Infantile hemangiomas: risk factors for complications, recurrence and unaesthetic sequelae

Abstract Background: Infantile hemangiomas (IH) occur in approximately 4% to 10% of the pediatric population. The identification of clinical subtypes and conditions that indicate increased risk for complications is essential for therapeutic success. Objectives: To identify risk factors for complications, recurrence and unaesthetic sequelae. Methods: Retrospective cohort of patients with infantile hemangiomas undergoing follow-up at the Dermatology Service of Universidade Federal de Ciências da Saúde de Porto Alegre, between 2006 and 2018. Results: 190 patients were included; 24% had some type of complication, ulceration being the most frequent, and 86% required treatment. On correlation, ulceration was statistically related to mixed IH (p = 0.004), segmental IH (p < 0.01) and location in the gluteal region (p = 0.001). The mean time of treatment with propranolol was 12.7 months. Patients with PHACES syndrome and segmental infantile hemangioma required longer treatment (p < 0.001 and p = 0.0407, respectively), as well as those who started treatment after five months of life (p < 0.0001). Recurrence occurred in 16.6% of the treated patients, all-female; 94% were located on the head and neck (mainly on the upper eyelid, cyrano, S3 segment, and with parotid involvement); 61% and 38.8% were of the mixed and deep subtypes, respectively. Approximately 1/3 of the patients had some unaesthetic sequelae. Study limitations: As this is a retrospective study, data and photos of some patients were lost. Conclusions: Mixed and segmental hemangiomas are risk factors for ulceration and sequelae. Recurrence occurs more often in females and segmental hemangiomas. Segmental infantile hemangioma and PHACES syndrome require a longer time of treatment. Specific protocols are required for infantile hemangiomas with a high risk of recurrence.

Infantile hemangiomas: risk factors for complications, recurrence and unaesthetic sequelae.

BACKGROUND: Infantile hemangiomas (IH) occur in approximately 4% to 10% of the pediatric population. The identification of clinical subtypes and conditions that indicate increased risk for complications is essential for therapeutic success. OBJECTIVES: To identify risk factors for complications, recurrence and unaesthetic sequelae. METHODS: Retrospective cohort of patients with infantile hemangiomas undergoing follow-up at the Dermatology Service of Universidade Federal de Ciências da Saúde de Porto Alegre, between 2006 and 2018. RESULTS: 190 patients were included; 24% had some type of complication, ulceration being the most frequent, and 86% required treatment. On correlation, ulceration was statistically related to mixed IH (p = 0.004), segmental IH (p < 0.01) and location in the gluteal region (p = 0.001). The mean time of treatment with propranolol was 12.7 months. Patients with PHACES syndrome and segmental infantile hemangioma required longer treatment (p < 0.001 and p = 0.0407, respectively), as well as those who started treatment after five months of life (p < 0.0001). Recurrence occurred in 16.6% of the treated patients, all-female; 94% were located on the head and neck (mainly on the upper eyelid, cyrano, S3 segment, and with parotid involvement); 61% and 38.8% were of the mixed and deep subtypes, respectively. Approximately 1/3 of the patients had some unaesthetic sequelae. STUDY LIMITATIONS: As this is a retrospective study, data and photos of some patients were lost. CONCLUSIONS: Mixed and segmental hemangiomas are risk factors for ulceration and sequelae. Recurrence occurs more often in females and segmental hemangiomas. Segmental infantile hemangioma and PHACES syndrome require a longer time of treatment. Specific protocols are required for infantile hemangiomas with a high risk of recurrence.

Caffeine-related genes influence anxiety disorders in children and adults with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders (AD) frequently co-occur, increasing morbidity and challenging treatment. Caffeine is a central nervous system stimulant and acts in the brain through adenosine receptors, influencing attention, alertness, and anxiety. In the present study, we performed a gene-set analysis to verify if genes related to caffeine response are associated with anxiety disorders in 240 children and 406 adults with ADHD. We demonstrated an association between the gene-set with AD in children (P = 0.0054) and with the number of anxiety disorders in adults (P = 0.0197). In order to test if this effect is a result of anxiety in general or is related to AD comorbid with ADHD, we evaluated the association between caffeine gene-set with AD in an adult control sample. The gene-set was neither associated with the AD presence (P = 0.3008) nor with the number of AD (P = 0.5594) in this control sample. We also test this gene set with ADHD (n = 55,374) and AD (n = 18,186) GWAS summary statistics, and we did not observe significant results with ADHD (P = 0.5587) or AD (P = 0.3930). These findings suggest the caffeine-related genes play a role in the etiology of an anxiety disorder phenotype present in children and adults with ADHD.

