Epididymis cell atlas in a patient with a sex development disorder and a novel NR5A1 gene mutation / 亚洲男科学杂志(英文版)

This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development (DSD) patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene. Next-generation sequencing found a heterozygous c.124C>G mutation in NR5A1 that resulted in a p.Q42E missense mutation in the conserved DNA-binding domain of NR5A1. The patient demonstrated feminization of external genitalia and Tanner stage 1 breast development. The surgical procedure revealed a morphologically normal epididymis and vas deferens but a dysplastic testis. Microfluidic-based single-cell RNA sequencing (scRNA-seq) analysis found that the fibroblast cells were significantly increased (approximately 46.5%), whereas the number of main epididymal epithelial cells (approximately 9.2%), such as principal cells and basal cells, was dramatically decreased. Bioinformatics analysis of cell-cell communications and gene regulatory networks at the single-cell level inferred that epididymal epithelial cell loss and fibroblast occupation are associated with the epithelial-to-mesenchymal transition (EMT) process. The present study provides a cell atlas of the epididymis of a patient with 46,XY DSD and serves as an important resource for understanding the pathophysiology of DSD.

Application of low-depth whole genome sequencing for copy number variation analysis in children with disorders of sex development / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of copy number variation sequencing (CNV-seq) for the diagnosis of children with disorders of sex development (DSD).@*METHODS@#Five children with DSD who presented at the First Affiliated Hospital of Zhengzhou University from October 2019 to October 2020 were enrolled. In addition to chromosomal karyotyping, whole exome sequencing (WES), SRY gene testing, and CNV-seq were also carried out.@*RESULTS@#Child 1 and 2 had a social gender of female, whilst their karyotypes were both 46,XY. No pathogenic variant was identified by WES. The results of CNV-seq were 46,XY,+Y (1.4) and 46,XY,-Y (0.75), respectively. The remaining three children have all carried an abnormal chromosome Y. Based on the results of CNV-seq, their karyotypes were respectively verified as 45,X[60]/46,X,del(Y)(q11.221)[40], 45,X,16qh+[76]/46,X,del(Y)(q11.222),16qh+[24], and 45,X[75]/46,XY[25].@*CONCLUSION@#CNV-seq may be used to verify the CNVs on the Y chromosome among children with DSD and identify the abnormal chromosome in those with 45,X/46,XY. Above results have provided a basis for the clinical diagnosis and treatment of such children.

An approach to the management and care of an individual with 46, XX ovotesticular disorder of sexual differentiation / Philippine Journal of Obstetrics and Gynecology

@#Ovotesticular disorder of sexual differentiation (OT-DSD) is a rare condition defined by the presence of both testicular and ovarian elements in the same individual. Definitive diagnosis is made based on histological assessment of the gonad/s confirming both ovarian and testicular components. In this paper, we describe how a diagnosis of 46XX, OT-DSD was made in a 20-year-old individual with enlarged breasts and ambiguous genitalia. The initial impression was congenital adrenal hyperplasia (CAH) based on 46, XX karyotype and absence of testes on physical examination and imaging. However, biochemical tests were inconsistent with CAH, hence a more probable diagnosis of 46, XX OT-DSD was considered. The patient suffered from gender dysphoria and after extensive counseling, he decided to undergo gender-affirming surgery: laparoscopic excision of the left gonad, subtotal hysterectomy, bilateral mastectomy, and a masculinizing genitoplasty. Histopathology of the left gonad revealed an ovotestes which confirmed the diagnosis of 46, XX OT-DSD.

Um capítulo esquecido na história da psicologia? sexualidades desviantes, psicopatologia e normalidade / A forgotten chapter in the history of psychology? deviant sexualities, psychopathology, and normality / ¿Un capítulo olvidado en la historia de la psicología? sexualidades desviadas, psicopatología y normalidad

Este artigo tem como objetivo produzir uma análise histórica sobre as intersecções entre Psicologia e sexualidade desviantes da norma no Brasil, de fins do século XIX a meados da década de 1980. Esta temporalidade foi escolhida por abarcar o surgimento das pesquisas científicas sobre sexualidade e desvios sexuais, a consolidação dos estudos psicológicos sobre a temática e o processo mais recente de despatologização da homossexualidade. Em termos teóricos e metodológicos, foram adotados os pressupostos da História Social da Psicologia e da historiografia das homossexualidades no Brasil. Desse modo, buscou-se compreender como as ideias, concepções e práticas psicológicas foram mudando ao longo do tempo, em conexão com as transformações socioculturais e políticas que ocorreram durante o século XX. Para isto, foram utilizadas fontes primárias e secundárias de pesquisa com vistas à produção de interpretações sobre as conexões entre as ideias, os atores e os eventos narrados. Argumenta-se, ao longo do artigo, que as ideias e práticas psicológicas estão intrinsecamente conectadas aos contextos socioculturais e políticos de seu tempo, sendo os movimentos dinâmicos e os conflitos presentes nesses contextos fatores determinantes para a sua constituição.(AU)

