Publications by authors named "Celia Badenas"

74 Publications

A New Stepwise Molecular Work-Up After Chorionic Villi Sampling in Women With an Early Pregnancy Loss.

Front Genet 2020 14;11:561720. Epub 2021 Jan 14.

BCNatal Department of Maternal-Fetal Medicine, Institute Gynecology, Obstetrics and Neonatology, Hospital Clínic de Barcelona, Barcelona, Spain.

To explore the use of a new molecular work-up based on the stepwise use of Quantitative Fluorescence PCR (QF-PCR) extended to eight chromosomes and single nucleotide polymorphism array (SNP-array) in chorionic villi obtained by chorionic villi sampling (CVS) offered to women experiencing an early pregnancy loss. During a 3-year period (January 2016-December 2018), CVS was offered to women experiencing an early pregnancy loss before the evacuation of the products of conception (POC) to retrieve chorionic villi, irrespective of the number of previous losses. A new molecular work-up was prospectively assayed encompassing a first QF-PCR round (with the 21, 18, 13, 7, X, and Y chromosomes), a second QF-PCR round (with the 15, 16, and 22 chromosomes), and a high resolution SNP-array in those cases with normal QF-PCR results. A control group in which POC were collected after surgical uterine evacuation was used to be compared with the intervention group. Around 459 women were enrolled in the intervention group (CVS) and 185 in the control group (POC after uterine evacuation). The QF-PCR testing success rates were significantly higher in the intervention group (98.5%: 452/459) as compared to the control group (74%: 109/147; < 0.001), while the chromosomal anomaly rate at the two QF-PCR rounds was similar between the two groups: 52% (234/452) in the intervention and 42% (46/109) in the control group ( = 0.073). The SNP-array was performed in 202 QF-PCR normal samples of the intervention group and revealed 67 (33%) atypical chromosomal anomalies (>10 Mb), 5 (2.5%) submicroscopic pathogenic copy number variants, and 2 (1%) variant of uncertain significance (VOUS). Eighty-two percent of women experiencing an early pregnancy loss opted for a CVS. The testing success rates were higher in the intervention group (CVS; 98%) as compared to the control group (POC; 74%). The overall yields were 52% by QF-PCR (including three complete hydatiform moles), and 16% by SNP-array, including 15% atypical chromosomal anomalies and 1.1% submicroscopic pathogenic copy number variants.
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http://dx.doi.org/10.3389/fgene.2020.561720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841437PMC
January 2021

Chromosome microarray analysis should be offered to all invasive prenatal diagnostic testing following a normal rapid aneuploidy test result.

Clin Genet 2020 10 4;98(4):379-383. Epub 2020 Aug 4.

Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, Barcelona, Spain.

Chromosomal microarray analysis (CMA) has now replaced karyotyping in the analysis of prenatal cases with a fetal structural anomaly, whereas in those pregnancies undergoing invasive prenatal diagnosis with a normal fetal ultrasound, conventional karyotyping is still performed. The aims of this study were to establish the diagnostic yield of CMA in prenatal diagnosis, and to provide new data that might contribute to reconsider current practices. We reviewed 2905 prenatal samples with a normal rapid aneuploidy detection test referred for evaluation by CMA testing. Our study revealed pathogenic and reported susceptibility copy number variants associated with syndromic disorders in 4.8% (n = 138/2905) of cases, being 2.8% (n = 81/2905) the estimated added diagnostic value of CMA over karyotyping. Clinically significant CMA abnormality was detected in 5.4% (107/1975) of the fetuses with ultrasound anomalies and in 1.4% (5/345) of those considered as low-risk pregnancies. Our series shows that in prenatal samples, CMA increases 2-fold the diagnostic yield achieved by conventional karyotyping.
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http://dx.doi.org/10.1111/cge.13810DOI Listing
October 2020

Maternal plasma genome-wide cell-free DNA can detect fetal aneuploidy in early and recurrent pregnancy loss and can be used to direct further workup.

Hum Reprod 2020 05;35(5):1222-1229

Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain.

Study Question: Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)?

Summary Answer: Genome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management.

What Is Known Already: Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing.

Study Design, Size, Duration: This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center.

Participants/materials, Setting, Methods: Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort.

Main Results And The Role Of Chance: Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases.

Limitations, Reasons For Caution: Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases.

Wider Implications Of The Findings: cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed.

Study Funding/competing Interest(s): Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina's Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.
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http://dx.doi.org/10.1093/humrep/deaa073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259365PMC
May 2020

Resolution of subclinical porphyria cutanea tarda after hepatitis C eradication with direct-acting anti-virals.

