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PURPOSE: Biological factors and mechanisms that drive higher prevalence of insomnia in females are poorly understood. This study focused on the neurological consequences of X-chromosome functional imbalances between sexes. METHODS: Benefited from publicly available large-scale genetic, transcriptional and epigenomic data, we curated and contrasted different gene lists: (1) X-liked genes, including assignments for X-chromosome inactivation patterns and disease associations; (2) sleep-associated genes; (3) gene expression markers for the suprachiasmatic nucleus. RESULTS: We show that X-linked markers for the suprachiasmatic nucleus are significantly enriched for clinically relevant genes in the context of rare genetic syndromes and brain waves modulation. CONCLUSION: Considering female-specific patterns on brain transcriptional programs becomes essential when designing health care strategies for mental and sleep illnesses with sex bias in prevalence.

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Intrachromosomal insertions are complex structural rearrangements that are challenging to interpret using classical cytogenetic methods. We report a male patient carrying a recombinant X chromosome derived from a maternally inherited intrachromosomal insertion. The patient exhibited developmental delay, intellectual disability, behavioral disorder, and dysmorphic facial features. To accurately identify the rearrangements in the abnormal X chromosome, additional cytogenetic studies were conducted, including fluorescence in situ hybridization (FISH), multicolor-banding FISH, and array comparative genomic hybridization. The results showed a recombinant X chromosome, resulting in a 13.05 Mb interstitial duplication of segment Xp22.33-Xp22.13, which was inserted at cytoband Xq26.1. The duplicated region encompasses 99 genes, some of which are associated with the patient's clinical manifestations. We propose that the combined effects of the Xp-duplicated genes may contribute to the patient's phenotype.

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Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme skewing of X-chromosome inactivation (XCI) can be associated with ID phenotypes caused by pathogenic variants in the X chromosome. We analyzed the XCI pattern in blood samples of 194 women with idiopathic ID, using the androgen receptor gene (AR) methylation assay. Among the 136 patients who were informative, 11 (8%) presented with extreme or total XCI skewing (≥ 90%), which was significantly higher than expected by chance. Whole-exome data obtained from these 11 patients revealed the presence of dominant pathogenic variants in eight of them, all sporadic cases, resulting in a molecular diagnostic rate of 73% (8/11 patients). All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (an XCI escape gene; two cases), WDR45, and PDHA1, and four variants in the autosomal genes KCNB1, CTNNB1, YY1, and ANKRD11. Three of the autosomal genes had no obvious correlation with the observed XCI skewing. However, YY1 is a known transcriptional repressor that acts in the binding of the XIST long noncoding RNA on the inactive X chromosome, providing a mechanistic link between the pathogenic variant and the detected skewed XCI in the carrier. These data confirm that extreme XCI skewing in females with ID is highly indicative of causative X-linked pathogenic variants, and point to the possibility of identifying causative variants in autosomal genes with a XCI role.

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El Fósforo es regulado por el riñón y el sistema óseo orquestado principalmente por la acción de la parathormona (PTH) y una molécula recientemente descrita como el factor de crecimiento fibroblástico 23 (FGF-23) . Presentamos los casos de dos pacientes madre-hijo con Raquitismo hipofosfatémico ligado al cromosoma X. Se realizó el estudio genético identificándose una mutación en el Gen PHEX: variante patogénica tipo splicing en hemicigosis: mutación previamente descrita como HGMD CS126536. El Raquitismo Hipofosfatémico forma parte de un grupo de tubulopatías caracterizadas hiperfosfaturia. La mutación del gen PHEX con pérdida de función conduce al aumento de FGF-23. PHEX degrada el FGF-23 en fragmentos inactivos, evitando la excreción excesiva de fosfatos y el desarrollo de hipofosfatemia. En un paciente con hipofosfatemia no dependiente de la hormona PTH o de la vitamina D y de presentación familiar debe considerarse el diagnóstico de Raquitismo hipofosfatémico ligado al cromosoma X.