This article aims to produce a historical analysis of the intersections between Psychology and sexualities that deviate from the norm in Brazil, from the late 19th century to the mid-1980s. This period was chosen because it encompasses the emergence of scientific research on sexuality and sexual deviations, the consolidation of psychological studies on the subject and the most recent process of de-pathologization of homosexuality. Theoretically and methodologically, the assumptions of the Social History of Psychology and the historiography of homosexualities in Brazil were adopted. Therefore, we sought to understand how psychological ideas, conceptions and practices have changed over time, in connection with the sociocultural and political transformations that occurred throughout the 20th century. For this, primary and secondary sources of research were used to produce interpretations about the connections between the ideas, the actors and the narrated events. It is argued, throughout the article, that the psychological ideas and practices are intrinsically connected to the sociocultural and political contexts of their time, being the dynamic movements and conflicts present in these contexts determining factors for their constitution.(AU)

Este artículo tiene como objetivo realizar un análisis histórico de las intersecciones entre la Psicología y las sexualidades desviadas de la norma en Brasil desde finales del siglo XIX hasta mediados de la década de 1980. Esta temporalidad fue elegida por abarcar el surgimiento de las investigaciones científicas sobre sexualidad y desvíos sexuales, la consolidación de los estudios psicológicos sobre el tema y el más reciente proceso de despatologización de la homosexualidad. En el marco teórico y metodológico, se adoptaron los presupuestos de la Historia Social de la Psicología y de la historiografía de las homosexualidades en Brasil. De esta manera, se pretende comprender cómo las ideas, concepciones y prácticas psicológicas han cambiado a lo largo del tiempo, en conexión con las transformaciones socioculturales y políticas ocurridas durante el siglo XX. Para ello, se utilizaron las fuentes de investigación primarias y secundarias con miras a generar interpretaciones sobre las conexiones entre las ideas, los actores y los eventos narrados. Se argumenta, a lo largo de este artículo, que las ideas y las prácticas psicológicas están intrínsecamente conectadas a los contextos socioculturales y políticos de su tiempo, y los movimientos dinámicos y los conflictos presentes en estos contextos fueron los factores determinantes para su constitución.(AU)

Clinical features of unrecognized congenital adrenal hyperplasia due to 17α-hydroxylase deficiency since adolescence: A case report / Journal of the ASEAN Federation of Endocrine Societies

@#The majority of patients with congenital adrenal hyperplasia (CAH) present with a deficiency of 21-hydroxylase or 11-beta-hydroxylase, which account for 90% and 7% of cases, respectively. However, CAH due to 17α-hydroxylase deficiency (17OHD) is an extremely rare form of CAH (<1% of all CAH cases) that leads to a deficiency of cortisol and sex steroids, along with features of aldosterone excess. This is a case of a 51-year-old single female who was referred to us for the evaluation of new-onset hypertension and hypokalaemia of one-year duration. She was born out of a second-degree consanguineous marriage and reared as a female. She was diagnosed to have testicular feminization syndrome when she presented with a history of primary amenorrhea, absence of secondary sexual characteristics, and bilateral labial swellings at pubertal age. Subsequently, she underwent gonadectomy at the age of 16. Due to the presence of hypertension, metabolic alkalosis and bilaterally enlarged adrenals on CT scan, 46, XY disorders of sexual development (DSD) was considered. A karyotype confirmed the presence of 46, XY chromosomal sex, and genetic analysis revealed a mutation in the CYP17A1 gene, thus confirming the diagnosis of 17a-hydroxylase deficiency.

Proporción sexual y hermafroditismo del molusco, Anadara tuberculosa (Bivalvia: Arcidae) en Panamá / Sexual proportion and hermaphroditism of the mollusc, Anadara tuberculosa (Bivalvia: Arcidae) in Panama