Aliment Pharmacol Ther 2020 05 15;51(10):968-973. Epub 2020 Apr 15.

Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.

Background: Hepatitis C virus (HCV) is a risk factor for porphyria cutanea tarda (PCT), a rare disease originating in the liver characterised by overproduction of porphyrins. Although hepatitis C infection is highly prevalent among patients with porphyria, only a minority of hepatitis C patients develop PCT.

Aims: To explore the presence of porphyrin abnormalities in a cohort of asymptomatic hepatitis C-infected patients and the impact of anti-viral therapy.

Methods: Eighty-four consecutive patients with HCV infection treated with direct-acting antivirals after 1 January 2018 were longitudinally evaluated for the presence of porphyrin abnormalities. Those patients with biochemical abnormalities at baseline were additionally evaluated at follow-up. Porphyrins in urine were screened by fluorometry and isomer separation was performed by liquid chromatography.

Results: In five patients, all of them asymptomatic, porphyrin profile abnormalities were detected: three presented significant increased urinary porphyrins with a typical PCT profile, and two showed normal levels of urinary porphyrins, but abnormal porphyria-like profiles. Urine evaluation after hepatitis C cure showed complete normalisation of the urinary porphyrins in all patients, confirming the biochemical cure of the disease.

Conclusions: We document the existence of rare cases of hepatitis C-infected patients with significant uroporphyrinuria in the absence of dermatological manifestations. Anti-viral therapy normalises the biochemical disorder, preventing patients from presenting PCT associated complications.
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http://dx.doi.org/10.1111/apt.15703DOI Listing
May 2020

Lack of Mutations in POT1 Gene in Selected Families with Familial Non-Medullary Thyroid Cancer.

Horm Cancer 2020 04 14;11(2):111-116. Epub 2020 Mar 14.

Department of Biochemistry and Molecular Genetics, CDB, Hospital Clínic de Barcelona, 08036, Barcelona, Spain.

To date, the genes involved in familial non-medullary thyroid cancer (FNMTC) remain poorly understood, with the exception of syndromic cases of FNMTC. It has been proposed that germline mutations in telomere-related genes, such as POT1, described in familial melanoma might also predispose individuals to thyroid cancer, requiring further research. We aimed to identify germline mutations in POT1 in selected FNMTC families (with at least three affected members) without a history of other cancers or other features, and to describe the clinical characteristics of these families. Sequencing of the 5'UTR and coding regions of POT1 was performed in seven affected people (index cases) from seven families with FNMTC. In addition, we performed whole-exome sequencing (WES) of DNA from 10 affected individuals belonging to four of these families. We did not find germline variants of interest in POT1 by Sanger sequencing or WES. We neither found putative causative mutations in genes previously described as candidate genes for FNMTC in the 4 families studied by WES. In our study, no germline potentially pathogenic mutations were detected in POT1, minimizing the possibilities that this gene could be substantially involved in non-syndromic FNMTC.
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http://dx.doi.org/10.1007/s12672-020-00383-5DOI Listing
April 2020

Genetic linkage analysis of a large family identifies as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension.

J Med Genet 2019 07 20;56(7):481-490. Epub 2019 Mar 20.

Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background: Mapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 () gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%.

Methods: We performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family.

Results: We identified a candidate chromosome region in 2q24.3, 38 Mb upstream from , with significant linkage (LOD=4.09) under a PAH susceptibility model. This region contains common variants associated with vascular aetiology and shows functional evidence that the putative genetic modifier is located in the upstream distal promoter of the fidgetin () gene.

Conclusion: Our results suggest that the genetic modifier acts through transcriptional regulation, whose expression variability would contribute to modulating heritable PAH. This finding may help to advance our understanding of RP in PAH across families sharing the p.Arg491Gln pathogenic mutation in .
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http://dx.doi.org/10.1136/jmedgenet-2018-105669DOI Listing
July 2019

Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q.

Eur J Hum Genet 2018 08 30;26(8):1188-1193. Epub 2018 Apr 30.

Department of Dermatology, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.

The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
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http://dx.doi.org/10.1038/s41431-018-0149-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057984PMC
August 2018

Parental Origin of the Retained X Chromosome in Monosomy X Miscarriages and Ongoing Pregnancies.

Fetal Diagn Ther 2019 5;45(2):118-124. Epub 2017 Oct 5.

BCNatal, Department of Maternal-Fetal Medicine, Institute of Gynecology, Obstetrics and Neonatology, Hospital Clínic Barcelona, Barcelona, Catalonia, Spain.

Objective: To assess the distribution of the parental origin of the retained X chromosome in monosomy X, either in miscarriages or in ongoing pregnancies.