Phosphate is regulated by the kidneys and the osseus system, mainly due to the action of parathyroid hormone (PTH) and a recently described molecule, fibroblast growth factor 23 (FGF-23). We present the cases of two patients, mother and son with X-chromosome linked hypophosphatemic rickets. The genetic study was performed, and a mutation in the PHEX gene was identified, a splicing type pathogenic variant in hemizygosis. This mutation was previously described as HGMD CS126536. Hypophosphatemic rickets belongs to a group of tubulopathies characterized by hyperphosphaturia. PHEX gene mutation with function loss leads to increased FGF-23 levels. PHEX degrades FGF-23 into inactive fragments, preventing excessive phosphate excretion and the development of hypophosphatemia. In patients with PTH or vitamin D non- dependent hypophosphatemia, a diagnosis of X-chromosome linked hypophosphatemic rickets should be considered.

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Biological factors and mechanisms that drive sex differences observed in sleep disturbances are understudied and poorly understood. The extent to which sex chromosome constitution impacts on sex differences in circadian patterns is still a knowledge void in the sleep medicine field. Here we focus on the neurological consequences of X-chromosome functional imbalances between males and females and how this molecular inequality might affect sex divergencies on sleep. In light of the X-chromosome inactivation mechanism in females and its implications in gene regulation, we describe sleep-related neuronal circuits and brain regions impacted by sex-biased modulations of the transcriptome and the epigenome. Benefited from recent large-scale genetic studies on the interplay between X-chromosome and brain function, we list clinically relevant genes that might play a role in sex differences in neuronal pathways. Those molecular signatures are put into the context of sleep and sleep-associated neurological phenotypes, aiming to identify biological mechanisms that link X-chromosome gene regulation to sex-biased human traits. These findings are a significant step forward in understanding how X-linked genes manifest in sleep-associated transcriptional networks and point to future research opportunities to address female-specific clinical manifestations and therapeutic responses.

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For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.

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Introduction: Ectodermal dysplasia is a rare genetic disorder that affects structures derived from ectoderm such as teeth, hair, nails, and sweat glands. Oligodontia is a common finding that affects the chewing, smiling and self- esteem of these pediatric patients. Case Report: We present a case report of a 7-years-old pediatric patient who consulted with his mother, showing the same condition. The intervention consisted of a removable prosthesis with satisfactory results. Conclusion: The X-linked hypohidrotic ectodermal dysplasia represents a challenge for a pediatric dentist who offers rehabilitation to the patient according to craniofacial development, age, socioeconomic status, and the number of missing teeth.

Introducción: La oligodoncia es un hallazgo común que afecta la masticación, la sonrisa y la autoestima de estos pacientes pediátricos. Case Report: Presentamos un reporte de caso de un paciente pediátrico de 7 años que consultó con su madre presentando la misma condición. La intervención consistió en una prótesis de remoción con resultados satisfactorios. Conclusión: La displasia ectodérmica hipohidrótica ligada al cromosoma X representa un desafío para un odontopediatra que ofrece rehabilitación al paciente de acuerdo con el desarrollo craneofacial, la edad, el nivel socioeconómico y el número de dientes faltantes.

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Microsatellite genetic markers are the gold standard for human genetic identification. Forensic analyses around the world are carried out through protocols using the analysis of STR markers in autosomal chromosomes and in the Y chromosome to solve crimes. However, these analyses do not allow for the resolution of all cases, such as rape situations with suspicion of incest, paternity without a maternal sample for comparison, and biological traces with DNA mixture where the profile sought is female, among other situations. In these complex cases, the study of X-chromosome STR markers significantly increases the probability of identification by complementing the data obtained for autosomal and Y-chromosome markers, due to the unique structure of the X chromosome and its exclusive method of inheritance. However, there are currently no validated Brazilian protocols for this purpose, nor are there any population data necessary for statistical analyses that must be included in the issuance of expert reports. Thus, the aim of this article is to provide a literary review of the applications of X-chromosomal markers in population genetics.

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Allan-Herndon-Dudley syndrome (AHDS) is characterized by neuropsychomotor developmental delay/intellectual disability, neurological impairment with a movement disorder, and an abnormal thyroid hormone profile. This disease is an X-linked disorder that mainly affects men. We described a female patient with a de novo variant in the SLC16A2 gene, a milder AHDS phenotype, and a skewed X chromosome inactivation profile. We discuss the mechanisms associated with the expression of the phenotypic characteristics in female patients, including SLC16A2 gene variants and cytogenomic alterations, as well as preferential inactivation of the normal X chromosome.

