Polymorphisms in autophagy genes are genetic susceptibility factors in glioblastoma development.

BACKGROUND: Glioblastoma is the most aggressive and common malignant primary brain tumor in adults. Many genetic, epigenetic and genomic mutations have been identified in this tumor, but no driving cause has been identified yet for glioblastoma pathogenesis. Autophagy has proved to be deregulated in different diseases such as cancer where it has a dual role, acting as a tumor suppression mechanism during the first steps of tumor development and promoting cancer cells survival in stablished tumors. METHODS: Here, we aimed to assess the potential association between several candidate polymorphisms in autophagy genes (ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183, ATG5 rs2245214, NOD2 rs2066844 and rs2066845) and glioblastoma susceptibility. RESULTS: Our results showed a significant correlation between ATG2B rs3759601, ATG10 rs1864183 and NOD2 rs2066844 variants and higher risk to suffer glioblastoma. In addition, the relationship between the different clinical features listed in glioblastoma patients and candidate gene polymorphisms was also investigated, finding that ATG10 rs1864183 might be a promising prognosis factor for this tumor. CONCLUSIONS: This is the first report evaluating the role of different variants in autophagy genes in modulating glioblastoma risk and our results emphasize the importance of autophagy in glioblastoma development.

Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: a retrospective case series.

BACKGROUND: X-linked recessive ichthyosis (XLI) is a relatively common type of ichthyosis caused by a deficiency in the steroid sulfatase (STS) enzyme. It is the only type of ichthyosis that can be both syndromic and nonsyndromic. Typical clinical features include dark-brown scale of variable size favouring the extensor surfaces of the extremities. OBJECTIVES: To characterize clinically nonsyndromic XLI, with a particular focus on extracutaneous manifestations. METHODS: This was a multicentre retrospective review of clinical findings from a case series of patients with a clinical and genetic diagnosis of XLI. RESULTS: We identified 30 patients with XLI belonging to 25 different families carrying a deletion in the STS locus. All patients had dark scales of variable size on the extensor surfaces of the extremities. Lack of flexural involvement and pruritus were common but inconsistent findings, whereas palmoplantar hyperlinearity was absent in all but one patient. A history of orchiopexy was present in 10% and thus was more common than expected vs. the general population (3%). Neurological disorders including epilepsy (13%) and attention deficit hyperactivity disorder (ADHD; 30%) were over-represented in patients with XLI. CONCLUSIONS: This was a retrospective study with a limited number of patients. In the absence of confirmatory genetic testing and family history of the disease, dark-brown scale of the extensor surfaces and the absence of palmoplantar hyperlinearity appear to be the most reliable clinical findings supporting a diagnosis of XLI. Dermatologists should be aware of the high prevalence of ADHD and epilepsy in patients with nonsyndromic XLI.

Análisis de la relación entre polimorfismos en regiones diana de micro-ARN y la enfermedad hepática alcohólica / Analysis of the relationship between interleukin polymorphisms within miRNA-binding regions and alcoholic liver disease

Introducción. El consumo de alcohol induce una respuesta inflamatoria mediada por los receptores de tipo Toll4 (TLR4) y el factor nuclear (NF)-?B, originando daño orgánico. Algunos micro-ARN (miARN) modulan la respuesta inflamatoria mediante retroalimentación negativa de mediadores como las interleucinas (IL). Así pues, polimorfismos en los genes de algunas IL localizados cerca de las dianas de los miARN podrían modificar el riesgo de daño orgánico inducido por el alcohol. Este estudio analizó la posible relación entre el alcoholismo o la enfermedad hepática alcohólica (EHA) y los polimorfismos IL12B 2124 G>T (rs1368439), IL16 5000 C>T (rs1131445), IL1R1 3114 C>T (rs3917328) y NFKB1 3400 A>G (rs4648143). Pacientes y métodos. Se incluyeron 301 pacientes alcohólicos varones y 156 voluntarios sanos varones. Los polimorfismos fueron genotipados mediante discriminación alélica utilizando el sistema de PCR TaqMan(R). Se compararon las frecuencias alélicas y genotípicas entre grupos y se realizó un análisis de regresión logística para dilucidar el modelo de herencia. Resultados. El análisis del polimorfismo de IL1R1 (rs3917328) mostró que la proporción de portadores del aleloT (genotipos CT y TT) era mayor en los controles sanos (9,7%) que en pacientes alcohólicos (6,5%, p=0,042). Sin embargo el análisis de regresión logística no mostró resultados significativos. No se encontraron diferencias significativas entre grupos con respecto al resto de polimorfismos estudiados. Conclusiones. Nuestro estudio describe, por primera vez, las frecuencias esperadas de polimorfismos en regiones diana de miARN en pacientes alcohólicos con y sin EHA. Serán necesarios nuevos estudios para aclarar la relevancia de estos polimorfismos en el desarrollo de alcoholismo o EHA

