Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier

Madrid, Spain

Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier

Madrid, Spain
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Morales-Piga A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Alonso-Ferreira V.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Villaverde-Hueso A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Posada de la Paz M.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Osteochondrodysplasias are a heterogeneous group of more than 200 entities, characterized by abnormalities of cartilage, bone growth, and skeletal development. The aim of this study was to assess temporal and spatial changes in overall mortality due to these disorders in Spain, using data from a nationwide registry. Annual deaths showing osteochondrodysplasias as the underlying cause of death were selected using the International Classification of Diseases-9th revision (ICD-9) codes for the period 1981 through 1998, and ICD-10 codes for the period 1999 through 2008. Age-adjusted mortality rates were calculated by sex, and geographic analysis was performed by municipality. A total of 679 deaths were recorded (53% men). Age-adjusted mortality rates went from 0.09 (0.06, 0.12) per 100,000 population in 1981 to 0.05 (0.03, 0.08) per 100,000 population in 2008. A changing trend in the age-standardized mortality rate was in evidence, with an annual increase of 2.4% (-0.4, 5.2) from 1981 to 1994, and an annual decrease of -7.3% (-10.9, -3.5) from 1995 onwards. Geographic analysis showed some places situated in the west and south of Spain with greater risk of mortality. There is a need to identify risk factors and to increase overall knowledge about the life expectancy and epidemiology of osteochondrodysplasias. © 2013 Wiley Periodicals, Inc.


Morales-Piga A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Bachiller-Corral J.,Ramon y Cajal Hospital | Villaverde-Hueso A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Alonso-Ferreira V.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | And 3 more authors.
Anthropologischer Anzeiger | Year: 2012

The aim of this paper is to investigate heritable factors that might be related to the recognised genetic susceptibility for developing Paget's disease of bone (PD). This was a hospital- based, case-control study of a systematically selected group of PD patients and a group of controls drawn from the same health setting. In these populations we assessed surname pattern, parental consanguinity and constitutional physical traits. In a separate case-control analysis, genetically-based features and pathological traits of interest for genetic inference in 43 demonstrated familial cases were then compared to those in 24 sporadic cases. Results showed coincidence of three or four surnames (Odds Ratio [OR] = 5.6; 95% CI = 1.7-18.5), degree of parental consanguinity (OR = 4.1; 95% CI = 2.1-1.8), and green or blue eye colour (OR = 1.5; 95% CI = 1.1-2.1) were significantly associated with PD. Comparison of proven familial and sporadic PD cases showed that the former had a stronger association with Monckeberg- type vascular calcifications (32% vs. 4 %; p = 0.02), percentage of skeleton affected (13.1 vs. 9.0), and green and blue eye colour (82% vs. 25%; p = 0.006), with Monckebergtype vascular calcifications being the main variable of interest (OR = 30.9; 95% CI = 12.75- 347.00) in the multivariate analysis. In conclusion, heritable factors are crucial in the pathogenesis of PD and, in line with other data sources, might account for the ethnic predisposition observed in different countries. © 2012 E. Schweizerbart'sche Verlagsbuchhandlung, Stuttgart, Germany.


Ramis R.,Institute Salud Carlos III ISCIII | Ramis R.,CIBER ISCIII | Gomez-Barroso D.,CIBER ISCIII | Tamayo I.,CIBER ISCIII | And 8 more authors.
PLoS ONE | Year: 2015

Background: Childhood cancer was the leading cause of death among children aged 1-14 years for 2012 in Spain. Leukemia has the highest incidence, followed by tumors of the central nervous system (CNS) and lymphomas (Hodgkin lymphoma, HL, and Non-Hodgkin's lymphoma, NHL). Spatial distribution of childhood cancer cases has been under concern with the aim of identifying potential risk factors. Objective: The two objectives are to study overall spatial clustering and cluster detection of cases of the three main childhood cancer causes, looking to increase etiological knowledge. Methods: We ran a case-control study. The cases were children aged 0 to 14 diagnosed with leukemia, lymphomas (HL and NHL) or CNS neoplasm in five Spanish regions for the period 1996-2011. As a control group, we used a sample from the Birth Registry matching every case by year of birth, autonomous region of residence and sex with six controls. We geocoded and validated the address of the cases and controls. For our two objectives we used two different methodologies. For the first, for overall spatial clustering detection, we used the differences of K functions from the spatial point patterns perspective proposed by Diggle and Chetwynd and the second, for cluster detection, we used the spatial scan statistic proposed by Kulldorff with a level for statistical significance of 0.05. Results: We had 1062 cases of leukemia, 714 cases of CNS, 92 of HL and 246 of NHL. Accordingly we had 6 times the number of controls, 6372 controls for leukemia, 4284 controls for CNS, 552 controls for HL and 1476 controls for NHL. We found variations in the estimated empirical D(s) for the different regions and cancers, including some overall spatial clustering for specific regions and distances. We did not find statistically significant clusters. Conclusions: The variations in the estimated empirical D(s) for the different regions and cancers could be partially explained by the differences in the spatial distribution of the population; however, according to the literature, we cannot discard environmental hazards or infections agents in the etiology of these cancers. © 2015 Ramis et al.


