Matías Mayor

Mondor's disease

Abstract

Genetic variants in PARP1 (rs3219090) and IRF4 (rs12203592) genes associated with melanoma susceptibility in a Spanish population

BackgroundFew high penetrance genes are known in Malignant Melanoma (MM), however, the involvement of low-penetrance genes such as MC1R, OCA2, ASIP, SLC45A2 and TYR has been observed. Lately, genome-wide association studies (GWAS) have been the ideal strategy to identify new common, low-penetrance susceptibility loci. In this case–control study, we try to validate in our population nine melanoma associated markers selected from published GWAS in melanoma predisposition.MethodsWe genotyped the 9 markers corresponding to 8 genes (PARP1, MX2, ATM, CCND1, NADSYN1, CASP8, IRF4 and CYP2R1) in 566 cases and 347 controls from a Spanish population using KASPar probes. Genotypes were analyzed by logistic regression and adjusted by phenotypic characteristics.ResultsWe confirm the protective role in MM of the rs3219090 located on the PARP1 gene (p-value 0.027). Additionally, this SNP was also associated with eye color (p-value 0.002). A second polymorphism, rs12203592, located on the IRF4 gene was associated with protection to develop MM for the dominant model (p-value 0.037). We have also observed an association of this SNP with both lentigines (p-value 0.014) and light eye color (p-value 3.76 × 10-4). Furthermore, we detected a novel association with rs1485993, located on the CCND1 gene, and dark eye color (p-value 4.96 × 10-4). Finally, rs1801516, located on the ATM gene, showed a trend towards a protective role in MM similar to the one firstly described in a GWAS study.ConclusionsTo our knowledge, this is the first time that these SNPs have been associated with MM in a Spanish population. We confirmed the proposed role of rs3219090, located on the PARP1 gene, and rs12203592, located on the IRF4 gene, as protective to MM along the same lines as have previous genome-wide associated works. Finally, we have seen associations between IRF4, PARP1, and CCND1 and phenotypic characteristics, confirming previous results for the IRF4 gene and presenting novel data for the last two, suggesting that pigmentation characteristics correlated with eye color are potential mediators between PARP1 and MM protection.

A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.

Long telomere length and a TERT-CLPTM1 locus polymorphism association with melanoma risk.

Telomere length has been associated with the development of cancer. Studies have shown that shorter telomere length may be related to a decreased risk of cutaneous melanoma. Furthermore, deregulation of the telomere-maintaining gene complexes, has been related to this oncogenic process. Some variants in these genes seem to be correlated with a change in telomerase expression. We examined the effect of 10 single nucleotide polymorphisms (SNPs) in the TERT gene (encoding telomerase), one SNP in the related TERT-CLPTM1L locus and one SNP in the TRF1 gene with telomere length, and its influence on melanoma risk in 970 Spanish cases and 733 Spanish controls. Genotypes were determined using KASP technology, and telomere length was measured by quantitative polymerase chain reaction (PCR) on DNA extracted from peripheral blood leucocytes. Our results demonstrate that shorter telomere length is associated with a decreased risk of melanoma in our population (global p-value, 2.69×10(-11)), which may be caused by a diminution of proliferative potential of nevi (melanoma precursor cells). We also obtained significant results when we tested the association between rs401681 variant (TERT-CLPTM1L locus) with melanoma risk (Odds ratio, OR; 95% confidence interval, CI=1.24 (1.08-1.43); p-value, 3×10(-3)). This is the largest telomere-related study undertaken in a Spanish population to date. Furthermore, this study represents a comprehensive analysis of some of the most relevant telomere pathway genes in relation to cutaneous melanoma susceptibility.

Enfermedad de Fox-Fordyce

Fox-Fordyce disease is an infrequent inflammatory disorder characterized by the appearance of pruritic papules with follicular distribution, localized in areas where apocrine glands are present. Its etiopathogenesis is not clearly known, and it involves the obstruction of the apocrine excretory duct as an early phenomenon in the process. We present a case of histologically confirmed Fox-Fordyce disease with high clinical expressivity in a 16-year-old female.

Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition.

Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high‐risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta‐analysis (3940 melanoma cases and 3620 controls) with two‐side p values of 0.002, (OR = 0.86) and 4.07 × 10−10 (OR = 0.80), respectively. Exome sequencing revealed a non‐synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma.

Carcinoma sebáceo extraocular de presentación atípica

Resumen —El carcinoma sebaceo es un tumor cutaneo maligno poco frecuente. Aparece en el 75 % de los casos en localizacion oculopalpebral, rica en varios tipos de glandulas sebaceas. La cabeza y cuello son las regiones extraoculares donde se han descrito con mayor frecuencia. Su curso clinico es agresivo y son habituales las recurrencias locales y las metastasis a distancia. Se presenta un caso de una mujer de 79 anos que fue diagnosticada de un carcinoma sebaceo extraocular en mejilla derecha, varias hiperplasias sebaceas y un carcinoma intraepidermico con diferenciacion sebacea. Tras realizar una completa evaluacion de historia familiar y personal de la paciente se descarto la asociacion con el sindrome de Muir-Torre.