Introducción: El bivalvo Anadara tuberculosa es un recurso pesquero y económico importante en el Pacífico Este Tropical. La proporción sexual varia a lo largo de su área de distribución, con casos de aparición de hermafroditismo, ocasional para algunas poblaciones, normal en otras. Estas características podrían ser una respuesta a presiones antropogénicas y ambientales. Objetivo: Evaluar la proporción sexual y el hermafroditismo en la especie en el Pacífico de Panamá. Métodos: Se analizó información reproductiva de A. tuberculosa generada entre 1994 y 2020 para el Golfo de Montijo, así como datos de 2017 para el manglar de David. Se aplicaron procedimientos macroscópicos, contrastados con histológicos y se generó un factor de corrección para ajustar la proporción sexual macroscópica, debido al efecto, sobre la proporción sexual, que ocasiona los organismos indeterminados. Resultados: Para el Golfo de Montijo, la histología indicó una proporción sexual hembra a macho de 1:1 hasta 3.2:1, entre 1994 y 2017, mientras que la macroscopía varió de 1.9:1 a 5.1:1 entre 2004 y 2020. Para el manglar de David, la histología indicó una proporción sexual de 3.7:1, y de 7.9:1 por macroscopía en el 2017. En ambas localidades, especímenes más grandes mostraron mayor variación en la proporción sexual, pese a la técnica implementada, así como hermafroditismo protándrico no casual en el 2017. Conclusiones: La aparición del hermafroditismo protándrico y los cambios en la proporción sexual indican que la población de A. tuberculosa, en ambas localidades, está respondiendo a presiones antropogénicas y ambientales.

Introduction: The bivalve Anadara tuberculosa is an important fishery in the Eastern Tropical Pacific. The sex ratio varies along its geographic range and there are cases of hermaphroditism, occasional in some populations, normal in others. These characteristics may be a response to anthropogenic and environmental pressure. Objective: To evaluate sex ratio and hermaphroditism of the species in the Panamanian Pacific. Methods: Data on reproductive features of A. tuberculosa generated between 1994 and 2020 for Gulf of Montijo, as well as 2017 data from mangroves of David was analyzed. Macroscopic diagnosis of individual sex is sensitive to the problem of indeterminate individuals, which in turn can skew the sex ratio analysis; therefore, the macroscopic method was compared with histological sections to generate a correction factor to adjust the macroscopically determined sex ratio. Results: For Montijo, histology indicated that the female to male sex ratio ranged from 1:1 to 3.2:1 between 1994 and 2017, while macroscopy indicated 1.9:1 to 5.1:1 between 2004 and 2020. For David, histology indicated a ratio of 3.7:1, and macroscopy 7.9:1. At both localities, larger specimens had more sex ratio variation, independently of the technique, and there was non-casual protandric hermaphroditism in 2017. Conclusion: The occurrence of protandric hermaphroditism and sex ratio changes suggest anthropogenic and environmental pressure in all populations.

Síndrome de insensibilidad completa a andrógenos / Complete androgen insensitivity syndrome

El síndrome de insensibilidad a los andrógenos (SIA), conocido también como un síndrome de feminización testicular, incluye un grupo variado de mutaciones que se relacionan con la disfunción de los receptores de andrógenos y la resistencia de los tejidos diana a la acción de las hormonas masculinas. Es causado por alteraciones genéticas localizadas en la secuencia de codificación de los receptores de andrógenos ligada al cromosoma Xq11 - 12, el gen que codifica al receptor de los andrógenos, de un individuo genéticamente masculino (46 XY). Las formas clínicas moderada, parcial o completa, dependen del grado de insensibilidad androgénica. Los avances en las causas genéticas han permitido que estas condiciones congénitas de desarrollo del sexo cromosómico, gonadal o anatómico atípico sean denominados trastornos de diferenciación sexual

Androgen insensitivity syndrome (AIS), also known as testicular feminization syndrome, includes a diverse group of mutations that are related to androgen receptor dysfunction and resistance of target tissues to the action of hormones masculine. It is caused by localized genetic alterations in the androgen receptor coding sequence linked to chromosome Xq11-12, the gene encoding the androgen receptor, of a genetically male (46 XY) individual. Moderate, partial, or complete clinical forms depend on the degree of androgen insensitivity. Advances in genetic causes have allowed these congenital conditions of atypical chromosomal, gonadal, or anatomical sex development to be called disorders of sexual differentiation

Leydig and Sertoli cell function in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion: a case-control study

Abstract BACKGROUND: Because normal male sexual differentiation is more complex than normal female sexual differentiation, there are more cases of disorders of sex development (DSDs) with 46,XY karyotype that have unclear etiology. However, Leydig and Sertoli cell markers are rarely used in distinguishing such individuals. OBJECTIVES: To evaluate the function of Leydig and Sertoli cells in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion. STUDY DESIGN AND SETTING: Case-control study with 77 patients, including eight with partial androgen insensitivity syndrome, eight with 5α-reductase deficiency type 2 (5ARD2) and 19 with idiopathic 46,XY DSD, and 42 healthy controls, from the Interdisciplinary Study Group for Sex Determination and Differentiation (GIEDDS), at the State University of Campinas (UNICAMP), Campinas, Brazil. METHODS: Baseline levels of gonadotropins, anti-Müllerian hormone (AMH), inhibin B, insulin-like 3 (INSL3), testosterone and dihydrotestosterone in cases, and AMH, inhibin B, and INSL3 levels in controls, were assessed. RESULTS: There was no significant difference in age between cases and controls (P = 0.595). AMH and inhibin B levels were significantly lower in cases than in controls (P = 0.031 and P < 0.001, respectively). INSL3 levels were significantly higher in cases than in controls (P = 0.003). Inhibin B levels were lower in 5ARD2 patients (P = 0.045) and idiopathic patients (P = 0.001), in separate comparisons with the controls. CONCLUSION: According to our findings, we can speculate that inhibin B levels may be used to differentiate among DSD cases.

