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J Med Genet ; 2021 Nov 08.
Article En | MEDLINE | ID: mdl-34750192

BACKGROUND: Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family. METHODS: We performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells. RESULTS: This study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells. CONCLUSION: Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype.

Plast Reconstr Surg ; 148(4): 760-770, 2021 Oct 01.
Article En | MEDLINE | ID: mdl-34550930

BACKGROUND: Subfascial breast augmentation is becoming popular because of a better understanding of breast anatomy. However, because the subglandular approach is also another popular method, it is critical to assess the influence of the superficial fascia of the pectoralis major muscle on the subfascial and subglandular pockets to determine if one method is superior to another. This study investigated whether there are clinical/radiological differences between subfascial and subglandular pockets following primary breast augmentation. METHODS: Twenty patients were recruited, and each was randomly sorted to the subfascial and/or subglandular pocket per breast. Both patients and surgeons were blinded. Differences were evaluated through five independent surgeons and by magnetic resonance imaging scans. Subsequently, 1-year and 5-year follow-ups were conducted. RESULTS: The results of the 5-year follow-up considering the aesthetics of the breast contour were significantly different between groups, with more good and excellent evaluations in the subfascial group. Regarding breast shape, there were also statistical differences, also with more good and excellent evaluations in the subfascial group. For breast consistency, subglandular had 84.20 percent of patients classified into Baker I and II, whereas subfascial had 100 percent. Magnetic resonance imaging scans showed a smaller implant base in the subglandular pockets, which was a significant result. There were no significant differences in implant projection. Comparison of the number of folds revealed significant differences between groups, with more folds in the subglandular group. CONCLUSION: Statistical differences between methods were found regarding breast shape and contour, capsular contracture, implant base, and the number of folds, showing that subfascial breast augmentation is superior to subglandular breast augmentation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Mol Syndromol ; 10(1-2): 40-47, 2019 Feb.
Article En | MEDLINE | ID: mdl-30976278

Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by EFNB1 mutations in which females are more severely affected than males. Severe male phenotypes are associated with mosaicism, supporting cellular interference for sex bias in this disease. Although many variants have been found in the coding region of EFNB1, only 2 pathogenic variants have been identified in the same nucleotide in 5'UTR, disrupting the stop codon of an upstream open reading frame (uORF). uORFs are known to be part of a wide range of post-transcriptional regulation processes, and just recently, their association with human diseases has come to light. In the present study, we analyzed EFNB1 in a female patient with typical features of CFNS. We identified a variant, located at c.-411, creating a new upstream ATG (uATG) in the 5'UTR of EFNB1, which is predicted to alter an existing uORF. Dual-luciferase reporter assays showed significant reduction in protein translation, but no difference in the mRNA levels. Our study demonstrates, for the first time, the regulatory impact of uATG formation on EFNB1 levels and suggests that this should be the target region in molecular diagnosis of CFNS cases without pathogenic variants in the coding and splice sites regions of EFNB1.

Plast Reconstr Surg ; 141(6): 1408-1415, 2018 06.
Article En | MEDLINE | ID: mdl-29750763

BACKGROUND: In the lipofilling procedures used in breast reconstruction, there is an unpredictability in the rate of reabsorption of the grafted fat. The objective of this study was to analyze the effect of tamoxifen, a medication commonly prescribed for patients with breast cancer, as a possible alternative to reduce the rate of autologous fat graft resorption. METHODS: The fatty cushion of the inguinal region of 20 female adult Wistar rats was removed and then autografted, using a standard volume of 0.2 ml in the subfascial plane of the dorsal region. The subject animals were randomized into two groups, the control and study groups. The study group animals were administered 20 mg/kg/day of tamoxifen citrate over a period of 21 days, by means of gavage. At the end of the experiment, the animals were killed and the grafts underwent morphologic and histopathologic analysis, with emphasis on the predominant inflammatory response pattern and collagen maturation. RESULTS: The rats undergoing treatment with tamoxifen (study group) presented higher values in relation to the weight and volume of fat grafts compared with the initial values and the control group. Histologic analysis using hematoxylin and eosin staining showed that resolution of the inflammatory process was faster in the control group. Analysis using the picrosirius method demonstrated higher percentages of immature collagen versus mature collagen. CONCLUSION: Use of tamoxifen reduced the rates of resorption and fibrosis of the injected fat, resulting in better integration of the autologous fat graft.

Adipose Tissue/transplantation , Antineoplastic Agents, Hormonal/pharmacology , Tamoxifen/pharmacology , Absorption, Physicochemical/physiology , Animals , Autografts/pathology , Female , Fibrosis , Graft Survival/drug effects , Random Allocation , Rats, Wistar , Transplantation, Autologous
Am J Med Genet A ; 173(4): 938-945, 2017 Apr.
Article En | MEDLINE | ID: mdl-28328130

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.

Ear Diseases/diagnosis , Ear/abnormalities , Genetic Predisposition to Disease , Micrognathism/diagnosis , Mutation , Phospholipase C beta/genetics , Pierre Robin Syndrome/diagnosis , Adult , Child , Ear/pathology , Ear Diseases/classification , Ear Diseases/genetics , Ear Diseases/pathology , Endothelin-1/genetics , Female , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Expression , Genes, Dominant , High-Throughput Nucleotide Sequencing , Humans , Male , Micrognathism/classification , Micrognathism/genetics , Micrognathism/pathology , Pedigree , Phenotype , Pierre Robin Syndrome/classification , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Terminology as Topic
Aesthetic Plast Surg ; 33(1): 84-9, 2009 Jan.
Article En | MEDLINE | ID: mdl-18797959

BACKGROUND: Wound contractures can cause severe deformities and disabilities. Recent studies have suggested that leukotriene receptor antagonists have an inhibitory effect on the healing contraction process. This study aimed to evaluate the influence of the leukotriene inhibitor montelukast on the cutaneous healing process and the wound contraction phenomenon in rats. METHODS: For this study, 60 male rats were randomly divided into four groups (MK-7d, SF-7d, MK-14d, and SF-14d) according to the drug given through a rigid orogastric tube (MK group: montelukast 10 mg/kg/day; SF group: normal saline solution) and the day the animals were killed (7d: postoperative day 7; 14d: postoperative day 14). An excisional wound (2 x 2 cm) was created on the dorsum of each rat. The wounds were left open to heal spontaneously and documented by standard digital photographs on different postoperative days. Wound contraction rates were calculated with specific software, and specimens were histologically evaluated using picrosirius red stain. Results were analyzed using the Aspin-Welch, Mann-Whitney, and t tests, assuming a significance level of 5%. RESULTS: The wound contraction rates were similar between the control and study groups (p > 0.05). On postoperative day 7, the wounds showed a marginally significant reduction in collagen maturation in the study group (40.1% +/- 6.88% vs 61.2% +/- 8.02%; p = 0.0607). On postoperative day 14, this reduction was statistically significant in the MK group (26% +/- 5.66% vs 68.3% +/- 7.76%; p = 0.0001). CONCLUSIONS: Montelukast does not alter the contraction rate of excisional wounds in rats but has a significant and progressive inhibitory effect on collagen maturation.

Acetates/administration & dosage , Collagen/drug effects , Dermatologic Surgical Procedures , Leukotriene Antagonists/administration & dosage , Quinolines/administration & dosage , Wound Healing/drug effects , Animals , Collagen/metabolism , Cyclopropanes , Disease Models, Animal , Male , Probability , Random Allocation , Rats , Rats, Wistar , Reference Values , Sensitivity and Specificity , Skin/injuries , Statistics, Nonparametric , Sulfides