Hospital Universitario Araba Txagorritxu

Gasteiz / Vitoria, Spain

Hospital Universitario Araba Txagorritxu

Gasteiz / Vitoria, Spain

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Fernandez-Rebollo E.,University of the Basque Country | Lecumberri B.,Hospital La Paz | Gaztambide S.,University of the Basque Country | Martinez-Indart L.,Hospital Universitario Of Cruces | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Recent advances in genetics and epigenetics have revealed an overlap between molecular and clinical features of pseudohypoparathyroidism (PHP) subtypes, broadening the previous spectrum of PHP genotype-phenotype correlations and indicating limitations of the current classification of the disease. Objectives: The aim of the study was to screen patients with clinical diagnoses of PHP type I or pseudo-PHP for underlying molecular defects and explore possible correlations between molecular findings and clinical features. Patients and Methods: We investigated the GNAS locus at the molecular level in 72 affected patients (46 women and 26 men) from 56 nonrelated families. Clinical data were obtained for 63 of these patients (38 women and 25 men). Results: The molecular analysis showed that 35 patients carried structural mutations, 32 had loss of methylation, and 2 had a 2q37 deletion but did not reveal any (epi)mutation for 3 patients. Comparing these results and the clinical data, we observed that a younger age at diagnosis was associated with structural defects at the GNAS gene and epigenetic defects with a diagnosis later in life (9.19 ± 1.64 vs 24.57 ± 2.28 years, P < .0001). Conclusions: This first global review of PHP in Spain highlights the importance of a detailed clinical and genetic study of each patient and the integrated analysis of the findings from the two approaches. It may also help geneticists and clinicians to raise the suspicion of PHP earlier, reach more accurate diagnoses, and provide patients with PHP and their families with useful genetic information and counseling, thereby improving outcomes and quality of life. Copyright © 2013 by The Endocrine Society.


Maupetit-Mehouas S.,French Institute of Health and Medical Research | Azzi S.,French Institute of Health and Medical Research | Steunou V.,French Institute of Health and Medical Research | Sakakini N.,University Hospital of Marseille Conception | And 11 more authors.
Human Mutation | Year: 2013

Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell-Silver or Beckwith-Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus but may affect other imprinted loci for some patients. Therefore, we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1, and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR, and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus (1) simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), (2) hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1), and (3) hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of "epidominance", that is, the phenotype is controlled by the most severely affected imprinted locus. Among patients with PTH resistance due to broad imprinting defect at the locus, some present with loss of imprinting -including hypo or hypermethylation- at several other imprinted loci. In accordance to other multilocus imprinted disorders, the prevailing phenotype is related to the most severely affected imprinted locus. © 2013 WILEY PERIODICALS, INC.


Court F.,Lhospitalet Of Llobregat | Martin-Trujillo A.,Lhospitalet Of Llobregat | Romanelli V.,Lhospitalet Of Llobregat | Garin I.,Hospital Universitario Araba Txagorritxu | And 6 more authors.
Human Mutation | Year: 2013

Genomic imprinting is the parent-of-origin-specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith-Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver-Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader-Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance. © 2013 Wiley Periodicals, Inc.


Shaw-Smith C.,University of Exeter | De Franco E.,University of Exeter | Allen H.L.,University of Exeter | Batlle M.,Institute dInvestigacions Biomediques August Pi i Sunyer | And 16 more authors.
Diabetes | Year: 2014

The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein. We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas. © 2014 by the American Diabetes Association.


PubMed | University Hospitals Leuven, Hospital Universitario Araba Txagorritxu, Laboratory of Genomic Imprinting and Cancer, University of Milan and 3 more.
Type: | Journal: Clinical epigenetics | Year: 2016

Pseudohypoparathyroidism (PHP) is caused by (epi)genetic defects in the imprinted GNAS cluster. Current classification of PHP patients is hampered by clinical and molecular diagnostic overlaps. The European Consortium for the study of PHP designed a genome-wide methylation study to improve molecular diagnosis.The HumanMethylation 450K BeadChip was used to analyze genome-wide methylation in 24 PHP patients with parathyroid hormone resistance and 20 age- and gender-matched controls. Patients were previously diagnosed with GNAS-specific differentially methylated regions (DMRs) and include 6 patients with known STX16 deletion (PHP(stx16)) and 18 without deletion (PHP(neg)).The array demonstrated that PHP patients do not show DNA methylation differences at the whole-genome level. Unsupervised clustering of GNAS-specific DMRs divides PHP(stx16) versus PHP(neg) patients. Interestingly, in contrast to the notion that all PHP patients share methylation defects in the A/B DMR while only PHP(stx16) patients have normal NESP, GNAS-AS1 and XL methylation, we found a novel DMR (named GNAS-AS2) in the GNAS-AS1 region that is significantly different in both PHP(stx16) and PHP(neg), as validated by Sequenom EpiTYPER in a larger PHP cohort. The analysis of 58 DMRs revealed that 8/18 PHP(neg) and 1/6 PHP(stx16) patients have multi-locus methylation defects. Validation was performed for FANCC and SVOPL DMRs.This is the first genome-wide methylation study for PHP patients that confirmed that GNAS is the most significant DMR, and the presence of STX16 deletion divides PHP patients in two groups. Moreover, a novel GNAS-AS2 DMR affects all PHP patients, and PHP patients seem sensitive to multi-locus methylation defects.