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Yin and Yang 1 gene (YY1; MIM#600,013) is recognized as a dual transcriptional activating and repressing factor, RNA-binding protein, and 3D chromatin regulator, with multi roles in neurodevelopmental and maintenance pathways. YY1 haploinsufficiency caused either by heterozygous sequence variants or deletions involving the whole gene has been recently associated with Gabriele-de Vries syndrome (GADEVS), a rare congenital autosomal dominant condition, leading to intellectual disability (ID) and multiple physical/behavioural abnormalities. Herein, we describe clinical and molecular findings from a Brazilian female harbouring a de novo missense pathogenic variant in YY1 gene (NM_003403.5:c.1106A > G; p.Asn369Ser) found by whole exome sequencing with potential implications for protein structure and function. Undescribed or uncommon clinical features in this patient included non-febrile seizures, severe scoliosis, hearing impairment, and chorioretinitis. Further bioinformatics analyses using YY1-other protein interaction networks reinforced the involvement of YY1 interactors in such phenotypes, in exception of chorioretinitis. Moreover, X-chromosome inactivation (XCI) skewing was evidenced in the patient and attributed to the haploinsufficiency of YY1, which direct and indirectly interacts with numerous XCI key regulators. Besides expanding the mutational and phenotype spectrum of GADEVS, our results highlight the role of YY1 as an essential autosomal regulator of XCI epigenetic process.

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Hemophilia A is an X-linked bleeding disorder caused by mutations in the FVIII gene. Genetic factors have been shown to be a risk factor for the development of inhibitors. We aimed to identify the specific variations of the FVIII gene of patients with hemophilia A with inhibitors and their association with the inhibitor titer. Methods: Cross-sectional descriptive study. We included 12 Colombian patients from a health care provider, "Integral Solutions SD", who underwent analysis of genetic material (DNA), which was reported by the Molecular Hemostasis Laboratory in Bonn, Germany. Results: All of these patients were diagnosed with severe hemophilia A with inhibitors; ages ranged between 6 and 48 years, with a median age of 13.5 years. Molecular analysis showed the inversion of intron 22 in six patients (50.0%), a small duplication in two patients (16.7%), the inversion of intron 1 in one patient (8.3%), a large deletion (8.3%), a nonsense mutation (8.3%) and a splice-site (8.3%), findings similar to those of other studies. A total of 58.3% of the patients presented inversion mutations with a high risk of developing inhibitors A total of 83.3% of the evaluated patients presented null mutations; however the presence of high inhibitor titers was 66.7%. The most frequent mutation was the inversion intron 22. Knowing the type of mutation and its association as a risk factor for generating inhibitors invites us to delve into other outcomes such as residual values of coagulation FVIII as well as its impact on the half-life of the exogenous factor applied in prophylaxis.

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RESUMEN Introducción: El síndrome de Wiskott-Aldrich, es una inmunodeficiencia primaria, poco frecuente heredada de forma recesiva ligado al cromosoma X. Está asociado a fenotipos clínicos variables que se correlacionan con el tipo de mutación presente en la proteína del síndrome de Wiskott-Aldrich. Objetivo: Examinar el caso de un paciente con diagnóstico de Wiskott Aldrich y presencia de una mutación no descrita anteriormente. Presentación del caso: Paciente masculino cuya sintomatología se inició a los tres meses de edad, con infecciones respiratorias recurrentes, lesiones purpúricas hemorrágicas tipo equimosis, eccema y plaquetopenia. El diagnóstico se confirmó al año de inicio de los síntomas con la detección de una mutación no descrita anteriormente, ubicada en el codón 88 de la proteína del síndrome de Wiskott-Aldrich (p. Y88X; c.264C > G), asociada a una variante clásica. Conclusiones: La identificación temprana, diagnóstico y estratificación del fenotipo, es esencial para reducir los eventos desfavorables y complicaciones de la afección. El estudio genético es el medio de confirmación diagnóstica definitivo para el síndrome, lo que permite aplicar el protocolo terapéutico más adecuado para este tipo de inmunodeficiencia.

