Functional and regulatory aspects of oxidative stress response in X monosomy.

The partial/complete loss of one X chromosome in a human female leads to Turner syndrome (TS). TS individuals display a range of phenotypes including short stature, osteoporosis, ovarian malfunction, diabetes, and thyroid dysfunction. Epigenetic factors and regulatory networks are distinctly different in X monosomy (45, X). In a lifetime, an individual is exposed to a variety of stress conditions. To study whether X monosomy cells display a differential response upon exposure to mild stress as compared to normal 46, XX cells and whether this may contribute to various co-morbidities in aneuploid individuals, we have carried out a transcriptomic analysis of human fibroblasts 45, X and 46, XX after exposure to mild oxidative stress. Under these conditions, over 350 transcripts were seen to be differentially expressed in 45, X and 46, XX cells. Pathways associated with oxidative stress were differentially expressed highlighting the differential regulation of genes and associated phenotypes. It could be seen that X monosomy cells are more susceptible to oxidative stress as compared to normal cells and have altered molecular pathways both in normal conditions and also upon exposure to mild oxidative stress. To explore this aspect in detail, we have mapped the expressions of transcription factors (TFs) in 45, X and 46, XX cells. The network of transcription activating factors is differentially regulated in 45, X and 46, XX cells under stress exposure. It is tempting to speculate that the altered ability of 45, X (Turner) cells to respond to stress may play a significant role in the physiological function and altered phenotypes in Turner syndrome.

Gestación en paciente con insuficiencia ovárica primaria secundaria a mosaicismo de Síndrome de Turner / Pregnancy in a patient with primary ovarian insufficiency owing to a mosaicism of Turner Syndrome

RESUMEN La Insuficiencia Ovárica Primaria se define por una amenorrea secundaria de al menos cuatro meses de duración, deficiencia de esteroides sexuales (estradiol) y altas concentraciones séricas de hormona folículoestimulante (FSH) con al menos un mes de diferencia entre estas determinaciones, en mujeres menores de 40 años. Es una causa insidiosa de infertilidad pero en algunas ocasiones es transitoria y permite una gestación espontánea. El Síndrome de Turner es un trastorno genético caracterizado por la pérdida o anomalías estructurales de un cromosoma X y que afecta a 1 de cada 2.500 mujeres nacidas vivas. Las manifestaciones clínicas varían entre pacientes, pero generalmente se relaciona con talla baja, coartación aórtica, disgenesia gonadal e insuficiencia ovárica primaria. Las técnicas de reproducción asistida como la criopreservación de ovocitos y de tejido ovárico, la maduración in vitro o la donación de ovocitos ofrecen opciones reproductivas en aquellos casos en los que no se produzca un embarazo espontáneo.

ABSTRACT Primary Ovarian Insufficiency is considered a secondary amenorrhea of at least four months duration, sex steroid deficiency (estradiol) and high serum concentrations of follicle stimulating hormone (FSH) with at least one month difference between these determinations, in women under 40 years. It is an insidious cause of infertility but sometimes it is transient and allows a spontaneous pregnancy. Turner syndrome is a genetic disorder characterized by the loss or structural abnormalities of an X chromosome that affects 1 in 2,500 women born alive. Clinical manifestations vary among patients, but it is usually associated with short stature, aortic coarctation, gonadal dysgenesis, and primary ovarian failure. Assisted reproduction techniques such as cryopreservation of oocytes and ovarian tissue, in vitro maturation or oocyte donation offer reproductive options in those cases in which there is no spontaneous pregnancy.

Síndrome de Turner: nuestra experiencia en la creación del Registro Institucional y de la Unidad Interdisciplinaria en el Hospital Italiano de Buenos Aires: un primer paso para el mejor seguimiento / Turner syndrome: our experience in the creation of the Registry Institutional and Interdisciplinary Unit at the Italian Hospital of Buenos Aires: a first step to the best follow-up