Swyer syndrome (46, XY complete gonadal dysgenesis): A rare case of primary amenorrhea / Philippine Journal of Obstetrics and Gynecology

@#Swyer syndrome is a type of gonadal dysgenesis wherein a 46,XY karyotype presents with a female phenotype. It is a rare cause of disorder in sexual development that occurs in 1:100,000 births. Local studies are currently limited to few case reports. Sex-determining region on the Y chromosome gene mutation is the root cause of nonfunctional gonads with no hormonal or reproductive potential. They are born with normal female external genitalia but not suspected until puberty when menses do not occur or if secondary sexual characteristics do not develop. This report presents the case of a 23-year-old phenotypically female presenting with primary amenorrhea and hypogastric discomfort. Ultrasound revealed an infantile cervix and uterus with streak left ovarian tissue and a cystic mass on the right pelvic area. Gonadotropin levels were elevated, and the karyotype showed a normal male 46,XY. Laparoscopic bilateral gonadectomy with salpingectomy was done, which revealed dysgerminoma on bilateral ovarian tissues. In conclusion, this report describes a rare case of Swyer syndrome associated with ovarian dysgerminoma. Accurate and prompt diagnosis, using a systematic approach in evaluating primary amenorrhea, is crucial in initiating treatment. Our goal is to ensure hormonal replacement, fertility preservation, psychosexual and emotional stress reduction, and overall patient survival.

Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development / 中华儿科杂志

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

Interpretación medicolegal para el abordaje de individuos con desórdenes del desarrollo sexual en Colombia / Interpretation of medical-legal Colombian legislation to treat individuals with disorders of sexual development

Objetivo Los desórdenes del desarrollo sexual (DDSs) son un grupo de condiciones médicas cuyo manejo implica un enfoque transdisciplinario. En la legislación colombiana, no existe una regulación específica en materia de intervenciones médicas en individuos con DDSs. La Corte Constitucional Colombiana se ha encargado de proferir sentencias, en las cuales se han establecido unos lineamientos y parámetros para el manejo jurídico de los casos de ambigüedad genital. Teniendo en cuenta lo anterior, nos proponemos en este artículo exponer y analizar, desde la visión de un grupo transdisciplinario, las sentencias más relevantes que han sido proferidas por la Corte Constitucional Colombiana. Métodos Se realizó una revisión narrativa en las bases de datos de la Corte Constitucional y de la literatura legal. Se recopilaron todas las sentencias disponibles, y se evaluaron lo casos clínicos identificados por el grupo transdisciplinario de DDSs del Hospital Universitario San Ignacio. Finalmente, los autores generaron por consenso un texto de discusión, como guía para los lectores, luego de analizar cada una de las sentencias y los casos presentados. Resultados Se identificaron 9 sentencias y los antecedentes que llevaron a la elaboración de cada una de ellas. Los nueve casos presentados contienen conceptos importantes para la articulación por parte del grupo transdisciplinario, tales como, autonomía, consentimiento sustituto y asistido, e indicación médica del tratamiento. Se excluyeron las sentencias T-692/99 y la T-918/2012, dado que daban información duplicada con referencia a sentencias incluidas en este documento. Conclusión La Corte Constitucional Colombiana ha proferido sentencias en las cuales no se ha contado con la participación de grupos de expertos. La terminología usada no describe apropiadamente el lenguaje técnico que se aplica al manejo de nuestros pacientes. Para el abordaje de individuos con DDSs, resulta muy importante conocer la relevancia de las sentencias basadas en un análisis individual de cada caso.