PubMed | University of Valencia, Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier and CIBER ISCIII
Type: Journal Article | Journal: PloS one | Year: 2015

Childhood cancer was the leading cause of death among children aged 1-14 years for 2012 in Spain. Leukemia has the highest incidence, followed by tumors of the central nervous system (CNS) and lymphomas (Hodgkin lymphoma, HL, and Non-Hodgkins lymphoma, NHL). Spatial distribution of childhood cancer cases has been under concern with the aim of identifying potential risk factors.The two objectives are to study overall spatial clustering and cluster detection of cases of the three main childhood cancer causes, looking to increase etiological knowledge.We ran a case-control study. The cases were children aged 0 to 14 diagnosed with leukemia, lymphomas (HL and NHL) or CNS neoplasm in five Spanish regions for the period 1996-2011. As a control group, we used a sample from the Birth Registry matching every case by year of birth, autonomous region of residence and sex with six controls. We geocoded and validated the address of the cases and controls. For our two objectives we used two different methodologies. For the first, for overall spatial clustering detection, we used the differences of K functions from the spatial point patterns perspective proposed by Diggle and Chetwynd and the second, for cluster detection, we used the spatial scan statistic proposed by Kulldorff with a level for statistical significance of 0.05.We had 1062 cases of leukemia, 714 cases of CNS, 92 of HL and 246 of NHL. Accordingly we had 6 times the number of controls, 6372 controls for leukemia, 4284 controls for CNS, 552 controls for HL and 1476 controls for NHL. We found variations in the estimated empirical D(s) for the different regions and cancers, including some overall spatial clustering for specific regions and distances. We did not find statistically significant clusters.The variations in the estimated empirical D(s) for the different regions and cancers could be partially explained by the differences in the spatial distribution of the population; however, according to the literature, we cannot discard environmental hazards or infections agents in the etiology of these cancers.


Morales-Piga A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Morales-Piga A.,Consortium For Biomedical Research In Rare Diseases Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Bachiller-Corral J.,Ramon y Cajal University Hospital | Gonzalez-Herranz P.,Teresa Herrera Mother and Child Hospital | And 3 more authors.
Rheumatology International | Year: 2015

Metaphyseal bony outgrowths are a well-recognized feature of fibrodysplasia ossificans progressiva (FOP) phenotype, but its genuine frequency, topographic distribution, morphological aspect, and potential implications are not fully established. To better ascertain the frequency and characteristics of osteocartilaginous exostoses in FOP disease, we conducted a cross-sectional radiological study based on all the traceable cases identified in a previous comprehensive national research. Metaphyseal exostoses were present in all the 17 cases of FOP studied. Although most often arising from the distal femoral (where metaphyseal exostoses adopt a peculiar not yet reported appearance) and proximal tibial bones, we have found that they are not restricted to these areas, but rather can be seen scattered at a variety of other skeletal sites. Using nuclear magnetic resonance imaging, we show that these exophytic outgrowths are true osteochondromas. As a whole, these results are in agreement with data coming from the literature review. Our study confirms the presence of metaphyseal osteochondromas as a very frequent trait of FOP phenotype and an outstanding feature of its anomalous skeletal developmental component. In line with recent evidences, this might imply that dysregulation of BMP signaling, in addition to promoting exuberant heterotopic ossification, could induce aberrant chondrogenesis and osteochondroma formation. Unveiling the molecular links between these physiopathological pathways could help to illuminate the mechanisms that govern bone morphogenesis. © 2015, Springer-Verlag Berlin Heidelberg.


PubMed | Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier, Teresa Herrera Mother and Child Hospital, University of San Carlos, Ramon y Cajal University Hospital and 2 more.
Type: Case Reports | Journal: Rheumatology international | Year: 2015

Metaphyseal bony outgrowths are a well-recognized feature of fibrodysplasia ossificans progressiva (FOP) phenotype, but its genuine frequency, topographic distribution, morphological aspect, and potential implications are not fully established. To better ascertain the frequency and characteristics of osteocartilaginous exostoses in FOP disease, we conducted a cross-sectional radiological study based on all the traceable cases identified in a previous comprehensive national research. Metaphyseal exostoses were present in all the 17 cases of FOP studied. Although most often arising from the distal femoral (where metaphyseal exostoses adopt a peculiar not yet reported appearance) and proximal tibial bones, we have found that they are not restricted to these areas, but rather can be seen scattered at a variety of other skeletal sites. Using nuclear magnetic resonance imaging, we show that these exophytic outgrowths are true osteochondromas. As a whole, these results are in agreement with data coming from the literature review. Our study confirms the presence of metaphyseal osteochondromas as a very frequent trait of FOP phenotype and an outstanding feature of its anomalous skeletal developmental component. In line with recent evidences, this might imply that dysregulation of BMP signaling, in addition to promoting exuberant heterotopic ossification, could induce aberrant chondrogenesis and osteochondroma formation. Unveiling the molecular links between these physiopathological pathways could help to illuminate the mechanisms that govern bone morphogenesis.