ABSTRACT Introduction: Wiskott Aldrich syndrome is a primary immunodeficiency, rarely inherited in a recessive way and linked to the X chromosome. It is associated with variable clinical phenotypes that correlate with the type of mutation present in the Wiskott Aldrich syndrome protein. Objective: Examine the case of a patient diagnosed with Wiskott Aldrich and presence of a mutation not described above. Case presentation: Male patient whose symptoms began at three months of age, with recurrent respiratory infections, purpuric hemorrhagic lesions such as ecchymosis, eczema and platelettopenia. The diagnosis was confirmed one year of after the symptoms onset with the detection of a mutation not previously described, located in codon 88 of the Wiskott Aldrich syndrome protein (p. Y88X; c.264C>G), associated with a classical variant. Conclusions: Early identification, diagnosis and stratification of the phenotype is essential to reduce unfavorable events and complications of the condition. The genetic study is the mean of definitive diagnostic confirmation for the syndrome, which allows to apply the most appropriate therapeutic protocol for this type of immunodeficiency.

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INTRODUCTION: Several studies have already shown that changes in the AR gene may be associated with a more aggressive disease phenotype and even castration-resistant prostate cancer. Thus, we investigated cytogenetic and molecular alterations linked to AR. MATERIALS AND METHODS: To evaluate AR methylation, we performed a cytogenetic-molecular analysis using fluorescence in situ hybridization that uses specific probes for the AR gene (Xq11.12) and the X chromosome centromere. For AR activity, we performed a qualitative analysis of human androgen receptor activity. To analyze the expression of AR in PC3 and LNCaP cell lines, we used qPCR assays. RESULTS: In the qPCR assay, we found downregulation of AR in the PC3 cell line compared with the LNCaP. We found the presence of X chromosome polysomy in PC-3 and LNCaP cell lines by FISH assay. In the HUMARA-Q assay, we found two X chromosomes/cell and the activity of both AR in the PC-3 cell line. In LNCaP cells, we found two X chromosomes/cell and methylation of only one AR. CONCLUSION: Castration-resistant prostate cancer phenotype represents a significant challenge in the setting of urological management. The X chromosomes and AR-linked alterations may contribute to a better understanding of the disease. However, further studies should be performed in an attempt to elucidate as much as possible the role of AR in the castration-resistant prostate cancer phenotype.

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Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing NR0B1/DAX1 and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the NR0B1/DAX1 gene, may have been the main cause of dysgenetic testes development, although the role of MAGEB and other genes mapped to the Xp21 segment could not be completely ruled out.

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Introducción: la enfermedad de Fabry es un defecto lisosomal caracterizado por una alteración de la enzima alfa-galactosidasa y que produce el acúmulo de glucoesfingolípidos en diferentes tejidos. Este defecto enzimático está ligado al cromosoma X y por ende es más frecuente en hombres. Sus manifestaciones clínicas varían de acuerdo al grupo etario afectado e incluyen lesiones en piel, anhidrosis, opacidades corneales, crisis de dolor, daño renal, entre otros. Objetivo: calcular la incidencia de enfermedad de Fabry en pacientes con diagnóstico de enfermedad renal crónica (ERC). Materiales y métodos: estudio ambispectivo realizado en los pacientes con diagnóstico de ERC que asistían a controles médicos en tres centros de prevención renal ubicados en el departamento del Atlántico, Colombia, y que además cumplían los criterios de inclusión y exclusión. Se revisaron las historias clínicas y se tomaron muestras para confirmar la presencia de enfermedad de Fray. Resultados: se identificaron 471 pacientes con ERC y se estableció una incidencia global de 21,23 casos por cada 1.000 habitantes para baja actividad de la alfa-galactosidasa. Sin embargo, solo en el 20% se confirmó la presencia de enfermedad de Fray mediante pruebas genéticas. Conclusiones: la incidencia de la enfermedad de Fabry en la población estudiada es mayor a la reportada en otras cohortes y además fue más frecuente en el sexo femenino.

Introduction: Fabry's disease consists of a lysosomal defect linked to the X chromosome that produces the accumulation of glycosphingolipids in different tissues. The clinical manifestations depend on the age of presentation, and includes skin lesions, acroparesthesia, pain crisis, anhidrosis, corneal opacities and hearing loss, among others. Objectives: Calculate the incidence of Fabry disease in patients diagnosed with chronic kidney disease Methodology: An ambispective study was designed, including all patients diagnosed with chronic kidney disease under medical control in three renal prevention centers located in the department of Atlántico, and which also met the inclusion and exclusion criteria. Subsequently, the review of the medical records and the sampling were carried out. Results: A total of 471 patients with chronic kidney disease were identified, with an overall incidence of 21.23 cases per 1000 people. However, only 20% were confirmed by genetic tests. Conclusions: The incidence of Fabry disease in the population studied is greater than that reported in other cohorts. In addition, it is more frequent in the female sex.