Introduction. Alcohol consumption promotes inflammation through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-?B pathway, leading to organic damage. Some micro-RNA (miRNA) molecules modulate this inflammatory response by downregulating TLR4/NF-?B pathway mediators, like interleukins (ILs). Thus, polymorphisms within IL genes located near miRNA binding sites could modify the risk of ethanol-induced damage. The present study analyzed potential relationships between alcoholism or alcoholic liver disease (ALD) and IL12B 2124 G>T (rs1368439), IL16 5000 C>T (rs1131445), IL1R1 3114 C>T (rs3917328), and NFKB1 3400 A>G (rs4648143) polymorphisms. Patients and methods. The study included 301 male alcoholic patients and 156 male healthy volunteers. Polymorphisms were genotyped using TaqMan(R) PCR assays for allelic discrimination. Allele and genotype frequencies were compared between groups. Logistic regression analysis was performed to analyze the inheritance model. Results. Analysis of the IL1R1 (rs3917328) polymorphism showed that the proportion of alleleT carriers (CT and TT genotypes) was higher in healthy controls (9.7%) than in alcoholic patients (6.5%; P=.042). However, multivariable logistic regression analyses did not yield a significant result. No differences between groups were found for other analyzed polymorphisms. Conclusions. Our study describes, for the first time, the expected frequencies of certain polymorphisms within miRNA-binding sites in alcoholic patients with and without ALD. Further studies should be developed to clarify the potential relevance of these polymorphisms in alcoholism and ALD development

Síndrome de Gorlin / Gorlin Syndrome

El síndrome de Gorlin es una enfermedad infrecuente de herencia autosómica dominante producida por mutaciones en genes de la vía de señalización Sonic Hedgehog, entre los que destaca PTCH1. Se caracteriza por el desarrollo de múltiples carcinomas basocelulares en edades tempranas, que pueden ir asociados a otras manifestaciones cutáneas como pits palmoplantares, o a manifestaciones extracutáneas, entre las que destacan los queratoquistes odontogénicos y el meduloblastoma. El papel del dermatólogo es importante en la sospecha de este síndrome, pero suele ser necesario un equipo multidisciplinar en el diagnóstico, seguimiento y en el tratamiento de estos pacientes. El tratamiento dermatológico puede ser complicado debido al alto número de carcinomas basocelulares y a su extensión. En los últimos años se han desarrollado nuevos fármacos que inhiben la vía Sonic Hedgehog y parecen prometedores para estos pacientes, aunque su eficacia está limitada por los efectos secundarios y la creación de resistencias

Gorlin syndrome is a rare autosomal dominant disease caused by mutations in the sonic hedgehog signaling pathway. Of particular importance is the PTCH1 gene. The disease is characterized by the development of multiple basal cell carcinomas at young ages. These tumors may present with other skin manifestations such as palmoplantar pits and with extracutaneous manifestations such as odontogenic keratocysts and medulloblastoma. Although the dermatologist may be key for recognizing clinical suspicion of the syndrome, a multidisciplinary team is usually necessary for diagnosis, treatment, and follow-up. Skin treatment may be complicated due to the large number of basal cell carcinomas and the extent of involvement. In recent years, new drugs that inhibit targets in the sonic hedgehog pathway have been developed. Although these agents appear promising options for patients with Gorlin syndrome, their efficacy is limited by adverse effects and the development of resistance

Analysis of the relationship between interleukin polymorphisms within miRNA-binding regions and alcoholic liver disease. / Análisis de la relación entre polimorfismos en regiones diana de micro-ARN y la enfermedad hepática alcohólica.