A vitamin D pathway gene-gene interaction affects low-density lipoprotein cholesterol levels.

Much evidence suggests an association between vitamin D deficiency and chronic diseases such as obesity and dyslipidemia. Although genetic factors play an important role in the etiology of these diseases, only a few studies have investigated the relationship between vitamin D-related genes and anthropometric and lipid profiles. The aim of this study was to investigate the association of three vitamin D-related genes with anthropometric and lipid parameters in 542 adult individuals. We analyzed the rs2228570 polymorphism in the vitamin D receptor gene (VDR), rs2134095 in the retinoid X receptor gamma gene (RXRG) and rs7041 in the vitamin D-binding protein gene (GC). Polymorphisms were genotyped by TaqMan allelic discrimination. Gene-gene interactions were evaluated by the general linear model. The functionality of the polymorphisms was investigated using the following predictors and databases: SIFT (Sorting Intolerant from Tolerant), PolyPhen-2 (Polymorphism Phenotyping v2) and Human Splicing Finder 3. We identified a significant effect of the interaction between RXRG (rs2134095) and GC (rs7041) on low-density lipoprotein cholesterol (LDL-c) levels (P=.005). Furthermore, our in silico analysis suggested a functional role for both variants in the regulation of the gene products. Our results suggest that the vitamin D-related genes RXRG and GC affect LDL-c levels. These findings are in agreement with other studies that consistently associate vitamin D and lipid profile. Together, our results corroborate the idea that analyzing gene-gene interaction would be helpful to clarify the genetic component of lipid profile.

Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes.

The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes.

The influence on DNA damage of glycaemic parameters, oral antidiabetic drugs and polymorphisms of genes involved in the DNA repair system.

The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative stress and production of reactive oxygen species, both of which are factors that can provoke DNA damage. Notwithstanding, other factors, including medications and individual susceptibility, can also induce this type of DNA lesion. The objective of this study was, therefore, to investigate the influence of glycaemic control, oral antidiabetic drugs (metformin and glibenclamide) and polymorphisms of the XRCC1 and XRCC3 genes on the frequency of DNA damage in DM2 patients, which was accessed by the cytokinesis-block micronucleus cytome and the comet assays on the ex vivo mitogenically stimulated lymphocytes. The 53 people recruited to take part in the study were already on treatment with metformin and were followed for 5 months. Ten of these patients were put on combined treatment with the addition of glibenclamide. It was observed that the greater the plasma metformin concentration, the lower the frequency of micronuclei (MN) in the sample total (P = 0.009) and also that the subset of patients using combined treatment including glibenclamide had a significantly higher MN rate 90 days after starting combined treatment (P = 0.024). In the subset who only took metformin, the rate of MN was significantly higher among carriers of the 399Gln allele on the XRCC1 gene (P = 0.008). In addition, homozygotes for the 241Thr allele exhibited a significant increase in MN in the combined treatment group (P = 0.008). Our results suggest that different combinations of oral antidiabetic drugs and polymorphisms on genes involved in the DNA damage repair system could influence the frequency of this type of chromosome lesion, which can be a useful biomarker for assessing the risk of developing cancer.

Avaliação da influência dos polimorfismos genéticos APOE e CETP na resposta ao tratamento com Garcinia cambogia / Evaluation of influence of APOE and CETP genetic polymorphisms on response to treatment with Garcinia cambogia

Objetivo - Avaliar se polimorfismos nos genes CETP (proteína transferidora de ésteres de colesterol) e APOE (apolipoproteína E) influenciam no peso e na resposta do perfil lipídico ao tratamento com G. cambogia. Métodos - Trinta e três pacientes com sobrepeso ou obesidade receberam diariamente uma dose de 2,4g de extrato padronizado de G. cambogia (52,4% de ácido-hidroxicítrico). Antes do início do tratamento e após oito semanas, dados antropométricos e perfil lipídico foram obtidos. Resultados - Após o período de tratamento, não foi possível perceber diferenças na resposta sobre o perfil lipídico entre portadores e não portadores do alelo APOE*2, ou do alelo APOE*4. Uma diferença modesta, porém não significante, foi encontrada na comparação entre portadores e não portadores do alelo B2 (gene CETP) para os níveis de colesterol HDL (p=0,086) e triglicerídeos (p= 0,098). Em relação ao peso, não foram detectadas diferenças na resposta ao tratamento entre os genótipos. Conclusão - Os resultados sugerem que a variante no gene CETP pode estar envolvida na modulação dos níveis de HDL-c após o tratamento com G. cambogia. Entretanto, uma investigação em uma amostra maior será necessária para confirmar esses resultados.