Morales-Piga A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Bachiller-Corral J.,Ramon y Cajal Hospital | Trujillo-Tiebas M.J.,Fundacion Jimenez Diaz | Trujillo-Tiebas M.J.,Consortium for Biomedical Research in Rare Diseases CIBERER | And 10 more authors.
Bone | Year: 2012

We aimed to investigate the epidemiological determinants, clinical features, and genetic pattern of FOP in our country by evaluating the entire population of patients identified according to a combination of methods. To achieve this, 24 individuals were confirmed as FOP cases, 17 of whom were alive at the end of 2011 (point prevalence=0.36×10-6). The gender distribution (male/female ratio=13/11) and the concurrent range of ages (from 4 to 53years; mean±SD: 30.2±13.8) are in agreement with similar reports. Twenty-one (87.5%) had characteristic congenital malformations of the big toe, and short thumbs were found in 65.2% of cases. In addition, other skeletal malformations such us fusion of the posterior elements of the cervical spine (89.0%), knee osteochondromas (71%), scoliosis (54.5%), and short and broad femoral neck (52.6%) were observed. All had developed mature ossicles of heterotopic bone in typical anatomic and temporal patterns, ranging in number from 1 to 17 (9.5±3.9). Age at appearance of first ossifying lesion varied from 3months to 15years. Mean age at diagnosis was 7.3±5.1years and the average delay in reaching the correct diagnosis after the onset of heterotopic ossification was 2.7years (range=0-12years). Biopsy of the pre-osseous lesions was performed in 11 of 20 (55.0%), providing no useful information for the diagnosis of FOP. Seven of 18 (38.9%) reported some hearing loss, and 5 (27.8%) experienced diffuse thinning of the hair or were bald. No patient had relatives with a typical FOP clinical picture. Fourteen of the 16 cases which were genetically investigated displayed the single heterozygous mutation c.617G>A in exon 4 of the ACVR1 gene. One of the two patients who did not present with the canonical ACVR1 mutation showed a heterozygous mutation c.774G>C in exon 5 leading to the substitution of Arginine 258 with a serine. The other patient had a heterozygous c.774G>T substitution in exon 5 leading to the same amino acid change (p.Arg258Ser). These two patients had only nonspecific abnormalities of the great toe, lacked the typical anatomic and developmental pattern of heterotopic ossification, and shared a trend toward uncommon clinical features. These results provide new insight on the epidemiological and clinical traits of FOP, reinforcing the notion of its worldwide homogeneity. The molecular characterization of ACVR1 sequence variation will contribute to the understanding of the genetic profile of this devastating disease in different geographical areas. © 2012 Elsevier Inc.


Bachiller-Corral J.,Ramon y Cajal Hospital | Diaz-Miguel C.,Ramon y Cajal Hospital | Morales-Piga A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier
Bone | Year: 2013

Background: Although radiological diagnosis of Paget's disease of bone (PD) is usually straightforward, monostotic cases may potentially raise specific problems which lead to performing invasive procedures. Therefore, the purpose of this study is to ascertain whether or not monostotic femoral Paget's disease (MFPD) presentation poses particular diagnostic difficulties which prompt excessive use of excisional biopsies. Methods: We retrospectively reviewed the medical records of 24 MFPD patients identified from a series of 412 patients; their clinical features were compared with those of the remaining 164 monostotic cases and the radiological images were systematically assessed. Results: When compared with the remaining monostotic cases, MFPD patients were more prone to having normal alkaline phosphatase levels (31.8% vs. 16.4%; 0.08) and a significantly higher percentage of patients have PD symptoms (75% vs. 51%; 0.02) and complain of bone pain (73.9% vs. 40.8%; 0.003). Six (25%) MFPD patients evidenced a fracture over the pagetic lesion. This incidence is higher than that of the monostotic cases of other locations (8.4%; p. = 0.02). The existence of PD lesion was not recognised initially in 10 cases and an excisional bone biopsy was performed in 7 (29%). One patient subsequently experienced a fracture through the biopsy site and another two experienced worsening of their previous bone pain. Conclusion: The femur is a relatively common monostotic PD location which often causes diagnostic confusion, prompting a bone biopsy in many cases. Careful assessment of this lesion by X-ray examination may help attain an early appropriate diagnosis and avoidance of unnecessary surgical morbidity. © 2013 Elsevier Inc.

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