INTRODUCTION: Alcohol consumption promotes inflammation through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-?B pathway, leading to organic damage. Some micro-RNA (miRNA) molecules modulate this inflammatory response by downregulating TLR4/NF-?B pathway mediators, like interleukins (ILs). Thus, polymorphisms within IL genes located near miRNA binding sites could modify the risk of ethanol-induced damage. The present study analyzed potential relationships between alcoholism or alcoholic liver disease (ALD) and IL12B 2124 G>T (rs1368439), IL16 5000 C>T (rs1131445), IL1R1 3114 C>T (rs3917328), and NFKB1 3400 A>G (rs4648143) polymorphisms. PATIENTS AND METHODS: The study included 301 male alcoholic patients and 156 male healthy volunteers. Polymorphisms were genotyped using TaqMan® PCR assays for allelic discrimination. Allele and genotype frequencies were compared between groups. Logistic regression analysis was performed to analyze the inheritance model. RESULTS: Analysis of the IL1R1 (rs3917328) polymorphism showed that the proportion of alleleT carriers (CT and TT genotypes) was higher in healthy controls (9.7%) than in alcoholic patients (6.5%; P=.042). However, multivariable logistic regression analyses did not yield a significant result. No differences between groups were found for other analyzed polymorphisms. CONCLUSIONS: Our study describes, for the first time, the expected frequencies of certain polymorphisms within miRNA-binding sites in alcoholic patients with and without ALD. Further studies should be developed to clarify the potential relevance of these polymorphisms in alcoholism and ALD development.

Gorlin Syndrome. / Síndrome de Gorlin.

Gorlin syndrome is a rare autosomal dominant disease caused by mutations in the sonic hedgehog signaling pathway. Of particular importance is the PTCH1 gene. The disease is characterized by the development of multiple basal cell carcinomas at young ages. These tumors may present with other skin manifestations such as palmoplantar pits and with extracutaneous manifestations such as odontogenic keratocysts and medulloblastoma. Although the dermatologist may be key for recognizing clinical suspicion of the syndrome, a multidisciplinary team is usually necessary for diagnosis, treatment, and follow-up. Skin treatment may be complicated due to the large number of basal cell carcinomas and the extent of involvement. In recent years, new drugs that inhibit targets in the sonic hedgehog pathway have been developed. Although these agents appear promising options for patients with Gorlin syndrome, their efficacy is limited by adverse effects and the development of resistance.

Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome.

BACKGROUND: Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein, which is unable to suppress Smoothened protein and continuously activates the downstream pathway. OBJECTIVES: We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain. METHODS: Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools. RESULTS: We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon-intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype-phenotype correlation, as seen in relatives carrying similar mutations. CONCLUSIONS: This study contributes to increase the pool of clinical manifestations of NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying factors, genetic, epigenetic or environmental.

Familial seborrhoeic keratosis associated with multiple 'pure reticulated acanthomas' and infundibulocystic basal cell carcinomas.