Objective Disorders of sexual development (DSDs) are a group of conditions that require a transdisciplinary approach. In the Colombian legislation, there are no specific regulations regarding medical interventions in individuals with DSDs. The Colombian Constitutional Court has issued sentences establishing some guidelines and parameters for the legal management of cases of genital ambiguity. Considering the aforementioned information, the present manuscript aims to describe and analyze, from the perspective of a transdisciplinary team, the most relevant sentences issued by the Colombian Constitutional Court. Methods We performed a narrative review of the database of the Colombian Constitutional Court and of the legal literature. We compiled all available court sentences and evaluated the clinical cases identified by the transdisciplinary team at Hospital Universitario San Ignacio. Lastly, the authors composed, through consensus, a text for discussion, as a guide to the readers, after the analysis of each of the sentences and cases presented. Results We identified nine sentences and the precedents that led to their development. The nine cases presented contain important concepts for the work of the transdisciplinary team, such as autonomy, substitute and assisted consent, and the medical indication of treatment. Sentences T-692/99 and T-918/2012 were excluded, as they provided duplicate information concerning sentences included in this document. Conclusion The Colombian Constitutional Court has issued sentences without the participation of a team of experts in DSDs. The terminology used does not properly describe the jargon that is applied in the management of our patients. In order to approach individuals with DSDs, awareness regarding the relevance of the sentences based on an individual analysis of each case is of great importance.

Cytogenetic and molecular characterization of an SRY-negative 46, XX ovotesticular DSD: a case report / Caracterização citogenética e molecular de um DDS ovotesticular 46, XX SRY-negativo: relato de caso

Introduction: Ovotesticular disorder of sex development is a rare condition characterized by the concomitant presence of testicular and ovarian tissue, and usually presents genital ambiguity. They are chromosomally heterogeneous, and cytogenetic analyses is relevant. Objective: to report a patient from Manaus, Amazonas state, Brazil, with ovotesticular disorder of sex differentiation 46,XX and SRY-negative. Case report: patient aged 19 years, first child of non-consanguineous parents, diagnosed at birth with genital ambiguity and, without correct diagnosis, was registered a male sex. The patient underwent surgery to correct bilateral cryptorchidism, orchiopexy and colpectomy. During puberty, he developed female and male sexual characteristics. Investigation at this time revealed: laboratory (normal total testosterone and estradiol as high follicle-stimulating hormone and luteinizing hormone, histopathological (right gonad, ovarian follicles and left gonad, atrophic testicles), karyotype (46, XX) and molecular (SRY-negative). Diagnosis of ovotesticular disorder of sex development was established. The patient chose to remain male and underwent bilateral mastectomy, vaginal colpectomy and bilateral gonadectomy. Currently, the patient receives hormonal replacement therapy, followup with a multi-professional approach and awaits masculinizing genitoplasty. Discussion: For OT-DSD individuals with 46, XX, the female sex is suggested as the best sex of rearing option. Unlike the reported cases, the patient chose the male sex, since the sex at registration of birth was important in his choice. Conclusion: Cytogenetic and molecular analyses allowed us to assist in the etiological diagnosis of the patient with OT-DSD. However, molecular analyses are necessary to elucidate the genes involved in the sexual determination of this patient.

Introdução: distúrbio da diferenciação do sexo ovotesticular é uma condição rara com presença concomitante de tecido testicular e ovariano, geralmente com ambiguidade genital. Os pacientes são cromossomicamente heterogêneos e a análise citogenética é fundamental. Objetivo: relatar o caso de um paciente do município de Manaus, Amazonas, portador de distúrbio da diferenciação do sexo ovotesticular 46, XX e SRY-negativo. Caso clínico: paciente de 19 anos, primeiro filho de pais não consanguíneos, que ao nascimento foi diagnosticado com ambiguidade genital, contudo, sem diagnóstico correto, foi registrado como sendo do sexo masculino. Foi submetido a cirurgias para correção da criptoquirdia bilateral, orquidopexia e colpectomia vaginal. Na puberdade, desenvolveu características sexuais feminina e masculina. Investigação diagnóstica mostrou: exames hormonais (testosterona total e estradiol normais enquanto hormônio folículo-estimulante e hormônio luteinizante elevados), histopatológicos (gônada direita, folículos ovarianos e gônadas esquerda, testículos atróficos), cariótipo (46, XX) e molecular (SRY-negativo). O diagnóstico de distúrbio da diferenciação do sexo ovotesticular foi estabelecido. O paciente optou por permanecer no sexo masculino e submeteuse à mastectomia bilateral, colpectomia vaginal e gonadectomia bilateral. Atualmente faz reposição hormonal, acompanhamento com abordagem multiprofissional e aguarda pela genitoplastia masculinizante. Discussão: aos indivíduos DDS-OT com 46, XX é sugerido como a melhor opção de sexo, o feminino. Diferentemente dos casos relatados, o paciente optou por permanecer no sexo masculino, visto que o registro de nascimento foi importante para a sua escolha. Conclusão: análises citogenéticas e moleculares permitiu auxiliar no diagnóstico etiológico do paciente com DDS-OT, contudo, análises moleculares são necessárias para elucidação de genes envolvidos na determinação sexual desse paciente.