Method: The parental origin of the X chromosome was determined in monosomy X pregnancies, either miscarriages or ongoing pregnancies. Microsatellite marker patterns were compared between maternal and fetal samples by quantitative fluorescence polymerase chain reaction. Distributions of maternally and paternally derived X chromosome were assessed in miscarriages and in ongoing pregnancies using two-tailed Fisher exact test.

Results: Forty monosomy X pregnancies were included in the study: 26 miscarried at 5-16 weeks, and 14 ongoing pregnancies were diagnosed at 11-20 weeks. The retained X chromosome was maternally derived in 67% of the cases. In miscarriages, maternal and paternal X chromosome were retained in a similar proportion (54% [95% CI: 35-73%] vs. 46% [95% CI: 27-65%]), while in ongoing pregnancies, the maternal rate was 13 times higher (93% [95% CI: 79-100%)] vs. 7% [95% CI: 0-20%]).

Conclusions: The retained X chromosome in individuals with monosomy X should theoretically be maternally derived in 2/3 of the cases. Our study suggests a preferential early miscarriage in pregnancies with a retained paternally derived X chromosome. This may explain the observation that 75-90% of individuals with monosomy X retain the maternal X chromosome.
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http://dx.doi.org/10.1159/000480499DOI Listing
September 2019

Melanocortin 1 receptor (MC1R) polymorphisms' influence on size and dermoscopic features of nevi.

Pigment Cell Melanoma Res 2018 01 17;31(1):39-50. Epub 2017 Oct 17.

Dermatology Department, Melanoma Unit, Hospital Clínic, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain.

The melanocortin 1 receptor (MC1R) is a highly polymorphic gene. The loss-of-function MC1R variants ("R") have been strongly associated with red hair color phenotype and an increased melanoma risk. We sequenced the MC1R gene in 175 healthy individuals to assess the influence of MC1R on nevus phenotype. We identified that MC1R variant carriers had larger nevi both on the back [p-value = .016, adjusted for multiple parameters (adj. p-value)] and on the upper limbs (adj. p-value = .007). Specifically, we identified a positive association between the "R" MC1R variants and visible vessels in nevi [p-value = .033, corrected using the FDR method for multiple comparisons (corrected p-value)], dots and globules in nevi (corrected p-value = .033), nevi with eccentric hyperpigmentation (corrected p-value = .033), a high degree of freckling (adj. p-value = .019), and an associative trend with presence of blue nevi (corrected p-value = .120). In conclusion, the MC1R gene appears to influence the nevus phenotype.
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http://dx.doi.org/10.1111/pcmr.12646DOI Listing
January 2018

AURKA Overexpression Is Driven by FOXM1 and MAPK/ERK Activation in Melanoma Cells Harboring BRAF or NRAS Mutations: Impact on Melanoma Prognosis and Therapy.

J Invest Dermatol 2017 06 7;137(6):1297-1310. Epub 2017 Feb 7.

IDIBELL (Bellvitge Biomedical Research Institute), Centre d' Oncologia Molecular, Barcelona, Spain. Electronic address:

The cell cycle-related genes AURKA and FOXM1 are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAF mutation. AURKA overexpression may also be driven by increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK/ERK signaling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAF and ERK inhibition results in reduced AURKA transcription and expression. We show a positive correlation between FOXM1 and AURKA expression in three independent cohorts of melanoma patients. FOXM1 silencing decreases expression of AURKA and late cell cycle genes in melanoma cells. We further found that FOXM1 expression levels are significantly higher in tumors carrying the BRAF mutation compared with the wild-type BRAF (BRAF). Accordingly, the knockdown of BRAF also reduces the expression of FOXM1 in BRAF cells. Moreover, Aurora kinase A and FOXM1 inhibition by either genetic knockdown or pharmacologic inhibitors impair melanoma growth and survival both in culture and in vivo, underscoring their therapeutic value for melanoma patients who fail to benefit from BRAF/MEK signaling inhibition.
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http://dx.doi.org/10.1016/j.jid.2017.01.021DOI Listing
June 2017

IRF4 rs12203592 functional variant and melanoma survival.

Int J Cancer 2017 04 6;140(8):1845-1849. Epub 2017 Feb 6.

Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.