BACKGROUND: A variety of genodermatoses with multiple cutaneous tumours and germline genetic alterations, such as PTCH1 mutations, have been described. Other cutaneous syndromes have been associated with somatic gene mutations, such as FGFR3 in familial seborrhoeic keratosis. OBJECTIVES: To describe the clinical, dermoscopic and histopathological features of multiple cutaneous lesions, mostly infundibulocystic basal cell carcinomas (ICBCCs) and pure reticulated acanthomas, present in a family affected by familial seborrhoeic keratosis. In addition, we tested for possible germline alterations in FGFR3 and PTCH1. METHODS: Ten members of one family were clinically examined and 92 skin biopsy specimens were evaluated. Blood samples from six individuals were analysed for FGFR3 and PTCH1 germline alterations. We reviewed the literature concerning genetic FGFR3 alterations in seborrhoeic keratosis. RESULTS: Individuals of all generations affected by familial seborrhoeic keratosis also presented other skin tumours that corresponded histologically to reticulated acanthomas without apocrine or sebaceous differentiation, as well as ICBCCs. In addition, two novel germline variants, p.Pro449Ser (c.1345C>T) in FGFR3 and p.Pro725Ser (c.2173C>T) in exon 14 of PTCH1 were identified in five participants. CONCLUSIONS: We characterize for the first time the clinical, dermoscopic and histopathological features of multiple reticulated acanthomas without apocrine or sebaceous differentiation, for which we propose the term 'pure reticulated acanthoma', and ICBCCs associated with familial seborrhoeic keratosis. We identified FGFR3 and PTCH1 germline polymorphisms whose influence in the development of reticulated acanthomas is unknown.

Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population.

OBJECTIVES: To examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab. MATERIAL AND METHODS: Multicenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: Acneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119-0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114-0.622]). CONCLUSION: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.

Association of IL1Β (-511 A/C) and IL6 (-174 G > C) polymorphisms with higher disease activity and clinical pattern of psoriatic arthritis.

The objective of this study is to analyze whether IL1ß (-511G > A) and IL6 (-174 G > C) polymorphisms are associated with inflammatory activity, radiographic damage or clinical pattern of psoriatic arthritis (PsA). One hundred twenty-five patients classified as PsA according to the Classification of Psoriatic Arthritis (CASPAR) criteria were included. Patients were stratified according to their clinical pattern at inclusion as peripheral, axial, or mixed involvement. Disease activity in peripheral or mixed forms was measured using the number of swollen and tender joints, pain analog visual scale, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and disease activity score 28 (DAS28). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used for axial and mixed forms, as were pain visual analog scale, ESR and CRP. Radiographic damage was evaluated using a modified Sharp score and modified stoke ankylosing spondylitis spinal score (SASSSm). The polymorphisms for the promoter region of IL1ß (-511 G/A) and IL-6 (-174 G/C) were analyzed. The G allele of IL1B (-511G/A) polymorphism was associated with higher peripheral joint disease activity (OR 3.13; p < 0.0004; CI 95 % 1.43-6.82, p (corrected) <0.008), while the G allele of the IL6 (174G > C) polymorphism presented a strong trend to be associated with peripheral forms (70.86 %) (OR 1.89; p < 0.03; CI 95 % 1.06-3.39, p-corrected 0.05). In addition, this allele showed a lower association with HLA-B27 (15.78 %) compared with C allele (28.57 %) (OR 0.469; p = 0.02; CI 95 % 0.238-0.923, p-corrected 0.03). This study suggests that the G allele polymorphism of IL1B (-511 A/C) is associated with higher peripheral joint disease activity. On the other hand, the IL6 (-174 G/C) polymorphism showed a strong trend to be associated with the peripheral pattern of PsA.

Relación de la presencia de polimorfismos de CFH, HTRA1, ARMS2,VEGF-A y VEGF-R con la aparición de los subtipos de degeneración macular asociada a la edad / The presence of CFH, HTRA1, ARMS2, VEGF-A and VEGF-R and the appearance of age-related macular degeneration sub-types