Síndrome de insensibilidad a andrógenos: revisión bibliográfica a propósito de 5 casos / Androgen insensitivity syndrome: literature review about 5 cases

El síndrome de insensibilidad a andrógenos (AIS en la sigla inglesa) es una entidad muy poco frecuente en endocrinología. Se caracteriza por la mutación del receptor de andrógenos de magnitud variable, por medio del cual individuos 46,XY no se virilizan normalmente, a pesar de conservar sus testículos y tener concentraciones de testosterona en rango masculino. El cuadro clínico es variable y depende la profundidad de la alteración del receptor. En un extremo, hay casos de insensibilidad androgénica completa (CAIS) con fenotipo femenino. En el otro extremo hay insensibilidad parcial (PAIS) que se extiende desde el fenotipo femenino, con o sin ambigüedad genital, hasta los casos de hombres infértiles o con subvirilización, que presentan insensibilidad androgénica más leve. En los fenotipos femeninos, los testículos suelen estar en posición ectópica y aquellos ubicados dentro del abdomen tienen riesgo de malignizarse, por lo que suelen extirparse. Estos son los casos de más difícil manejo, pues aparte de la necesidad de gonadectomía seguida de terapia hormonal femenina, existe una vagina estrecha y en fondo de saco ciego y que suele requerir corrección quirúrgica para permitir la actividad sexual. En este trabajo presentamos 5 casos de AIS vistos recientemente en 2 centros clínicos de Santiago y que ilustran la heterogeneidad de presentación. Además, hacemos una revisión actualizada de los criterios diagnósticos, los tratamientos más adecuados y el manejo global de esta condición.

The Androgen insensitivity syndrome (AIS, in its English acronym) is a very rare entity in endocrinology. It is characterized by a variable magnitude androgen receptor mutation, whereby 46, XY individuals are not normally virilized, despite retaining their testicles and having testosterone concentrations in the male range. The clinical picture is variable and depends on the depth of the receptor alteration. At one extreme, there are cases of complete androgenic insensitivity (CAIS) with a female phenotype. At the other extreme, there is partial insensitivity (PAIS) that extends from the female phenotype, with or without genital ambiguity, to cases of infertile or undervirilized men, who have milder androgenic insensitivity. In female phenotypes, the testes are usually in an ectopic position and those located within the abdomen are at risk of malignancy, and therefore are usually removed. These are the most difficult cases to manage because apart from the need for gonadectomy followed by female hormonal therapy, there is a narrow vagina and a deep blind pouch that usually requires surgical correction to allow sexual activity. In this work, we present 5 cases of AIS recently seen in 2 clinical centers in Santiago and that illustrate the heterogeneity of presentation. In addition, we make an updated review of the diagnostic criteria, the most appropriate treatments, and the overall management of this condition.

Genetic analysis of 46,XY disorders of sex development in children caused by a new NR5A1 gene variant / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with 46,XY disorders of sex development (DSD) and explore its genotype-phenotype correlation.@*METHODS@#The child was subjected to whole exome sequencing (WES), and exons 1 to 7 of NR5A1 were subjected to multiplex ligation-dependent probe amplification (MLPA) analysis.@*RESULTS@#The patient presented with rudimentary vulva of a female with Tanner stage 1. B-mode ultrasonography has detected ovary and uterus. The child was found to have a chromosome karyotype of 46,XY. WES revealed that the patient has harbored heterozygous deletion of exon 5 of the NR5A1 gene, which was a novel pathogenic variant inherited from the mother. No abnormality was found in the father.@*CONCLUSION@#The main symptoms of 46,XY DSD children are insufficient external genitalia masculinization, for which variants of the NR5A1 gene are an important cause. WES has improved the detection rate of genetic variants and provided a solid basis for genetic counseling of the affected families.

Advance in research on the role of MAMLD1 gene in disorders of sex development / 中华医学遗传学杂志

MAMLD1 gene has been implicated in 46,XY disorders of sex development (DSD) in recent years. Patients carrying MAMLD1 gene variants showed a "continuous spectrum" of simple micropenis, mild, moderate and severe hypospadias with micropenis, cryptorchidism, split scrotum and even complete gonadal dysplasia. The function of MAMLD1 gene in sexual development has not been fully elucidated, and its role in DSD has remained controversial. This article has reviewed recent findings on the role of the MAMLD1 gene in DSD, including the MAMLD1 gene, its encoded protein, genetic variants, clinical phenotype and possible pathogenic mechanism in DSD.