El síndrome de Turner (ST) resulta de la ausencia completa o parcial del segundo cromosoma sexual en fenotipos femeninos. Tiene una incidencia de 1:2000- 2500 nacidas vivas. Recién en la última década se ha puesto atención a la salud de las adultas con ST. La mortalidad es 3 veces superior respecto de la población general debido al riesgo de disección aórtica por anomalías cardiovasculares estructurales y aterosclerosis vinculada a hipertensión arterial, diabetes, dislipidemia y obesidad. También presentan elevada prevalencia de enfermedades autoinmunitarias. Objetivo: evaluar la calidad del seguimiento clínico de pacientes adultas con ST, comparando los controles de salud preconformación y posconformación del Registro y de la Unidad Interdisciplinaria. En el año 2017 fuimos convocados para integrar el Programa de Enfermedades Raras del Hospital Italiano de Buenos Aires. A partir de la creación del Registro Institucional y del equipo multidisciplinario obtuvimos mejoría significativa en los controles por las especialidades de cardiología, endocrinología y otorrinolaringología, en los controles bioquímicos del metabolismo lipídico, hidrocarbonado, hepatograma, TSH y anticuerpos para celiaquía e imágenes cardiovasculares y densitometría ósea. En conclusión, el seguimiento sistematizado e institucional, mediante el Registro y la creación de la Unidad Interdisciplinaria de Síndrome de Turner, permitió encontrar las falencias del sistema de atención y optimizar el seguimiento de esta población. (AU)

Turner syndrome (TS) results from the complete or partial absence of the second sex chromosome in female phenotypes. It has an incidence of 1: 2000-2500 girls born alive. Only in the last decade has been paid attention to the health of adults women with TS. Mortality is 3 times higher than in the general population due to the risk of aortic dissection cause to structural cardiovascular anomalies and atherosclerosis related to hypertension, diabetes, dyslipidemia and obesity. They also have a high prevalence of autoimmune diseases. Until nowadays in Argentina do not exist a national registry of this disease that complies with the international follow-up recommendations for these patients. We proposed to develop the institutional register at 2014 and a multidisciplinary team was created to care and follow up girls and women with TS during 2015. It was indexed to Italian Hospital of Buenos Aires' Rare Diseases Program since 2017. After the creation of the institutional registry and the multidisciplinary team we obtained a significant improvement in cardiology, endocrinology and otorhinolaryngology schedule visits, in lipids and hydrocarbon metabolism, liver, thyroid and celiac diseases biochemical controls and in the performance of cardiovascular MNR and bone densitometry. In conclusion, the systematized and institutional follow-up, through the registry and the creation of the Interdisciplinary Unit of Turner Syndrome, allowed us to find the flaws of the care system and to optimize the follow up of this population. (AU)

Síndrome de Turner e polimorfismo genético: uma revisão sistemática / Turner syndrome and genetic polymorphism: a systematic review

Objetivo:Apresentar os principais resultados dos estudos que investigaram polimorfismos genéticos em síndrome de Turner, bem como sua associação com alguns sinais clínicos e etiologia desse distúrbio cromossômico.Fontes de dados:Revisão bibliográfica feita no PubMed, sem limite de período, com os seguintes termos: Turner syndrome and genetic polymorphism. Foram identificados 116 artigos e, de acordo com os critérios de inclusão e exclusão, 17 foram selecionados para leitura.Síntese dos dados:Os polimorfismos investigados em pacientes com síndrome de Turner estavam relacionados com déficit de crescimento, que causou baixa estatura, densidade mineral óssea baixa, autoimunidade e anomalias cardíacas, que podem estar presentes com frequências significativas nas pacientes. Também foi verificado o papel dos polimorfismos de único nucleotídeo (SNPs) na etiologia da síndrome de Turner, ou seja, na não disjunção cromossômica.Conclusões:Os polimorfismos genéticos parecem estar associados à síndrome de Turner. Entretanto, por conta dos poucos estudos publicados e dos achados contraditórios, pesquisas em diferentes populações são necessárias para esclarecer o papel dessas variantes genéticas para os sinais clínicos e a etiologia do distúrbio cromossômico.

Objective:To present the main results of the literature on genetic polymorphisms in Turner syndrome and their association with the clinical signs and the etiology of this chromosomal disorder.Data sources:The review was conducted in the PubMed database without any time limit, using the terms Turner syndrome and genetic polymorphism. A total of 116 articles were found, and based on the established inclusion and exclusion criteria 17 were selected for the review.Data synthesis:The polymorphisms investigated in patients with Turner syndrome were associated with growth deficit, causing short stature, low bone mineral density, autoimmunity and cardiac abnormalities, which are frequently found in patients with Turner syndrome. The role of single nucleotide polymorphisms in the etiology of Turner syndrome, i.e., in chromosomal nondisjunction, was also confirmed.Conclusions:Genetic polymorphisms appear to be associated with Turner syndrome. However, in view of the small number of published studies and their contradictory findings, further studies in different populations are needed in order to clarify the role of genetic variants in the clinical signs and etiology of the Turner syndrome.

Turner syndrome and metabolic derangements: another example of fetal programming.