OBJETIVO: Demostrar la influencia genética en el desarrollo de los distintos tipos de degeneración macular asociada a la edad (DMAE) analizando las distribuciones genotípicas de polimorfismos de CFH,ARMS2, HTRA1, VEGF-A y VEGF-R en pacientes con DMAE exudativa y DMAE atrófica. MÉTODO: Se toman 101 pacientes diagnosticados de DMAE (74 exudativa y 27 atrófica) según las normas del sistema internacional de clasificación Wisconsin. Analizamos los polimorfismos rs1410996 del genCFH, rs10940923 de ARMA2, rs833061 y rs699947 de VEGF-A y rs2071559 de VEGF-R mediante PCR a tiempo real con sondas Taqman y el HTRA1 rs112000638 mediante digestión con endonucleasas de restricción. Analizamos la distribución genotípica de los distintos polimorfismos en nuestro grupo de pacientes con DMAE exudativa y los que presentan DMAE atrófica y comparamos los resultados para cada uno de los genes a estudio. RESULTADOS: No encontramos diferencias estadísticamente significativas (p > 0,05) en la distribución genotípica de los distintos polimorfismos entre pacientes con DMAE atrófica y pacientes con DMAE exudativa en nuestra población, si bien los genotipos considerados «de riesgo» por otros estudios tienden a aparecer de forma más frecuente en la DMAE exudativa, a pesar de no obtener diferencias significativas. CONCLUSIONES: Las variantes alélicas de los genes CFH, ARMS2, HTRA1, VEGF-A o VEGF-R no se asocian con los diferentes subtipos de DMAE, lo que indica que, aunque parece que están implicados en la susceptibilidad a padecer la enfermedad, no están implicados en el desarrollo de las variantes clínicas en nuestra población. Son necesarios nuevos estudios en diferentes poblaciones y con un mayor tamaño muestral para confirmar estos resultados

OBJECTIVE: To demonstrate the genetic influence in the onset of the different age-related macular disease (AMD) subtypes by analysing the genotype distribution of CFH, ARMS2, HTRA1, VEGF-A and VEGF-Rpolymorphisms in patients with neovascular and atrophic AMD. MATERIALS AND METHODS: The study was conducted on 101 consecutive patients with AMD diagnosis (74 exudative, 27 atrophic) following Wisconsin international classification criteria. The CFH rs1410996, ARMS2 rs10940923,VEGF-A rs833061, rs699947, and VEGF-R rs2071559 polymorphisms were analysed using real time PCR with taqman probes, and HTRA1 rs112000638 using restriction endonucleases digestion. A study was made of the genotype distribution of the different polymorphisms in our group of patients with neovascular AMD and those with the atrophic type, and a comparison was made of the results for each one of the genes studied. RESULTS: No statistically significant differences (P>.05) were found in the genotype distribution of the different polymorphisms between patients with neovascular AMD and patients with atrophic AMD in our population, although the 'risk' genotypes tended to appear more frequently in patients with neovascular AMD, despite the lack of statistical significance. CONCLUSIONS: Allelic variants of CFH, ARMS2, HTRA1, VEGF-A or VEGF-R genes are not associated with the different AMD subtypes. This suggests that, although the polymorphisms seem to be associated with the disease susceptibility, they are not involved in the onset of the different clinical variants of AMD. Further studies in different populations, and with a larger cohort of patients, are needed to confirm these results

The presence of CFH, HTRA1, ARMS2, VEGF-A and VEGF-R and the appearance of age-related macular degeneration sub-types.

OBJECTIVE: To demonstrate the genetic influence in the onset of the different age-related macular disease (AMD) subtypes by analysing the genotype distribution of CFH, ARMS2, HTRA1, VEGF-A and VEGF-R polymorphisms in patients with neovascular and atrophic AMD. MATERIALS AND METHODS: The study was conducted on 101 consecutive patients with AMD diagnosis (74 exudative, 27 atrophic) following Wisconsin international classification criteria. The CFH rs1410996, ARMS2 rs10940923, VEGF-A rs833061, rs699947, and VEGF-R rs2071559 polymorphisms were analysed using real time PCR with taqman probes, and HTRA1 rs112000638 using restriction endonucleases digestion. A study was made of the genotype distribution of the different polymorphisms in our group of patients with neovascular AMD and those with the atrophic type, and a comparison was made of the results for each one of the genes studied. RESULTS: No statistically significant differences (P>.05) were found in the genotype distribution of the different polymorphisms between patients with neovascular AMD and patients with atrophic AMD in our population, although the "risk" genotypes tended to appear more frequently in patients with neovascular AMD, despite the lack of statistical significance. CONCLUSIONS: Allelic variants of CFH, ARMS2, HTRA1, VEGF-A or VEGF-R genes are not associated with the different AMD subtypes. This suggests that, although the polymorphisms seem to be associated with the disease susceptibility, they are not involved in the onset of the different clinical variants of AMD. Further studies in different populations, and with a larger cohort of patients, are needed to confirm these results.