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Klinefelter syndrome (KS) displays a broad dysmorphological, endocrinological, and neuropsychological clinical spectrum. We hypothesized that the neurocognitive dysfunction present in KS relies on an imbalance in X-chromosome gene expression. Thus, the X-chromosome inactivation (XCI) pattern and neurocognitive X-linked gene expression were tested and correlated with intelligence quotient (IQ) scores. We evaluated 11 KS patients by (a) IQ assessment, (b) analyzing the XCI patterns using both HUMARA and ZDHHC15 gene assays, and (c) blood RT-qPCR to investigate seven X-linked genes related to neurocognitive development (GTPBP6, EIF2S3, ITM2A, HUWE1, KDM5C, GDI1, and VAMP7) and XIST in comparison with 14 (male and female) controls. Considering IQ 80 as the standard minimum reference, we verified that the variability in IQ scores in KS patients seemed to be associated with the XCI pattern. Seven individuals in the KS group presented a random X-inactivation (RXI) and lower average IQ than the four individuals who presented a skewed X-inactivation (SXI) pattern. The evaluation of gene expression showed higher GTPBP6 expression in KS patients with RXI than in controls (p = 0.0059). Interestingly, the expression of GTPBP6 in KS patients with SXI did not differ from that observed in controls. Therefore, our data suggest for the first time that GTPBP6 expression is negatively associated with full-scale IQ under the regulation of the type of XCI pattern. The SXI pattern may regulate GTPBP6 expression, thereby dampening the impairment in cognitive performance and playing a role in intelligence variability in individuals with KS, which warrants further mechanistic investigations.

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mundo se encuentra en medio de la pandemia de la enfermedad por coronavirus 2019 (COVID-19). En la mayoría de los países, la tasa de mortalidad, así como, la severidad de la enfermedad es más alta en hombres que en mujeres. Este sesgo sexual sugiere que los hombres son más propensos a desarrollar complicaciones graves o a sucumbir a las mismas, lo que conduce a la muerte. Por lo tanto, es importante comprender los elementos biológicos basados en el sexo que inciden en la respuesta inmunitaria. El objetivo de ésta revisión fue hacer un análisis en relación a la evidencia disponible sobre los diferentes factores que permitirían explicar esta disparidad sexual. Abordamos las diferencias en la respuesta inmunitaria en ambos sexos tomando en cuenta el aspecto genético, hormonal y el papel del sistema renina-angiotensina. Para ello, se realizó una búsqueda minuciosa en diferentes bases de datos utilizando las siguientes palabras clave: (Diferencia de sexo, genética, hormonas sexuales, COVID-19, SARS-CoV-2, respuesta inmunitaria, inflamación, hombres, mujeres). Los resultados de nuestro análisis ofrecen una comprensión más clara sobre la influencia de las diferencias sexuales en la capacidad de respuesta a una infección, con especial énfasis en la infección por SARS-CoV-2. Conocer estos factores no solo ayudará a comprender mejor la patogenia de la COVID-19, sino, además, guiará el diseño de terapias efectivas para la medicina personalizada basada en las diferencias sexuales

The world is during the 2019 coronavirus disease pandemic (COVID-19). In most countries, the mortality rate, as well as, the severity of the disease is higher in men than in women. This sex bias suggests that men are more likely to develop severe complications or succumb to severe complications, leading to death. Therefore, it is important to understand the sex-based biological elements that influence the immune response. The aim of this review was to review the available evidence on the different factors that could explain this sex disparity. We addressed the differences in the immune response in both sexes taking into account genetic, hormonal and the role of the renin-angiotensin system. For this purpose, a thorough search was performed in different databases using the following keywords: (Sex difference, genetics, sex hormones, COVID-19, SARS-CoV-2, immune response, inflammation, men, women). The results of our analysis provide a clearer understanding on the influence of sex differences on the ability to respond to an infection, with special emphasis to SARS-CoV-2 infection. Knowing these factors will not only help to better understand the pathogenesis of COVID-19, but will also guide the design of effective therapies for personalized medicine based on sex differences.