BACKGROUND AND AIM: Turner syndrome (TS) patients have an increased risk of weight gain and metabolic syndrome. To date, it is unknown what factors are involved in this metabolic process, even though it is recognized that TS patients are frequently born small-for-gestational age. The aim of this study was to evaluate the correlation between lipid and glucose profiles with being overweight and birth weight and length in TS patients. STUDY DESIGN: This was a cross-sectional study. SUBJECTS AND OUTCOME MEASURES: Serum glucose, insulin (HOMA-IR), total cholesterol, and triglycerides were measured in 64 patients with TS. Data regarding birth weight and length and current body mass index (BMI) were also evaluated. RESULTS: Total cholesterol showed a significant negative correlation with birth weight and a positive correlation with BMI; triglycerides showed significant negative correlation with birth weight and length and a positive correlation with BMI; and HOMA-IR showed a significant negative correlation with birth weight and length. Low birth weight and a high BMI were predictive for 28% of total cholesterol and triglycerides; and low birth weight for 22% of HOMA-IR. CONCLUSIONS: Lipid profile was correlated with a high current BMI and low birth weight and length in TS patients and glucose profile only with low birth weight. Thus far, growth retardation may play a role in metabolic derangements in this group of patients, being considered another example of fetal programming.

The role of SRY mutations in the etiology of gonadal dysgenesis in patients with 45,X/46,XY disorder of sex development and variants.

BACKGROUND: The potential involvement of SRY in abnormal gonadal development in 45,X/46,X,der(Y) patients was proposed following the identification of SRY mutations in a few patients with Turner syndrome (TS). However, its exact etiological role in gonadal dysgenesis in patients with Y chromosome mosaicisms has not yet been clarified. AIMS: it was the aim of this study to screen for allelic variation in SRY in a large cohort of patients with disorders of sex development due to chromosomal abnormalities with 45,X/46,X,der(Y) karyotype. PATIENTS: twenty-seven patients, 14 with TS and 13 with mixed gonadal dysgenesis (MGD), harboring 45,X/46,X,der(Y) karyotypes were selected. METHODS: Genomic DNA was extracted from peripheral blood leukocytes of all patients and from gonadal tissue in 4 cases. The SRY coding region was PCR amplified and sequenced. RESULTS: We identified only 1 polymorphism (c.561C→T) in a 45,X/46,XY MGD patient, which was detected in blood and in gonadal tissue. CONCLUSION: our results indicate that mutations in SRY are rare findings in patients with Y chromosome mosaicisms. Therefore, a significant role of mutated SRY in the etiology of gonadal dysgenesis in patients harboring 45,X/46,XY karyotype and variants seems very unlikely.

Patología nefrourológica en niñas con síndrome de Turner / Nephrourologic pathology in girls with Turner syndrome

Las malformaciones nefrourológicas en el síndrome de Turner son frecuentes, por lo que su diagnóstico y seguimiento son importantes para disminuir la morbilidad de esta entidad. El objetivo de este trabajo retrospectivo fue analizar la patología nefrourológica en 72 niñas con síndrome de Turner atendidas entre 1989 y 2008 en el Hospital Garrahan. La prevalencia de patología nefrourológica fue del 33% (24 pacientes). Predominaron las anomalías del sistema urinario aisladas (10 pacientes, 42%) o asociadas a malformaciones renales (9 pacientes, 37%); 5 pacientes (21%) tuvieron anomalías estructurales renales aisladas. El 50% presentó complicaciones (8 infección urinaria, 2 proteinuria y 2 hipertensión arterial).

Nephrourologic malformations in Turner syndrome are frequent, its diagnosis and follow-up is important in order todiminish the morbidity of this disease. The aim of this retrospective study was to analyze the nephrourologic pathologyin 72 girls with Turner syndrome followed between 1989 and 2008 at Garrahan Hospital. The prevalence of nephrourologic involvement was 33% (24 patients). The most frequent findings were urinary system malformations, isolated (10 pacientes,42%) or associated with renal malformations (9 patients, 37%); 5 patients (21%) had only renal malformations. Fifty percent of patients developed complications (8 urinary tractinfection, 2 proteinuria and 2 arterial hypertension); however, none progressed to chronic renal failure. The prevalence of nephrourologic involvement was 33% and a half of these girls developed complications, our findings show the need of routine nephrological follow-up of girls with Turner syndrome and nephrourologic malformations.

Fragile X prenatal analyses show full mutation females at high risk for mosaic Turner syndrome: fragile X leads to chromosome loss.