Why pediatricians need to know the disorders of sex development: experience of 709 cases in a specialized service / Por que os pediatras precisam conhecer os distúrbios da diferenciação do sexo: experiência de 709 casos de um serviço especializado

Abstract Objective: To evaluate, in a sample of patients with disorders of sex development (DSD), data related to the age at referral and their correlation with the initial complaints, gender at referral, defined gender after diagnosis and etiological diagnosis. Methods: Retrospective review of the age at the first consultation and the reason for it, initial social gender and gender after the diagnosis, karyotype and etiological diagnosis of all cases treated at a DSD outpatient clinic between 1989 and 2016. Cases that did not involve DSD and DSD diagnoses that do not usually involve ambiguous genitalia, thus not requiring specialized monitoring, were excluded. Results: Of the 1793 treated cases, 1139 were diagnosed with some type of DSD. This study excluded 430 cases (272 with Turner's syndrome, 66 with Klinefelter syndrome, and 92 with pure gonadal dysgenesis), thus a total 709 individuals were included. Of these, 82.9% were referred due to ambiguous genitalia; only one-quarter were still in the first month of life, and 6.6% were referred due to pubertal delay, with most of them aged 10 years or older. Of these patients, 68.6% had a diagnosis of XY DSD, 22.4% of XX DSD, and 9% of sex chromosome abnormalities. Conclusions: This study presents the largest series in the literature of patients with DSD treated in a single center. The time of referral of the majority of patients with ambiguous genitalia fell short of the ideal, and milder cases of ambiguous genitalia and many with pubertal manifestations were referred even later. The results reinforce the importance of continuing education for professionals who will have the first contact with these patients, mainly pediatricians and neonatologists.

Resumo Objetivo: Avaliar em uma amostra de pacientes com distúrbios da diferenciação do sexo (DDS), dados relacionados à idade, ao encaminhamento e sua correlação com as queixas iniciais, ao sexo ao encaminhamento e ao sexo final e diagnóstico etiológico. Métodos: Revisão retrospectiva da idade por ocasião da primeira consulta e motivo dela, sexo social inicial e após definição do diagnóstico, cariótipo e diagnóstico etiológico de todos os casos atendidos em um ambulatório especializado em DDS entre 1989 e 2016. Foram excluídos casos que não compreendiam DDS e diagnósticos de DDS que não cursam comumente com ambiguidade genital, não necessitam de acompanhamento especializado. Resultados: Dos 1.793 casos atendidos, 1.139 foram diagnosticados com algum DDS. Excluíram-se 430 (272 síndrome de Turner, 66 síndrome de Klinefelter e 92 disgenesia gonadal pura), totalizando 709. Desses, 82,9% foram encaminhados por ambiguidade genital, somente um quarto ainda no primeiro mês de vida e 6,6% por atraso puberal, a maioria com 10 anos ou mais; 68,6% tiveram diagnóstico de DDS XY; 22,4% DDS XX e 9% de anomalias dos cromossomos sexuais. Conclusões: Este estudo apresenta a maior casuística na literatura de pacientes com DDS atendidos em um único serviço. O momento de encaminhamento da maioria dos pacientes com ambiguidade genital foi aquém do ideal e casos mais leves de ambiguidade e muitos com manifestações puberais foram encaminhados ainda mais tardiamente. Os resultados reforçam a importância do ensino continuado a profissionais que terão o primeiro contato com esses pacientes, principalmente pediatras e neonatologistas.

O legado das regulações esportivas. Diagnóstico e consentimento na elegibilidade da categoria feminina / The legacy of sports regulations. Diagnosis and consent in the female category eligibility / El reglamento del legado del deporte. Diagnóstico y consentimiento para la elegibilidad de la categoría femenina

Resumo As regulações esportivas para definir a elegibilidade na categoria feminina são políticas antigas, datadas do começo do século XX, que atravessam disputas sobre o corpo, suas inscrições e possibilidades de futuro. De modo que a definição de um diagnóstico, com suas articulações de saúde, doença e cuidado terapêutico, concentram alguns atributos significativos para essa determinação de elegibilidade. Acompanhando um pouco da história da ex-judoca brasileira Edinanci Silva, vamos compreender como tais regulações constituem estratégias normativas de controle do corpo e da população, assim como mobilizam os cenários em que os sujeitos existem, se individualizam e cuidam de si. Essa difícil tarefa de consentir num contexto de crise, de risco e de humilhação diz muito sobre os limites dessas mesmas inclusões pelo esporte. No fim, também vamos entender porque a virilização feminina continua a ser medicalizada e importa mais do que a eficiência do rendimento esportivo propriamente dito.

Abstract The sports regulations to define the eligibility in the female category are old policies, dating from the beginning of the 20th century, which go through disputes over the body, its inscriptions and possibilities for the future. In this sense, the definition of a diagnosis, with its articulations of health, disease and therapeutic care, concentrate some significant attributes for this eligibility. Following a bit of the history of former Brazilian judoka Edinanci Silva, we'll understand how such regulations constitute normative strategies for controlling the body, the population, as well as mobilizing the scenarios in which the subjects exist, individualize and take care of themselves. This difficult task of consenting in a context of crisis, risk and humiliation says a lot about the limits of these same inclusions by sport. In the end, we'll also understand why female virilization continues to be medicalized and matters more than the efficiency of sports performance itself.