The role of the TERC-63G>A and TERT-1327C>T telomerase polymorphisms in the study of men with acute coronary syndrome.

AIM: Telomerase is a ribonucleoprotein that maintains telomere length. Telomeres and telomerase are involved in cellular ageing and have been connected to some ageing related diseases, like cardiovascular disease. Telomerase dysfunction could be the main underlying mechanism in this connection but this point is still unclear. The aim of this article is to investigate the possible influence of cellular ageing, measured by two telomerase polymorphisms, TERC-63G>A (rs2293607) and TERT-1327C>T (rs2735940), on the whole spectrum of acute coronary artery disease (CAD). METHODS: We studied 150 middle aged men admitted for an acute coronary syndrome (ACS). Cardiovascular risk factors prevalence was collected at admission. Severity variables analyzed were Killip class and number of vessels affected. Telomerase polymorphisms were studied by real time PCR in DNA samples extracted from peripheral blood leukocytes. Clinical follow-up had been developed for more than 600 days and a prognostic combined event was defined. RESULTS: C allele of TERT polymorphism was more prevalent among hypertensive patients (OR: 3.19; 95% CI: 1.37-7.42; P=0.006). None of polymorphisms showed any prognostic value or relation to CAD severity. CONCLUSION: Telomerase dysfunction could be involved in hypertension prevalence. This finding could support new screening strategies in high risk population. The two telomerase polymorphisms analyzed did not show any prognostic value or connection to CAD severity. However, further studies are required to determine the molecular mechanisms responsible for cellular ageing in ACS.

Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis.

BACKGROUND: Several studies have reported an association between alcoholic liver cirrhosis (ALC) or other forms of alcoholic liver disease (ALD) and the genetic variant rs738409 (C>G) in adiponutrin/patatin-like phospholipase domain-containing 3 gene (PNPLA3). AIM: To evaluate the influence of this variant on ALC and other forms of ALD. METHODS: We performed a systematic review of previous studies on the relationship between rs738409 of PNPLA3 and ALD and meta-analysis was conducted in a random-effects model. Calculations of the odds ratios (ORs) and their confidence intervals (CIs), tests for heterogeneity and sensitivity analyses were performed. RESULTS: Database search identified 11 previous studies available for inclusion with a total of 3495 patients with ALD (2087 with ALC) and 5038 controls (4007 healthy subjects and 1031 alcoholics without ALD). Patients with ALC compared to controls had a significantly higher prevalence of the G allele when comparing GG vs. CC (OR 4.30, 95% CI 3.25-5.69; P < 0.00001) or GC vs. CC genotypes (GC vs. CC: OR 1.91, 95% CI 1.67-2.17) or under a recessive or dominant model. Similar results were found when comparing separately patients with ALC vs. alcoholics without ALD or healthy subjects. An association of the G allele with ALD emerged when comparing ALD patients vs. alcoholics without ALD and/or healthy subjects although moderate to large heterogeneity was observed. Our data suggested an additive genetic model for this variant in ALD. CONCLUSION: Our meta-analysis shows that the rs738409 variant of PNPLA3 is clearly associated with alcoholic liver cirrhosis.

Early-onset acral basal cell carcinomas in Gorlin syndrome.

Two patients are reported in whom early-onset, distal papules with a histopathological diagnosis of basal cell carcinoma were the first manifestation of Gorlin syndrome (GS). These lesions showed no progression and remained stable through follow-up. Two different PTCH1 gene mutations were detected in the two patients, and thus a phenotype-genotype correlation of this manifestation of GS was not possible.