The fragile X mutation is an expansion of a CGG triplet repeat in the 5' untranslated region of the FMR1 gene. Expansion to >200 repeats (the "full mutation") silences FMR1 transcription and leads to the fragile X mental retardation syndrome in males and in some females. It also affects the structure of the mitotic chromosome as evidenced by a folate sensitive fragile site. Isolated cases of 45,X/46,XX (mosaic Turner syndrome) in full mutation females have been reported but an increased prevalence was not apparent from these reports. PCR and Southern analysis of the CGG repeat in 423 prenatal female samples identified 106 full mutation cases. Surprisingly five of these had 45,X/4,6XX mosaicism while none of the other 317 female fetuses did. In two of the five cases >or=50% of the cells were reported to be 45,X and in the other three,

Revisitando o desvendamento da etiologia da síndrome de Turner / Revisiting establishment of the etiology of Turner syndrome

Com base em entrevista com José Carlos Cabral de Almeida, o artigo aborda a investigação que culminou no estabelecimento da etiologia genética da síndrome de Turner. Além de discutir especificamente esse processo, do qual fez parte, o entrevistado discorre sobre outros trabalhos que, em sua avaliação, marcaram as origens da citogenética. O artigo apresenta ainda a visão atual de Cabral sobre o desenvolvimento da genética clínica e a importância da citogenética em prover meios mais precisos de diagnose, prognóstico e controle das doenças genéticas. A conclusão aponta os trabalhos referidos como pioneiros e, até hoje, relevantes para a genética médica, especialmente no estudo dos cromossomos humanos, aspecto ainda fundamental para o sucesso da correlação de genética humana e processos de adoecimento.(AU)

Hidrops fetal no inmune: presentación de un caso y revisión de la literatura / No immune fetal hydrops: a case report and literature review

El hidrops fetal no inmune (HFNI) es una importante causa de pérdida perinatal, con mortalidad que varía entre 50-100 por ciento. El HFNI es una condición causada por un grupo heterogéneo de patologías. La fisiopatología del desorden que lo produce se conoce en muchos casos. Sin embargo, existen muchos casos en que la causa no se puede detérminar. Presentar un caso de hidrops fetal no inmune, el estudio realizado y la revisión de la literatura. Un caso de hidrops fetal no inmune, fue diagnósticado por ultrasonido antenatal a las 298 semanas de gestación. El feto murió al nacer, el cariotipo de muestra de sangre obtenida del cordón umbilical fue anormal. El examen postmorten fue compatible con Síndrome de Tuner e Higroma Quístico. En el presente caso el HFNI fue causado por la cromosomopatía tipo monosomía X y la anatomía linfática denominada higroma quístico. Todos los casos de HFNI deben ser evaluados prenatalmente para un adecuado diagnóstico y tratamiento cuando la mortalidad es prevenible.

Female pseudohermaphroditism due to classical 21-hydroxylase deficiency and insulin resistance in a girl with Turner syndrome.

We report five-year-old girl with female pseudohermaphroditism due to classical form of 21-hydroxylase deficiency associated with Turner's syndrome (45,X/46,XX) and insulin resistance. She had clitoromegaly since birth, but Turner's syndrome and 21-hydroxylase deficiency were diagnosed incidentally at one and five years of age, respectively. Moreover, we determined insulin resistance, which resolved following corticosteroid therapy for disease. We regard the rare combination as a coincidental occurrence. We stress that adrenal function should be assessed, at least in the presence of clitoral enlargement, in patients with Turner's syndrome, particularly if their karyotype does not contain a Y chromosome. We conclude that chronic hypersecretion of androgen precursors due to an inborn error of metabolism can induce a reduction in insulin sensitivity. Improvement in insulin resistance after treatment of hyperandrogenism has not been previously reported.

Disgenesia gonadal mixta con fórmula cromosómica 45,X/46,X, (mar): Presentación de una paciente / Mixed gonodal dysgenesis with chromosomic formula 45, X/46,X (mar): A case report

Se presentó una paciente con estigmas turnerianos y cariotipo 45,X/46,XX con diagnóstico inicial de síndrome de Turner a la que se le realizó clitoridectomía por hipertrofia del clítoris a los 8 meses de edad. Se reevaluó a los 6 años de edad y se le realizó cariotipo con técnicas de bandas G (GTG) con fórmula cromosómica de 45,X/46,X, (cromosoma marcador -mar); dicho marcador dio la impresión de una deleción del cromosoma X desde Xq13 ®Xq ter y Xp22 ®Xp ter. Se completó dicho estudio con técnica molecular de reacción en cadena de la polimerasa (PCR) y se identificó el gen SRY en el cromosoma marcador. Se realizó intervención quirúrgica por mínimo acceso y se comprobó ausencia de útero así como trompa en el lado derecho con ausencia de gónada y en el lado opuesto, testículo rudimentario; se planteó el diagnóstico de disgenesia gonadal mixta(AU)