Tratamiento tópico de las metástasis cutáneas de melanoma con imiquimod

Resumen El tratamiento de las metastasis cutaneas de melanoma puede ser dificil en muchos casos debido a la edad de los pacientes, asi como al numero, tamano y localizacion de las lesiones. Se presenta el caso de un varon de 82 anos con metastasis cutaneas de melanoma en el cuero cabelludo que respondieron satisfactoriamente al tratamiento con imiquimod al 5% en crema. El imiquimod es un inmunomodulador de uso topico con actividad antiviral y antineoplasica. El presente caso, junto con otros recientemente publicados, apoya la utilidad de este tratamiento en casos seleccionados de metastasis cutaneas de melanoma, al menos con un fin paliativo.The treatment of skin metastases of melanoma can be difficult in many cases because of the patients age, as well as the number, size and location of the lesions. We present the case of an 82-year-old male with melanoma skin metastases on the scalp, which responded satisfactorily to treatment with 5 % imiquimod cream. Imiquimod is a topical immunomodulator with antiviral and antineoplastic action. This case, along with others that have recently been published, supports the usefulness of this treatment in selected cases of melanoma skin metastases, at least for palliative purposes.

ERYTHEMA ELEVATUM DIUTINUM AFTER LIVER TRANSPLANTATION: DISAPPEARANCE OF THE LESIONS ASSOCIATED WITH A REDUCTION IN CYCLOSPORIN DOSAGE

When Drs. Esterly and Enjolras talk about hemangiomas, they usually mean the problematic ones. When I talk about hemangiomas, I mainly mean the “harmless” superficial ones, and, in this group, mainly the singular elevated hemangiomas with a regular circumference, because they represent 80% of all hemangiomas (in my opinion). These hemangiomas are mostly harmless for us doctors, but are they really that harmless for the children and their parents? They are very annoying when located in the facial area (54%), and they tend to ulcerate when located in the anal-genital area (4%). If we have a therapy at hand which takes 10 seconds, can be done without anesthesia, and does not have any side effects, why should we not help these children and their parents? In 875 cases which were treated by contact surgery, I have only seen the development of scars in three cases, and all three cases did not belong to the group of singular elevated hemangioma with a regular circumference, but were telangiectatic patches. If treatment were necessary at all, they should have been treated by pulsed dye laser. Treating singular elevated hemangiomas with a regular circumference by contact surgery, especially when they are still small, is relatively easy. It is neither spectacular nor life saving, but it saves the parents and children a lot of grief. Of course, it has to be done properly. That means not using a spray (sprays often cause ulcerations) but using a metal stick which is cooled by liquid nitrogen until it has reached a temperature of -196°C. Contact surgery does not need to be done in a famous center, which is probably one of the reasons why the big names are not very interested. And rightly so, because this leaves more time for them to care for the rare, complicated, and serious cases. But this does not mean that therapy for the overwhelming number of “harmless” hemangiomas should be neglected.

Severe cutaneous reaction due to terazosin

A 56-year-old white man consulted us with a generalised rash that had occurred 3 days after being started on terazosin 2 mg/day for benign prostatic hyperplasia. His medical and family history was unremarkable, and he had not taken any other medication. He had mild fever and asthenia, and pruritus was intense. We saw a widespread eruption of scaling erythematous plaques with a violaceous hue on the trunk (figure) and extremities, affecting his palms and soles but sparing the mucous membranes. The lesions had sharp borders and covered almost the entire body surface, with patches of normal skin among them. We noted non-specific inguinal lymphadenopathy, but the remainder of clinical examination was normal. Haematological and biochemical parameters, including liver-function tests, were normal, except for mild leucocytosis (leucocytes 14·4 10/L, eosinophils 1·4 10/L) and a slightly raised erythrocyte sedimentation rate (25 mm/h). Serological tests for antinuclear antibodies, rheumatoid factor, syphilis, hepatitis B and C, and EpsteinBarr virus were all negative. Histopathological assessment of a skin biopsy sample showed a pattern suggestive of a drug reaction, consisting of subtle basal spongiosis and mild lymphocytic exocytosis, with some apoptotic keratinocytes in the basal epidermal layer. In addition, a mild perivascular lymphocytic infiltrate with scant eosinophils was present in the upper dermis. Terazosin was stopped, and treatment with oral methylprednisolone (40 mg/day) and emollients resulted in complete recovery in 2 weeks. Terazosin is a long-acting -1 selective blocking agent that was used originally for treatment of hypertension. Multicentre placebo-controlled studies have reported its efficacy in benign prostatic hypertrophy. The rare and usually mild adverse effects related to the drug’s pharmacological action are dose-related and include headache, dizziness, and asthenia. Adverse cutaneous reactions are rare, although non-specific mild rashes have been occasionally reported. In view of the clear temporal relation between the onset of terazosin therapy and the cutaneous eruption and the resolution of the skin lesions when terazosin was 95