Inherited genetic factors may modulate clinical outcome in melanoma. Some low-to-medium risk genes in melanoma susceptibility play a role in melanoma outcome. Our aim was to assess the role of the functional IRF4 SNP rs12203592 in melanoma prognosis in two independent sets (Barcelona, N = 493 and Essen, N = 438). Genotype association analyses showed that the IRF4 rs12203592 T allele increased the risk of dying from melanoma in both sets (Barcelona: odds ratio [OR] = 6.53, 95% CI 1.38-30.87, Adj p = 0.032; Essen: OR = 1.68, 95% CI 1.04-2.72, Adj p = 0.035). Survival analyses only showed significance for the Barcelona set (hazard ratio = 4.58, 95% CI 1.11-18.92, Adj p = 0.036). This SNP was also associated with tumour localization, increasing the risk of developing melanoma in head or neck (OR = 1.79, 95% CI 1.07-2.98, Adj p = 0.032) and protecting from developing melanoma in the trunk (OR = 0.59, 95% CI 0.41-0.85, Adj p = 0.004). These findings suggest for the first time that IRF4 rs12203592 plays a role in the modulation of melanoma outcome and confirms its contribution to the localization of the primary tumour.
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http://dx.doi.org/10.1002/ijc.30605DOI Listing
April 2017

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer's Disease Risk.

J Alzheimers Dis 2017 ;56(3):1065-1074

Dermatology Department, Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain.

Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways.
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http://dx.doi.org/10.3233/JAD-161113DOI Listing
February 2018

The p. R151C Polymorphism in MC1R Gene Modifies the Age of Onset in Spanish Huntington's Disease Patients.

Mol Neurobiol 2017 07 6;54(5):3906-3910. Epub 2016 Dec 6.

Dermatology Department, Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain.

The expansion of CAG repeats (≥36 CAG) in the HTT gene is the only known genetic cause of Huntington's disease (HD) and the main determinant of the course of the disease. The length of the expanded CAG repeats correlates inversely with the age of onset (AOO) but does not completely determine it. We investigated the role of the melanocortin 1 receptor (MC1R) gene as a modifier factor of AOO in 600 HD patients from Spain. We sequenced the entire region of the MC1R gene and analyzed all the nonsynonymous MC1R genetic variants with a minor allele frequency of at least 0.01 in HD patients. The variability in AOO attributable to the CAG repeats and MC1R polymorphisms was evaluated using a multiple linear regression model. We found that the loss-of-function p. R151C MC1R polymorphism has a significant influence on the AOO (P = 0.004; Bonferroni-corrected P = 0.032) which explains 1.42% of the variance in AOO that cannot be accounted for by the expanded CAG repeat. Our results suggest that the MC1R gene could modify the AOO in Spanish HD patients and encourage the evaluation of loss-of-function MC1R polymorphisms in other HD populations with a higher frequency of these MC1R polymorphisms.
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http://dx.doi.org/10.1007/s12035-016-0305-5DOI Listing
July 2017

Genomic Microarray in Fetuses with Early Growth Restriction: A Multicenter Study.

Fetal Diagn Ther 2017 2;42(3):174-180. Epub 2016 Nov 2.

BCNatal, Hospital Clínic de Barcelona, Barcelona, Spain.

Background: Little information is available about the risk of microdeletion and microduplication syndromes in fetal growth restriction (FGR) with a normal karyotype.

Objective: To assess the incremental yield of genomic microarray over conventional karyotyping in fetuses with early growth restriction.

Study Design: Genomic microarray was prospectively performed in fetuses with early growth restriction defined as a fetal weight below the 3rd percentile estimated before 32 weeks of pregnancy, and a normal quantitative fluorescent polymerase chain reaction result. The incremental yield of genomic microarray was defined by the rate of fetuses presenting with a pathogenic copy number variant below 10 Mb.

Results: Among 133 fetuses with early FGR, a 6.8% (95% CI: 2.5-11.0) incremental yield of genomic microarray over karyotyping was observed. This incremental yield was 4.8% (95% CI: 0.2-9.3) in isolated FGR, 10% (95% CI: 0-20.7) in FGR with nonstructural anomalies, and 10.5% (95% CI: 0-24.3) in FGR with structural anomalies.

Conclusion: Our multicenter study reveals that 6.8% of fetuses with early growth restriction present with submicroscopic anomalies after common aneuploidies were excluded. Even when FGR is observed as an isolated finding, genomic microarray analysis should be considered after or instead of karyotyping, due to its 4.8% incremental yield.
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http://dx.doi.org/10.1159/000452217DOI Listing
June 2018

A 92,XXXY Miscarriage Consecutive to a Digynic Triploid Pregnancy.

Cytogenet Genome Res 2016 22;149(4):258-261. Epub 2016 Sep 22.

Servei de Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, Barcelona, Spain.

