%) fair and 261 (29.1%) poor/very poor. Quality of life was below the Spanish-population reference in 84% of the TOS patients (87.2% for women and 78.6% for men) for the Physical Component Summary (PCS) and in 75.4% (81.7% for women and 64.8% for men) for the Mental Component Summary (MCS). PCS and MCS scores decreased similarly for both sexes with worse self-rated health. CONCLUSIONS: Very low quality of life and self-rated health, especially for women, were found in the total TOS participants that can be extrapolated to the TOS survivors' cohort. The TOS cohort still requires standardization of care with integral plans around the country.

The ASDEU autism prevalence study in northern Spain.

The prevalence of autism spectrum disorders (ASD) was studied in children in the County of Gipuzkoa (Basque Country, Spain) as part of the European Union's Autism Spectrum Disorder in Europe project (ASDEU- https://asdeu.eu ). To identify cases in a total community sample of 7- to 9-year-old pupils (N = 14,734), a multistage approach was adopted: in the first stage, a teacher nomination (TN) form was completed by school teachers; and in the second stage, all families with a child nominated by their teachers were invited to complete the Social Communication Questionnaire (SCQ). A total of 108 (59%) schools participated fully, yielding a final sample of 9177 of 14.734 (61.9%) pupils. A total of 212 (2.3%) children were nominated via the TN form, and of these, 105 (49.5%) returned the completed SCQ. Twenty-five (23.8%) cases with SCQ scores ≥ 15 were invited to undergo a free clinical assessment, and 10 (40%) new cases of ASD were identified. The prevalence estimate included the 55 cases already being supported by the Gipuzkoa's only ASD association, the Gipuzkoa Autism Society (Asociación Guipuzcoana de Autismo/GAUTENA)), as well as the 10 new subjects identified by the ASDEU field diagnostic process. A sensitivity analysis was performed to estimate new potential ASD cases among the non-participant schools, leading to a final figure of 87 cases of ASD in this age-bracket at the date of the study. This global probabilistic estimate, including non-participating schools, would thus provide a population prevalence of 0.59% (95% CI 0.48-0.73), a result lower than those reported by some other studies. Attrition rates in cross-sectional studies are challenging and support the need for developing longitudinal ASD incidence surveillance study areas (ASD observatories).

Explaining Age at Autism Spectrum Diagnosis in Children with Migrant and Non-Migrant Background in Austria.

This study explored (i) differences in age at Autism Spectrum Disorder (ASD) diagnosis between children with and without a migrant background in the main diagnostic centre for ASD in Upper Austria (ii) factors related to the age at diagnosis and (iii) whether specific factors differed between the two groups. A retrospective chart analysis included all children who received their first diagnosis before the age of 10 years (n = 211) between 2013 and 2018. Children with a migrant background were diagnosed 13 months earlier than those without (r = 0.278, p < 0.001), and had more severe delays in language, more severe autism, no Asperger's syndrome, lower parental educational level and more frequent referrals by paediatricians. For the total sample, expressive language delay, severity of restricted and repetitive behaviours, higher nonverbal development, and paediatric referrals explained earlier diagnoses. There was a stronger effect of parental education and weaker effect of language impairment on age at ASD diagnosis in children with a migrant background. In conclusion, no delay in diagnosing ASD in children with a migrant background in a country with universal health care and an established system of paediatric developmental surveillance was found. Awareness of ASD, including Asperger's syndrome, should be raised among families and healthcare professionals.

Towards Harmonized Biobanking for Biomonitoring: A Comparison of Human Biomonitoring-Related and Clinical Biorepositories.

Human biomonitoring (HBM) depends on high-quality human samples to identify status and trends in exposure and ensure comparability of results. In this context, much effort has been put into the development of standardized processes and quality assurance for sampling and chemical analysis, while effects of sample storage and shipment on sample quality have been less thoroughly addressed. To characterize the currently applied storage and shipment procedures within the consortium of the European Human Biomonitoring Initiative (HBM4EU), which aims at harmonization of HBM in Europe, a requirement analysis based on data from an online survey was conducted. In addition, the online survey was addressed to professionals in clinical biobanking represented by members of the European, Middle Eastern and African Society for Biopreservation and Biobanking (ESBB) to identify the current state-of-the-art in terms of sample storage and shipment. Results of this survey conducted in these two networks were compared to detect processes with potential for optimization and harmonization. In general, many similarities exist in sample storage and shipment procedures applied by ESBB members and HBM4EU partners and many requirements for ensuring sample quality are already met also by HBM4EU partners. Nevertheless, a need for improvement was identified for individual steps in sample storage, shipment, and related data management with potential impact on sample and data quality for HBM purposes. Based on these findings, recommendations for crucial first steps to further strengthen sample quality, and thus foster advancement in HBM on a pan-European level are given.

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum.

BACKGROUND: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement. RESULTS: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient's lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation. CONCLUSIONS: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.

Spanish Cultural Validation of the Modified Checklist for Autism in Toddlers, Revised.

The Modified Checklist for Autism in Toddlers-revised/follow-up (M-CHAT-R/F) was developed to reduce the number of cases requiring telephone verification. The aim of this study was to validate a Spanish version of the M-CHAT-R/F in the Spanish public health system. The M-CHAT-R/F was translated, culturally adapted, and then administered to 6625 children. Of the 39 positive screening cases, 15 children were diagnosed with autism spectrum disorder (ASD) and 24 with non-ASD disorders or delays. The sensitivity was 0.79 and specificity of 0.99. Positive and negative predictive values were 0.39 and 0.99, respectively. These results are similar to the English equivalent, though observed prevalence was lower. This study supports Spanish National Health System policy makers to consider a universal ASD screening program.

[Mortality attributed to hereditary haemorrhagic telangiectasia and geographical variability in Spain (1981-2016)]. / Mortalidad atribuida a telangiectasia hemorrágica hereditaria y variabilidad geográfica en España (1981-2016).

OBJECTIVE: To identify the mortality directly attributed to hereditary haemorrhagic telangiectasia (HHT) in Spain, and to analyze its time trends and geographic variability. METHOD: Population-based deaths due to HHT were selected from the Spanish National Statistics Institute: codes 448.0 (ICD-9, 1981-1998) and I78.0 (ICD-10, 1999-2016) as the basic cause of death. Specific and age-adjusted mortality rates were calculated by sex, as well as standardized mortality ratios (SMR) by province and district, and smoothed SMR. RESULTS: We identified 327 deaths attributed to HHT (49.5% women), with the highest mortality at 80-84 years in men (0.220 per 100,000 inhabitants) and at 75-79 years in women (0.147 per 100,000 inhabitants). Age-adjusted mortality rates did not show any significant time trend between 1981 and 2016 in Spain. The provinces of Navarra, Cantabria, Guipúzcoa, Pontevedra and Las Palmas had higher than expected mortality, as well as the regions of Monte Sur (Ciudad Real) and Ripollès (Girona). CONCLUSIONS: This study has identified some regions with higher risk of death due to HHT in Spain. It is unknown whether these differences are associated with the distribution of types HHT1 and HHT2, and further studies will be necessary to know the determinants of this geographical variability. These findings are useful to complement the information provided by other studies and registries, and for health planning.