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Grayson Ramirez
Grayson Ramirez

Facial Anal


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Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare syndrome with only 27 cases reported worldwide so far, but none was reported in the population of Eastern Asia. Such extremely low prevalence might be contributed by misdiagnosis due to its similarities in ocular manifestations with facial cleft. In our study, we discovered the first case of MOTA syndrome in the population of China, with 2 novel FRAS1 related extracellular matrix 1 (FREM1) gene stop-gain mutations confirmed by whole exome sequencing.


A 12-year-old Chinese girl presented with facial cleft-like deformities including aberrant hairline, blepharon-coloboma and broad bifid nose since birth. Whole exome sequencing resulted in the identification of 2 novel stop-gain mutations in the FREM1 gene. Diagnosis of MOTA syndrome was then established.


Manitoba oculo-tricho-anal syndrome (MOTA syndrome, OMIM 248,450) is a rare syndrome characterized by aberrant hairline, blepharon-coloboma, broad bifid nose with or without anorectal stenosis. It was first reported in 6 children from 4 related families in the Manitoba Indian pedigree by Marles et al. in 1992 [1]. Several published pedigree reports have revealed that the inheritance pattern of MOTA syndrome was primarily autosomal recessive [1, 2]. The pathogenic gene, however, remained ambiguous until 2011, when Slavotinek et al. confirmed that MOTA syndrome was caused by mutations in the gene called FRAS1 related extracellular matrix 1 (FREM1, OMIM 608,944), demonstrated in both patients and mutant mice models [3].


FREM1 gene, located on the chromosome 9p22.3, encodes the basement membrane protein which can potentially affect the craniofacial and renal development [4]. Mutations of this gene may cause 3 distinct clinical phenotypes including bifid nose with or without anorectal and renal anomalies (BNAR syndrome, OMIM 608,980), MOTA syndrome, or trigonocephaly (OMIM 614,485) [3, 5, 6].


Despite its clear genetic etiology and clinical manifestations, currently only 27 cases of MOTA syndrome have been reported worldwide. There has been no single case of MOTA syndrome reported in the Chinese population, likely due to underdiagnosis or misdiagnosis especially in the plastic and reconstructive clinics, since both MOTA syndrome and facial cleft share several similarities in ocular manifestations [7]. In this study, we reported an analysis of whole exome sequencing from 1 Chinese girl with a highly concordant clinical phenotype of MOTA syndrome. The diagnosis of MOTA syndrome was confirmed by the identification of 2 novel stop-gain mutations in the FREM1 gene.


The fact that both MOTA syndrome and facial cleft sharing similarities in ocular manifestation might have contributed to the chance of misdiagnosis of MOTA syndrome especially by the plastic surgeons. On one side, MOTA syndrome exhibits heterogeneous symptoms and among which there were several phenotypes resembling the features of Tessier number 10 cleft. Chacon-Camacho OF et al. have conducted a systematic review of the 27 reported cases of MOTA syndrome worldwide till 2017 [7], apart from our current report, there has no other new case been reported since then. Of the 28 reported cases of MOTA syndrome to date, 15 merely suffered from facial deformities, and 5 with no observable nasal defect [7]. On the other side, the most frequently seen organ abnormalities in MOTA syndrome, the anteriorly placed anus and anal stenosis could be asymptomatic, thus might easily be neglected by surgeons.


Considering the main disadvantage of the existing gaze point estimation methods which restrict user's head movement and have potential injury on eyes, we propose a gaze point estimation method based on facial normal and binocular vision. Firstly, we calibrate stereo cameras to determine the extrinsic and intrinsic parameters of the cameras; Secondly, face is quickly detected by Viola-Jones framework and the center position of the two irises can be located based on integro-differential operators; The two nostrils and mouth are detected based on the saturation difference and their 2D coordinates can be calculated; Thirdly, the 3D coordinates of these five points are obtained by stereo matching and 3D reconstruction; After that, a plane fitting algorithm based on least squares is adopted to get the approximate facial plane, then, the normal via the midpoint of the two pupils can be figured out; Finally, the point-of-gaze can be obtained by getting the intersection point of the facial normal and the computer screen. Experimental results confirm the accuracy and robustness of the proposed method.


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