The patient was referred for prenatal diagnosis due to the sonographic finding of a polymalformed male fetus, and an amniocentesis was performed before termination of pregnancy. The pathological study of the placenta did not show morphological alterations. In her next pregnancy, sonographic examination disclosed a missed abortion with a visible embryo, and a chorionic villi sample was obtained for cytogenetic analysis before evacuation. Macroscopic examination of the villi sample did not reveal molar vesicular appearance. QF-PCR and cytogenetic analyses were performed on amniotic fluid (first pregnancy) and chorionic villi samples (second pregnancy). A 69,XXY and 92,XXXY karyotype was found, respectively. QF-PCR results disclosed 2 maternal and 1 paternal alleles in the first pregnancy (digynic triploidy), and double maternal and double paternal contribution to the tetraploid pregnancy. Among the few reported cases of 92,XXXY tetraploidy, those associated with partial moles show a PPPM genotype (3 paternal and 1 maternal alleles), and the only case with a PPMM genotype was found in a spontaneously aborted fetus similar to our case. We are not aware of other cases with combination of a digynic triploid pregnancy and a tetraploid pregnancy with a PPMM contribution. Our case adds evidence to the influence of the balance between paternal and maternal genomic doses on the phenotype.
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http://dx.doi.org/10.1159/000448827DOI Listing
January 2017

Association Between Confocal Morphologic Classification and Clinical Phenotypes of Multiple Primary and Familial Melanomas.

JAMA Dermatol 2016 10;152(10):1099-1105

Hospital Clinic I Provincial de Barcelona, Universitat de Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain4Centro de Investigación Biomédica en Red en Enfermedades Raras, Barcelona, Spain.

Importance: The improved knowledge of clinical, morphologic, and epidemiologic heterogeneity of melanoma in the context of multiple primary and familial melanomas may improve prevention, diagnosis, and prognosis of melanoma.

Objective: To characterize reflectance confocal microscopy (RCM) morphologic patterns of melanomas in multiple primary and familial melanomas.

Design, Setting, And Participants: In this cross-sectional, retrospective study, patients in a hospital-based referral center were recruited from March 1, 2010, through August 31, 2013; data analysis was conducted from September 1, 2013, through May 31, 2014. Consecutive primary melanomas, documented by dermoscopic and confocal examination, from multiple primary and familial melanomas with known CDKN2A mutational status were studied.

Main Outcomes And Measures: Epidemiologic, genetic, dermoscopic, and histologic data were evaluated according to an RCM morphologic classification: dendritic cell, round cell, dermal nest, combined, and nonclassifiable types.

Results: Fifty-seven melanomas from 50 patients (28 women [56%] and 49 white patients [98%]) were included: 23 dendritic cell (40%), 21 round cell (37%), 2 dermal nests (4%), 2 combined (4%), and 9 nonclassifiable (16%). The median (SD) age of the participants was 53.0 (16.9) years (interquartile range, 41.8-71.2 years), and the median (SD) age at the first melanoma was 46.0 (17.1) years (interquartile range, 35.8-61.5 years). Dendritic cell melanoma was characterized by older age at diagnosis, phototypes 2 and 3, more intense solar exposure, and moderate to severe solar lentigines; it was the most prevalent confocal type in facial lesions and was associated with the lentigo maligna histologic subtype. Round cell melanomas were identified more often in the familial context and in individuals with phototype 1 skin types; RCM features, such as junctional thickening, dense dermal nests, and nucleated cells within papillary dermis, were more frequently found in this subtype. Dermal nest and combined melanoma were associated with the absence of pigmented network on dermoscopy and thicker tumors on histologic analysis. Nonclassifiable type was associated, by RCM, with the absence of pagetoid cells on confocal examination and lower frequency of marked atypia on melanocytes in the basal cell layer; it presented with lower ABCD Total Dermoscopy Scores and RCM scores compared with the other types. CDKN2A mutation carriers may develop any RCM type of melanoma.

Conclusions And Relevance: Different routes to develop melanoma can be identified according to RCM morphologic classification, with dendritic cell melanomas being associated with chronic sun damage and round cell melanoma with early age at onset and phototype 1 in the context of multiple primary and familial melanomas. The morphologic expression of melanomas via dermoscopy and confocal examination varies according to differences in tumor stage and biological behavior.
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http://dx.doi.org/10.1001/jamadermatol.2016.1189DOI Listing
October 2016

Time and tumor type (primary or metastatic) do not influence the detection of BRAF/NRAS mutations in formalin fixed paraffin embedded samples from melanomas.

Clin Chem Lab Med 2016 Nov;54(11):1733-1738

Background: BRAF and NRAS mutation detection is crucial for advanced melanoma treatment. Our aim was to evaluate how different characteristics from formalin-fixed paraffin-embedded (FFPE) samples, age of the block or DNA concentration could influence the success of BRAF and NRAS mutational screening.