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RESUMEN La incontinencia pigmentaria, también conocida como síndrome de Bloch-Sulzberger, es una rara genodermatosis ligada al cromosoma X, localizado en el Xq28. Afecta al sexo femenino y tiene diferentes expresiones clínicas en una misma familia. Es una enfermedad multisistémica, caracterizada por afectar de forma variable a los tejidos derivados del neuroectodermo, la piel, ojos, dientes y el sistema nervioso central. Las lesiones cutáneas son las más significativas desde el nacimiento, y la biopsia confirma el diagnóstico. Debido a la rareza de esta entidad, se presentó el caso de una lactante de un mes, con antecedente familiar de incontinencia pigmentaria, quien exhibía lesiones típicas en la piel desde la primera semana de vida, en diferentes fases, que siguen las líneas de Blaschko. Se constataron manifestaciones oculares y eosinofilia (AU).

ABSTRACT Pigmentary incontinence, also known as Bloch-Sulzberger syndrome, is a rare X chromosome-linked genodermatosis, located in Xq28. It affects the female sex and has different clinical manifestations in the same family. Ii is a multi-systemic disease characterized by affecting, in a variable way, the tissues derived from the neuroectoderm, the skin, the eyes, the teeth and the central nervous system. Skin lesions are the most significant ones since birth time, and skin biopsy confirms the diagnosis. Due to the rareness of this entity, we presented the case of a nursing female infant aged one month, with a family history of pigmentary incontinence, who presented typical lesions in the skin, since his first week of life, in different phases, following the lines of Blaschko. Ocular manifestations and eosinophilia were confirmed (AU).

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OBJECTIVES: According to demographic history, Ecuador has experienced shifts in its Native American populations caused by European colonization and the African slave trade. The continuous admixture events among Europeans, Native Americans, and Africans occurred differently in each region of the country, producing a stratified population. Thus, the aim of this study was to investigate the level of genetic substructure in the Ecuadorian Mestizo population. MATERIALS AND METHODS: A total of 377 male and 209 female samples were genotyped for two sets of X-chromosomal markers (32 X-Indels and 12 X-STRs). Population analyses performed included Hardy-Weinberg equilibrium tests, LD analysis, PCA, pairwise FST s, and AMOVA. RESULTS: Significant levels of LD were observed between markers separated by distances of less than 1 cM, as well as between markers separated by distances varying from 10.891 to 163.53 cM. Among Ecuadorian regions, Amazonia showed the highest average R2 value. DISCUSSION: When X-chromosomal and autosomal differentiation values were compared, a sex-biased admixture between European men and Native American and African women was revealed, as well as between African men and Native American women. Moreover, a distinct Native American ancestry was discernible in the Amazonian population, in addition to sex-biased gene flow between Amazonia and the Andes and Pacific coast regions. Overall, these results underline the importance of integrating X chromosome information to achieve a more comprehensive view of the genetic and demographic histories of South American admixed populations.

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ABSTRACT BACKGROUND: Turner syndrome (TS) is a rare genetic disease. Understanding its clinical findings contributes to better management of clinical conditions. OBJECTIVE: To investigate the clinical and karyotypic characteristics of patients diagnosed with TS at two reference services for clinical genetics in southern Brazil. DESIGN AND SETTING: Retrospective cross-sectional study conducted in two clinical genetics services in Porto Alegre (RS), Brazil. METHODS: The sample consisted of 59 patients with TS diagnosed from 1993 to 2019. A review of their medical records was performed and a standard protocol was filled out. RESULTS: The average age of the patients at diagnosis was 15.9 years, and 40.7% were over 13 years old. The largest proportion of them (42.4%) had been referred from an endocrinology department and their constitution was 45,X (40.7%). The most common clinical findings were short stature (85.7%), hypoplastic/ hyperconvex nails (61.2%), low posterior hairline (52.1%) and cubitus valgus (45.8%). There was no difference regarding the presence of short stature (P = 0.5943), number of dysmorphia (P = 0.143), anatomical regions affected and malformations identified through imaging examinations (P = 1.0000), regarding the presence or absence of 45,X constitution. Only 6% of the patients had used growth hormone and 43%, estrogen. CONCLUSION: We found that, in general, patients with TS were being diagnosed late. This has important implications for their treatment. In addition, only a small proportion of the patients were undergoing further examination or evaluation, which appeared to be leading to underdiagnosis of many abnormalities.

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