Resumen La normativa deportiva para definir la elegibilidad en la categoría femenina son políticas antiguas, fecha del comienzo del siglo 20, que pasan por disputas sobre el cuerpo, sus inscripciones y posibilidades de futuro. De modo que la definición de un diagnóstico, con sus articulaciones de salud, enfermedad y atención terapéutica, concentre algunos atributos significativos para esta determinación de elegibilidad. Siguiendo un poco de la historia de la ex-judoca brasileña Edinanci Silva, entenderemos cómo estas regulaciones constituyen estrategias normativas para controlar el cuerpo y la población, así como movilizar los escenarios en que los sujetos existen, se individualizan y se cuidan. Esta difícil tarea de consentir en un contexto de crisis, riesgo y humillación dice mucho sobre los límites de estas mismas inclusiones para el deporte. Al final, también entenderemos por qué la virilización femenina sigue medicalizada y es más importante que la eficacia del rendimiento deportivo en sí.

Disorders of sex development: A 5-year review of patients at a Tertiary Care Hospital

Background@#Disorders of Sex Development (DSD) are conditions that arise from an abnormality of the typical structural, chromosomal and/or gonadal characteristics of sex development. The incidence of DSD is not well established in the Philippines and there is no published local data. The complex nature of DSD requires streamlined multidisciplinary team management and guidelines from the 2006 Consensus meeting have become the standard of care for patients.@*Objective@#The study describes the phenotype, biochemical, diagnostic and management profiles of patients with Disorders of Sex Development (DSD) excluding congenital adrenal hyperplasia (CAH) at the Philippine General Hospital, a tertiary care medical facility. @*Methods@#Medical records of patients with DSD seen at the Division of Clinical Genetics from 2012-2016 were reviewed. Histories, demographic profiles, clinical features, co-existing health conditions, laboratory, imaging results, and interventions (medical or surgical) were recorded into a clinical report form. @*Results@#Fifty-five (55) patient charts were included of all the patients with DSD listed in the registry. The neonatal period was the most common time DSD was first noted (69.09%). Most (58.18%) were assigned the male sex. The most common genital anomalies were hypospadias (45.45%), cryptorchidism (21.82%), and micropenis (12.73%). Associated health conditions included multiple congenital anomalies (32.73%), genitourinary with or without gastrointestinal anomalies (16.36%) and dysmorphic features (12.73%). Among 28 patients with karyotypes, there were 12 patients with sex chromosome DSD; two 46, XX DSD and fourteen 46, XY DSD. Four patients were prescribed hydrocortisone, three of whom had higher levels of 17-OH progesterone beyond cut-off level (2 preterm, 1 full term) while 1 full term presented with genital ambiguity; one case of Klinefelter syndrome was given testosterone replacement. Ten patients underwent corrective surgery for urogenital anomalies. Repair of hypospadias was the most common procedure. Repairs of associated anomalies (neurologic, cardiac, gastrointestinal, genitourinary) were done in 6 patients.@*Conclusion@#Complete history, meticulous physical examination and comprehensive investigations are important for the confirmation of DSDs. Uniform classification, use of standardized terminology, and proper documentation of findings are crucial for the integrated and appropriate management of these patients.

Exploration of the pathogenesis for a SRY-negative male with 46,XX disorder of sex development / 中华医学遗传学杂志

OBJECTIVE@#To explore the pathogenesis for a SRY-negative male with 46,XX disorder of sex development (DSD).@*METHODS@#Peripheral blood samples of the patient and his family members were subjected to chromosomal karyotyping, routine PCR, real-time fluorescence quantitative PCR, whole exome sequencing and whole genome sequencing. The data was analyzed with NextGENe software.@*RESULTS@#Both the proband and his brother presented a 46,XX karyotype with negative SRY gene, while their father presented normal phenotype and karyotype with positive SRY gene. No pathogenic variant associated with sex development was detected by whole exome sequencing, while a 243 kb duplication was detected by whole genome sequencing in the 5' upstream region of the SOX9 gene in the proband, his brother and father. The same duplication was not found in his sister and mother.@*CONCLUSION@#The 243 kb duplication at the 5' upstream of the SOX9 gene may predispose to the 46,XX DSD in this family. It is speculated that there exist an unknown core regulatory element in the upstream of the SOX9, and its duplication may trigger expression of SOX9 and initiate testicular differentiation in the absence of SRY gene.