Methods: DNA was obtained from 144 FFPE samples (62 primary melanoma, 43 sentinel lymph nodes [SLN] and 39 metastasis). BRAF and NRAS were sequenced by Sanger sequencing.

Results: Complete sequencing results were obtained from 75% (108/144) of the samples, and at least one gene was sequenced in 89% (128/144) of them. BRAF was mutated in 55% (29/53) and NRAS in 11% (5/45) of the primary melanomas sequenced. DNA concentration correlated with the tumor area used for DNA extraction (mm2) (adj p-value<0.01, r=0.73). The age of the block did not affect sequencing success. In 60% of samples kept for more than 10 years, both BRAF and NRAS were successfully sequenced.

Conclusions: Preserving sufficient tumor area in FFPE blocks is important. It is necessary to keep the FFPE blocks, no matter their age, as they are necessary to decide the best treatment for the melanoma patient.
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http://dx.doi.org/10.1515/cclm-2015-1048DOI Listing
November 2016

Reply.

Ann Neurol 2016 May 22;79(5):868. Epub 2016 Mar 22.

Dermatology Department, Melanoma Unit, Hospital Clínic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

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http://dx.doi.org/10.1002/ana.24629DOI Listing
May 2016

Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma.

Genet Med 2016 07 17;18(7):727-36. Epub 2015 Dec 17.

Centro Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.

Purpose: CDKN2A is the main high-risk melanoma-susceptibility gene, but it has been poorly assessed in Latin America. We sought to analyze CDKN2A and MC1R in patients from Latin America with familial and sporadic multiple primary melanoma (SMP) and compare the data with those for patients from Spain to establish bases for melanoma genetic counseling in Latin America.

Methods: CDKN2A and MC1R were sequenced in 186 Latin American patients from Argentina, Brazil, Chile, Mexico, and Uruguay, and in 904 Spanish patients. Clinical and phenotypic data were obtained.

Results: Overall, 24 and 14% of melanoma-prone families in Latin America and Spain, respectively, had mutations in CDKN2A. Latin American families had CDKN2A mutations more frequently (P = 0.014) than Spanish ones. Of patients with SMP, 10% of those from Latin America and 8.5% of those from Spain had mutations in CDKN2A (P = 0.623). The most recurrent CDKN2A mutations were c.-34G>T and p.G101W. Latin American patients had fairer hair (P = 0.016) and skin (P < 0.001) and a higher prevalence of MC1R variants (P = 0.003) compared with Spanish patients.

Conclusion: The inclusion criteria for genetic counseling of melanoma in Latin America may be the same criteria used in Spain, as suggested in areas with low to medium incidence, SMP with at least two melanomas, or families with at least two cases among first- or second-degree relatives.Genet Med 18 7, 727-736.
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http://dx.doi.org/10.1038/gim.2015.160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940430PMC
July 2016

Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations.

JAMA Dermatol 2016 Apr;152(4):405-12

Melanoma Unit, Dermatology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques d'August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain2Centro de Investigación Biomédica en Red en Enfermedades Raras, Valencia, Spain.

Importance: The main high-penetrance melanoma susceptibility gene is CDKN2A, encoding p16INK4A and p14ARF. The gene MITF variant p.E318K also predisposes to melanoma and renal cell carcinoma. To date, the prevalence of MITF p.E318K and its clinical and phenotypical implications has not been previously assessed in a single cohort of Spanish patients with melanoma or in p16INK4A mutation carriers.

Objectives: To evaluate the prevalence of MITF p.E318K in Spanish patients with melanoma and assess the association with clinical and phenotypic features.

Design, Setting, And Participants: A hospital-based, case-control study was conducted at the Melanoma Unit of Hospital Clinic of Barcelona, with MITF p.E318K genotyped in all patients using TaqMan probes. We included 531 patients: 271 patients with multiple primary melanoma (MPM) without mutations affecting p16INK4A (wild-type p16INK4A); 191 probands from melanoma-prone families with a single melanoma diagnosis and without mutations affecting p16INK4A, and 69 probands from different families carrying CDKN2A mutations affecting p16INK4A. A population-based series of 499 age- and sex-matched cancer-free individuals from the Spanish National Bank of DNA were included as controls. Patients were recruited between January 1, 1992, and June 30, 2014; data analysis was conducted from September 1 to November 30, 2014.

Main Outcomes And Measures: The genetic results of the MITF p.E318K variant were correlated with clinical and phenotypic features.