Objective - To investigate the influence of polymorphisms of the CETP (cholesterol ester transfer protein) and APOE (apolipoprotein E) genes on weight changes and lipid levels during the treatment with G. cambogia. Methods - Thirty three patients with overweight or obesity received a daily dose of 2.4 grams of a standardized extract of G. cambogia (52.4% hydroxycitric acid). Before the start of treatment and after eight weeks, lipid profile and anthropometric data were obtained. Results - After the treatment, there were no significant differences in the response of serum lipids between carriers and noncarriers of the allele APOE*2 and APOE*4. A slight difference, but not significant, was observed in the comparison between carriers and noncarriers of allele B2 (CETP gene) for HDL cholesterol levels (p=0,086) and triglycerides levels (p= 0,098). There were no significant differences in the weight after treatment according to genotypes. Conclusion - The results suggest that the variant in the CETP gene may be associated with levels of HDL-c after treatment with G. cambogia. However, an investigation in a larger sample is needed to confirm these results.

Metformina e diabetes melito tipo 2: passado, presente e farmacogenética / Metformin and type 2 diabetes mellitus: past, present and pharmacogenetics

O diabetes melito tipo 2 (DM2) é uma desordem heterogênea caracterizada por resistência à insulina e diminuição progressiva de sua secreção, o que resulta em hiperglicemia. Inevitavelmente, pacientes com DM2 necessitam controlar seus níveis glicêmicos com mudanças no estilo de vida e terapia farmacológica. Entre os fármacos mais prescritos para o tratamento do DM2, encontra-se a metformina, um anti-hiperglicemiante oral pertencente à classe das biguanidas. A resposta terapêutica a este fármaco apresenta uma considerável variação interindividual e depende da atuação de produtos protéicos de vários genes. Por este motivo, a farmacogenética tem emergido como uma ciência capaz de explicar porque há tanta variabilidade na resposta farmacológica, como aquela relacionada à terapia com metformina. Alguns genes candidatos a predizerem a resposta a esse fármaco já tiveram variantes avaliadas. Entre eles, os genes SLC22A1, SLC22A2 e SLC47A1, que codificam os transportadores de cátions orgânicos responsáveis pela entrada e saída da metformina no fígado e rins. Além destes, outros genes, como os que codificam as subunidades da proteína quinase ativada por adenosina monofosfato (AMPK) tem emergido com importantes candidatos a predizerem a resposta à metformina. De qualquer forma, a farmacogenética desta droga está dando seus primeiros passos e serão necessários mais estudos, em diferentes populações, para elucidar outros fatores genéticos que estão envolvidos na sua resposta. Além disso, modelos poligênicos capazes de avaliar a eficácia da metformina em pacientes individuais devem ser criados.

Diabetes mellitus type 2 (DM2) is a heterogeneous disorder characterized by insulin resistance and progressive decrease in secretion, resulting in hyperglycemia. Inevitably, patients with type 2 diabetes need to control their glucose levels with changes in lifestyle and pharmacologic therapy. Among the most prescribed drugs for the treatment of type 2 diabetes, is metformin, an oral anti-hyperglycaemic that belongs to biguanide class. Therapeutic response to this drug has considerable interindividual variation and depends on the activity of protein products of several genes. For this reason, pharmacogenetics has emerged as a science able to explain why there is so much variability in pharmacologic response, as that related to metformin therapy. Some candidate genes to predict the response to this drug had variants evaluated already. Among them, the genes SLC22A1, SLC22A2 and SLC47A1, which encode the organic cation transporters responsible for the entry and exit of metformin in the liver and kidneys. In addition, other genes, such as those that encode the subunits of protein kinase activated by adenosine monophosphate (AMPK) have emerged as important candidates to predict the response to metformin. Anyway, the pharmacogenetics of this drug is in its firsts studies and will require further investigation in different populations, to elucidate other genetic factors involved in the response. In addition, polygenic models capable of evaluating the effectiveness of metformin in individual patients should be created.