Yurrebaso I.,Hospital Universitario Cruces | Casado O.L.,Osatek Alta Tecnologia Sanitaria S.A. | Barcena J.,Hospital Universitario Cruces | Perez de Nanclares G.,Hospital Universitario Araba Txagorritxu
Neuromuscular Disorders | Year: 2014

Hereditary neuropathy with liability to pressure palsies (HNPP) is a disorder mainly caused by a 1.5-Mb deletion at 17p11.2-12 (and in some rare cases by point mutations) and clinically associated with recurrent painless palsies. Here, we performed electrophysiological (motor, sensory and terminal latency index), MRI and genetic studies in a family referred for ulnar neuropathy with pain.Surprisingly, we found typical neurophysiological features of HNPP (prolongation of distal motor latencies and diffuse SNCV slowing with significant slowing of motor nerve conduction velocities). Besides, the proband presented conduction block in left ulnar, left median and both peroneal nerves. MRI findings were consistent with an underlying neuropathy. Molecular studies identified a novel frameshift mutation in PMP22 confirming the diagnosis of HNPP.Our data suggest that neurophysiological studies are essential to characterize underdiagnosed HNPP patients referred for peripheral neuropathy. Our experience shows that MRI could be a complementary tool for the diagnosis of these patients. © 2013 Elsevier B.V.


Beristain E.,Hospital Universitario Araba Txagorritxu | Vicente M.-A.,Endocrinology and Nutrition Service | Guerra I.,Hospital Universitario Araba Txagorritxu | Gutierrez-Corres F.-B.,Hospital Universitario Araba Txagorritxu | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Succinate dehydrogenase complex, subunit D (SDHD) mutations cause pheochromocytoma/paraganglioma syndrome. SDHD, located at chromosome 11q23, shows a parent-of-origin effect because the disease is observed almost exclusively when the mutation is transmitted from the father, although some cases of maternal transmission have been reported. Several hypotheses have been proposed for this peculiar inheritance pattern, but the underlying mechanisms have not yet been clearly elucidated. Objective: The objective of the study was to explain the parent-of-origin effect in a family, mainly affected by paternally transmitted paragangliomas, and with a maternally transmitted renal tumor. Patients: Peripheral blood DNA from 15 carriers and 7 tumor DNA samples from SDHD-p.Trp5* carriers were studied. Methods: We conducted mutation genotyping and microsatellite marker analysis in germline and tumor DNA and methylation status analysis in tumor DNA by methylation-specific multiplex ligation-dependent probe amplification. Results: Mutation genotyping and microsatellite marker analysis demonstrated loss of heterozygosity of the wild-type allele (maternal) in all studied tumors, except the renal tumor, which lost the mutated allele (maternal), and the prostate tumor, which had no loss of heterozygosity. The methylation-specific multiplex ligation-dependent probe amplification demonstrated that the methylation profile corresponded exclusively to the paternal chromosome without genomic loss, suggesting paternal uniparental disomy as the mechanism underlying the parent-of-origin effect in this SDHD family. Conclusions: The paternal uniparental disomy involves the loss of maternally imprinted cell cycle regulators and the overexpression of paternally imprinted growth activators, leading to tumorigenesis in this syndrome. Copyright © 2013 by The Endocrine Society.


Pereda A.,Hospital Universitario Araba Txagorritxu | Garin I.,Hospital Universitario Araba Txagorritxu | Garcia-Barcina M.,Hospital Universitario Basurto | Gener B.,Hospital Universitario Cruces | And 3 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypopthyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E, some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals. © 2013 Pereda et al.; licensee BioMed Central Ltd.


Elalaoui S.C.,Institute National dHygiene | Elalaoui S.C.,Mohammed V University | Garin I.,Hospital Universitario Araba Txagorritxu | Sefiani A.,Institute National dHygiene | And 2 more authors.
Molecular Syndromology | Year: 2014

Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a heterogeneous overgrowth syndrome characterized by visceromegaly, macroglossia, tumor predisposition, and other congenital abnormalities. BWS is usually associated with abnormalities of chromosome 11p15, including (epi)genetic changes, paternal disomy and point mutations. A number of identical twin pairs, mostly female, have been reported to be clinically discordant for BWS. Studies of monozygotic twins discordant for BWS provide more information about failure in the DNA methylation maintenance machinery during very early embryonic development. Here, we report a case of monozygotic male twins discordant for BWS phenotype. Methylation analysis of the 2 imprinted domains at 11p15.5 (H19DMR and KvDMR) was performed by methylation-specific MLPA and pyrosequencing of DNA extracted from peripheral blood and buccal swabs of both twins. Hypomethylation at KvDMR was identified in both cell types of the affected twin, whereas his healthy brother presented hypomethylation only in blood cells and a normal methylation profile in buccal swab. For diagnostic purposes, it is important to remember that twins can share fetal circulation and possibly share hematopoietic stem cells early in development; therefore, the affected and unaffected twins can share an epigenotype that will resemble partial hypomethylation. If a patient is a twin, it is valuable to obtain a sample from a tissue other than blood. © 2013 S. Karger AG, Basel.


PubMed | Pediatric Endocrinology, French Institute of Health and Medical Research and Hospital Universitario Araba Txagorritxu
Type: Case Reports | Journal: American journal of medical genetics. Part A | Year: 2016

Autosomal-dominant brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Alterations that predict haploinsufficiency of PTHLH, the gene coding for parathyroid hormone related protein (PTHrP), have been identified as a cause of this disorder in seven families. Here, we report three patients affected with brachydactyly type E, caused by PTHLH mutations expected to result in haploinsufficiency, and discuss our data compared to published reports.

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