Results: Among the 531 patients, the prevalence of the MITF p.E318K variant was calculated among the different subsets of patients included and was 1.9% (9 of 462) in all melanoma patients with wild-type p16INK4A, 2.6% (7 of 271) in those with MPM, and 2.9% (2 of 69) in the probands of families with p16INK4A mutations. With results reported as odds ratio (95% CI), the MITF p.E318K was associated with an increased melanoma risk (3.3 [1.43-7.43]; P < .01), especially in MPM (4.5 [1.83-11.01]; P < .01) and high nevi count (>200 nevi) (8.4 [2.14-33.19]; P < .01). Two fast-growing melanomas were detected among 2 MITF p.E318K carriers during dermatologic digital follow-up.

Conclusions And Relevance: In addition to melanoma risk, MITF p.E318K is associated with a high nevi count and could play a role in fast-growing melanomas. Testing for MITF p.E318K should not exclude patients with known mutations in p16INK4A. Strict dermatologic surveillance, periodic self-examination, and renal cell carcinoma surveillance should be encouraged in this context.
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http://dx.doi.org/10.1001/jamadermatol.2015.4356DOI Listing
April 2016

Skewed X Inactivation in Women Carrying the FMR1 Premutation and Its Relation with Fragile-X-Associated Tremor/Ataxia Syndrome.

Neurodegener Dis 2016 27;16(3-4):290-2. Epub 2015 Nov 27.

Biochemistry and Molecular Genetics Department, Hospital Clinic, Barcelona, Spain.

Background: Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a late-onset multisystem neurological disorder characterized by intention tremor and cerebellar ataxia.

Objective: We hypothesized that in FMR1 premutation females with FXTAS, a normal X chromosome might more frequently be inactivated; therefore, the aim of this study was to determine the relationship between skewed X chromosome inactivation (XCI) and FXTAS.

Methods: We studied the XCI patterns of cases of FMR1 premutation in 10 women with FXTAS and 21 without FXTAS.

Results: The distribution of XCI patterns in the FXTAS and no-FXTAS groups showed differences regarding the allele presenting severe skewed XCI. In the FXTAS group, all cases preferentially inactivated the non-expanded X chromosome, whereas in the no-FXTAS group, all inactivated the expanded X chromosome. Nevertheless, no significant differences were found on comparing XCI frequencies among FMR1 premutation carriers with and without FXTAS. As expected, we found statistically significant differences in the skewed XCI on comparing FMR1 premutation women and controls.

Conclusion: Although the reduced sample size and blood XCI patterns are two limitations of this study, our results suggest that the skewed XCI of the normal FMR1 allele may be a risk factor for the development of FXTAS. Furthermore, our findings also support the protective effect of the expression of a normal FMR1 allele.
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http://dx.doi.org/10.1159/000441566DOI Listing
December 2016

Update in genetic susceptibility in melanoma.

Ann Transl Med 2015 Sep;3(15):210

1 Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain ; 2 Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Valencia, Spain ; 3 Molecular Biology and Genetics Department, Melanoma Unit, Hospital Clínic de Barcelona, Barcelona, Spain.

Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual.
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http://dx.doi.org/10.3978/j.issn.2305-5839.2015.08.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583600PMC
September 2015

Reply.

Ann Neurol 2016 Jan 12;79(1):161-3. Epub 2015 Dec 12.

Dermatology Department, Melanoma Unit, Hospital Clinic and August Pi i Sunyer Biomedical Research Institute.

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http://dx.doi.org/10.1002/ana.24526DOI Listing
January 2016

Atypical Clinical Presentation of Xeroderma Pigmentosum in a Patient Harboring a Novel Missense Mutation in the XPC Gene: The Importance of Clinical Suspicion.

Dermatology 2015 5;231(3):217-21. Epub 2015 Aug 5.

Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

Background: Xeroderma pigmentosum (XP) is a genodermatosis caused by abnormal DNA repair. XP complementation group C (XPC) is the most frequent type in Mediterranean countries. We describe a case with a novel mutation in the XPC gene.

Case: A healthy Caucasian male patient was diagnosed with multiple primary melanomas. Digital follow-up and molecular studies were carried out.

Results: During digital follow-up 8 more additional melanomas were diagnosed. Molecular studies did not identify mutations in CDKN2A, CDK4 or MITF genes. Two heterozygous mutations in the XPC gene were detected: c.2287delC (p.Leu763Cysfs*4) frameshift and c.2212A>G (p.Thr738Ala) missense mutations.

Conclusion: The p.Thr738Ala missense mutation has not been previously described. Missense mutations in the XPC gene may allow partial functionality that could explain this unusual late onset XP. Atypical clinical presentation of XPC could be misdiagnosed when genetic aberrations allow partial DNA repair capacity.
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http://dx.doi.org/10.1159/000433527DOI Listing
June 2016

Reply: To PMID 25631192.