Características del crecimiento en pacientes con síndrome de Turner y sus posibilidades terapéuticas actuales / Growth characteristics in patients with Turner's syndrome and therapeutic possibilities

Se describen las características del crecimiento estatural de pacientes con síndrome de Turner, señalando las variaciones en la velocidad de crecimiento que se producen a diferentes edades y las alteraciones hormonales que podrían estar condicionando el retraso estatural. Se analizan los resultados de estudios que han probado diferentes combinaciones de hormonas, entre ellas la hormona de crecimiento, oxandrolona y estrógenos con la finalidad de mejorar la talla final de estos pacientes

Disgenesia gonadal / Gonadal dysgenesis

Entre as causas de amenorreia primaria destacam-se, por sua importancia, as disgenesias gonadais. Essa entidade clinica apresenta-se com variados tipos de anomalias cromossomicas, tendo como caracteristica comum a presenca de gonadas em fita, contendo tecido sem atividade endocrina. Os autores fazem revisao da literatura e tecem comentarios acerca do diagnostico e tratamento desse grupo de anomalias relativamente incomuns na pratica ginecologica

Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features.

Although clinical features in Turner syndrome have been well defined, underlying genetic factors have not been clarified. To deduce the factors leading to the development of clinical features, we took the following four steps: (1) assessment of clinical features in classic 45,X Turner syndrome; (2) review of clinical features in various female sex chromosome aberrations (karyotype-phenotype correlations); (3) assessment of factors that could lead to Turner features; and (4) correlation of the clinical features with the effects of specific factors. The results indicate that the clinical features in 45,X and in other female sex chromosome aberrations may primarily be determined by: (1) degree of global non-specific developmental defects caused by quantitative alteration of a euchromatic or non-inactivated region; (2) dosage effect of a pseudoautosomal growth gene(s), a Y-specific growth gene(s), and an Xp-Yp homologous lymphogenic gene(s); and (3) degree of chromosome pairing failure in meiocytes that are destined to develop as oocytes in the absence of SRY. 1991; Grumbach and Conte 1992). However, the pertinent factors have not been determined to date. The method to clarify the factors responsible for the development of the Turner phenotype can be broken down into the following steps: (1) assessment of clinical features in classic 45,X Turner syndrome; (2) review of clinical features in various female sex chromosome aberrations (karyotype-phenotype correlations); (3) assessment of factors that could lead to Turner features; and (4) correlation of the clinical features with the effects of specific factors. If the clinical features in 45,X and in other female sex chromosome aberrations are explained by the effects of specific factors, it can be said that such factors contribute to the development of Turner features. In this paper, we take each of the above steps, and propose the principal factors involved in the development of clinical features in Turner syndrome.

Estrogen therapy in Turner's syndrome.

Girls with Turner's syndrome are born short, grow slowly, and usually fail to enter puberty spontaneously and to undergo a pubertal growth spurt. The goal of estrogen therapy is to correct estrogen deficiency in a manner that optimizes height potential, permits attainment of normal bone mass, and provides appropriate feminization with minimal risk of adverse effects. The issues to be resolved include the age at which treatment should be begun, the preparation, route of administration, and dosage to be given, the effect on concurrent growth hormone administration, the rate of dose increase during treatment, the timing and nature of progestin administration, and the total duration of treatment. The available data suggest that treatment should be initiated between the ages of 12 and 14 years. The dose-response relationship between growth rate and estrogen dose is biphasic. Optimal growth stimulation for ethinyl estradiol occurs at approximately 100 ng/kg body weight per day, which is below the dose that produces full feminization. Although suboptimal doses of estrogen and growth hormone appear to have additive effects, estrogen causes only a minor increase in the short-term growth response to an optimal dose of growth hormone. The long-term effects of estrogen combined with growth hormone are unknown. In the absence of data concerning the outcome of different dose schedules, we treated for 2 years at 100 ng/kg/day of ethinyl estradiol, then double the dose annually until menstruation, at which time cyclic monthly progestin therapy is added (medroxyprogesterone acetate 10 mg daily from days 16 to 25). The importance of estrogen in maintaining normal bone mass suggests that treatment should be lifelong. Current research in our clinic is assessing the long-term effect on adult height of ultra-low-dose treatment (25 to 50 ng/kg/day of ethinyl estradiol) during the childhood years (ages 5 to 11), alone or in conjunction with supplemental growth hormone.