Ann Neurol 2015 Jul 25;78(1):153-4. Epub 2015 May 25.

Dermatology Department, Melanoma Unit, Hospital Clínic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

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http://dx.doi.org/10.1002/ana.24418DOI Listing
July 2015

Clinical and Histopathological Characteristics between Familial and Sporadic Melanoma in Barcelona, Spain.

J Clin Exp Dermatol Res 2014 Sep;5(5):231

Dermatology Department, Melanoma Unit, Hospital Clínic, IDIBAPS, Barcelona, Spain ; CIBER on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.

Background: About 6 to 14% of melanoma cases occur in a familial setting. Germline mutations in CDKN2A are detected in 20 to 40% of melanoma families.

Objective: To characterise the clinical and histopathological characteristics of familial melanoma thus providing more information to clinicians and contribute to the understanding of the genetic-environment interplay in the pathogenesis of melanoma.

Methods: Clinical, histological and immunohistochemical characteristics of 62 familial melanomas were compared with 127 sporadic melanomas.

Results: variables associated with familial melanoma were earlier age at diagnosis (OR 1.036; 95% CI 1.017-1.055), lower Breslow thickness (OR 1.288; 95% CI 1.013-1.683) and in situ melanomas (OR 2.645; 95% CI 1.211-5.778). Variables associated with CDKN2A mutation carriers were earlier age at diagnosis (OR 1.060; 95% CI 1.016-1.105), in situ melanomas (OR 6.961; 95% CI 1.895-25.567), the presence of multiple melanomas (OR 8.920; 95% CI 2.399-33.166) and the immunopositivity of the tumours for cytoplasmic survivin (OR 9.072; 95% CI 1.025-85.010).

Conclusions: Familial melanoma was significantly associated with the earlier age of onset, lower Breslow thickness and with a higher number of in situ melanomas; and also carriers of CDKN2A mutations were associated with a higher risk of multiple melanomas and cytoplasmic survivin immunostaining.
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http://dx.doi.org/10.4172/2155-9554.1000231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399806PMC
September 2014

Multiple BRAF Wild-Type Melanomas During Dabrafenib Treatment for Metastatic BRAF-Mutant Melanoma.

JAMA Dermatol 2015 May;151(5):544-8

Melanoma Unit, Department of Dermatology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain2Centro de Investigación Biomédica en Red en Enfermedades Raras, Instituto de Salud Carlos III, B.

Importance: BRAF inhibitors have become the standard of care in metastatic BRAF-mutant melanomas. Compared with chemotherapies, BRAF inhibitors improve overall and disease-free survival and speed the recovery of symptomatic patients with metastatic disease. The most worrisome finding is the possible development of resistance to new malignant tumors.

Observations: A patient in her 30s developed massive BRAFV600E melanoma metastasis during her 30th week of pregnancy. After emergency cesarean delivery, oral dabrafenib treatment was initiated, and a partial radiologic response was confirmed within 1 month. At dermatologic digital follow-up aided by confocal microscopy 8 weeks after initiation of dabrafenib treatment, 4 melanomas were detected. Unfortunately, within the next month, the melanoma rapidly progressed. The 4 new melanomas were wild-type BRAFmelanomas, whereas the new metastasis carried a different BRAF mutation (S467L).

Conclusions And Relevance: Cutaneous malignant tumors are the most frequent adverse events of BRAF inhibitors; therefore, strict dermatologic surveillance in a referral center aided by digital follow-up is mandatory, especially when multiple nevi are present and these drugs are used in an adjuvant setting. In view of our findings, the pathogenesis of the development of new melanomas seems to be different from therapy resistance. Whether paradoxical RAF activation could explain these BRAF wild-type secondary malignant tumors is still unknown.
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http://dx.doi.org/10.1001/jamadermatol.2014.4115DOI Listing
May 2015

The MC1R melanoma risk variant p.R160W is associated with Parkinson disease.

Ann Neurol 2015 May 13;77(5):889-94. Epub 2015 Mar 13.

Dermatology, Department, Melanoma Unit, Hospital Clínic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Center for Biomedical Network Research on Rare Diseases (CIBERER), Carlos III Health Institute (ISCIII).

Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population.
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http://dx.doi.org/10.1002/ana.24373DOI Listing
May 2015

TERT gene amplification is associated with poor outcome in acral lentiginous melanoma.

J Am Acad Dermatol 2014 Oct;71(4):839-41

Department of Pathology, Hospital Clínic, IDIBAPS, University of Barcelona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2014.05.035DOI Listing
October 2014