scholarly journals SUN-712 Familial 46, XY Complete Female External Sex Development with a Non-Mosaic Inherited SRY Gene Variation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Elisa Vaiani ◽  
Yen-Shan Chen ◽  
Pablo Ramirez ◽  
Maria Sonia Baquedano ◽  
Maria del carmen Malosetti ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Histopathological Examination ◽  
Genetic Diagnosis ◽  
High Mobility ◽  
Breast Development ◽  
Primary Amenorrhea ◽  
Gene Variation ◽  
Molecular Features ◽  
Sex Development ◽  
Normal Father

Abstract Context: SRY, an architectural transcription factor containing a SOX-related high-mobility group (HMG) box, initiates testis formation in the mammalian bipotential gonadal ridge. Inherited human SRY mutations can be associated with differences in sexual differentiation (DSD) with variable phenotypes in a family. Objective: To describe the clinical, histopathological and molecular features of a novel inherited SRY allele (pMet64Val; consensus box position 9) observed within an extensive pedigree: two 46, XY sisters with primary amenorrhea (16 and 14 years of age; probands P1 and P2), their normal father and brother, and an affected paternal XY grandaunt. Design, Setting, Participants and Outcome Measurements: Following DNA sequencing to identify the SRY mutation, hormonal studies of the probands and histopathological examination of their gonads were performed. Functional consequences of p.Met64Val (and other mutations at this site) were also investigated. Results: Breast development in P1 and P2was Tanner II and IV, respectively. Müllerian structures and gonads resembling ovaries were found in each sister. Histopathology revealed gonadal dysgenesis, gonadoblastoma and dysgerminoma. AMH/MIS, P450 SCC, and P450 aromatase were expressed in gonadoblastoma tissues. Variant p.Met64Val impaired Sox9 transcriptional activation associated with attenuated occupancy of the testis-specific enhancersEnh13 and TESCO. Conclusion: The partial biological activity of p.Met64Val SRY, maintained at the threshold of SRY function, rationalizes opposing paternal and proband phenotypes (the “the father-daughter paradox”).Sex steroids biosynthesis by gonadoblastoma may delay genetic diagnosis and recognition of gonadal tumors. Quantitative assessment of inherited SRY alleles highlights the tenuous transcriptional threshold of developmental decision-making in the bipotential gonadal ridge.

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

2021 ◽  
pp. 1-9
Author(s):  
Maria T.M. Ferrari ◽  
Andreia Watanabe ◽  
Thatiane E. da Silva ◽  
Nathalia L. Gomes ◽  
Rafael L. Batista ◽  
...  
Keyword(s):  
Kidney Development ◽  
Wilms Tumor ◽  
Genetic Diagnosis ◽  
Germ Cell Tumors ◽  
Disorders Of Sex Development ◽  
Medical Attention ◽  
Primary Amenorrhea ◽  
Normal Female ◽  
Sex Development ◽  
Pathogenic Variants

Wilms’ tumor suppressor gene 1 (<i>WT1</i>) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of <i>WT1</i> have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between <i>WT1</i> disorders has been frequently observed. New <i>WT1</i> variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic <i>WT1</i> variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of <i>WT1</i> between exons 9 and 10. Two pathogenic missense <i>WT1</i> variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were &#x3c;1 year of age at the time of diagnosis. A novel <i>WT1</i> variant<i>,</i> c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with <i>WT1</i> variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

scholarly journals 46,XY Disorder of Sex Development Caused by 17α-Hydroxylase/17,20-Lyase Deficiency due to Homozygous Mutation ofCYP17A1Gene: Consequences of Late Diagnosis

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Giampaolo Papi ◽  
Rosa Maria Paragliola ◽  
Paola Concolino ◽  
Carlo Di Donato ◽  
Alfredo Pontecorvi ◽  
...  
Keyword(s):  
Ethinyl Estradiol ◽  
Tanner Stage ◽  
Pubic Hair ◽  
Breast Development ◽  
Normal Male ◽  
Primary Amenorrhea ◽  
Homozygous Mutation ◽  
Tall Stature ◽  
Disorder Of Sex Development ◽  
Sex Development

Context.Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease due to specific enzyme deficiencies in the adrenal steroidogenesis pathway.Case Description.A 40-year-old Chinese woman was referred to the Endocrine Unit for the work-up of a syndrome characterized by long-lasting and multidrug resistant high blood pressure, severe hypokalemia with metabolic alkalosis, and primary amenorrhea. The patient presented with sexual infantilism, lack of breast development, absence of axillary and pubic hair, tall stature, and slenderness. CT scan revealed enlarged adrenal glands bilaterally and the absence of the uterus, the ovaries, and the Fallopian tubes. Furthermore, diffuse osteopenia and osteoporosis and incomplete ossification of the growth plate cartilages were demonstrated. Chromosomal analysis showed a normal male 46,XY, karyotype, and on molecular analysis of theCYP17A1gene she resulted homozygous for the g.4869T>A; g.4871delC (p.Y329Kfs?) mutation in exon 6. Hydrocortisone and ethinyl-estradiol supplementation therapy led to incomplete withdrawal of antihypertensive drug and breast development progression to Tanner stage B2 and slight height increase, respectively.Conclusions.We describe a late-discovered case of CAH with 46,XY disorder of sex development. Deficiency of 17α-hydroxylase/17,20-lyase due to a homozygous CYP17A1 gene mutation was the underlying cause. Laboratory, imaging, and genetic features are herein reported and discussed.

scholarly journals Unraveling of Diagnosis Odyssey in A Girl with Primary Amenorrhea: A case report

2020 ◽  
Vol 6 (1) ◽  
pp. 19-22
Author(s):  
Ni Made Indri Dwi Susanti ◽  
Inu Mulyantoro ◽  
Dik Puspasari ◽  
Nurin Aisyiyah Listyasari ◽  
Sultana MH Faradz
Keyword(s):  
Gonadal Dysgenesis ◽  
Histopathological Examination ◽  
Laboratory Data ◽  
External Genitalia ◽  
Primary Amenorrhea ◽  
Normal Range ◽  
Immunohistochemical Markers ◽  
Sex Development ◽  
Pathogenic Variants ◽  
The Right

ABSTRACT Background:Primary amenorrhea may result from congenital abnormalities in the development of the gonads, genital tract, or external genitalia or from a disturbance within the hypothalamic-pituitary-ovarian axis. Gonadal dysgenesis is a disorder of sex development in which the diagnosis is based on the histology of gonads and is the main cause of primary amenorrhea. Optimal protocol of management for phenotypic female with 46, XY gonadal dysgenesis involves prophylactic gonadectomy at diagnosis.Case Presentation: The patient was referred to our hospital at the age of 15 years old for primary amenorrhea. She was obese with no secondary sex sign. Gynecologic examination revealed a normal vagina and clitoris. Rectal Toucher examination revealed no internal genitalia structure. The laboratory data: FSH levels was above normal range, LH and testosterone levels were within normal range. Pelvic Ultrasonography uterus and vaginal structure and testis were not visualized. Cytogenetic and ARgene analysis found a 46, XY karyotype and no pathogenic variants. On laparoscopy, Mullerian structure and Wolffian remnant structure were identified and biopsies were performed. Based on histopathological examination and immunohistochemical markers of the right and left gonad showed the impression of Malignant Mixed Germ Cell-Sex Cord Stromal Tumor. SRY gene examination was positive.Examination of other DSD gene analysis has not been done. Second laparoscopy for gonadectomy and removal of Mullerian and Wolfiian remnant structure were performed. Conclusion:Chromosomal analysis should become the first line testing in primary amenorrhea followed by advanced molecular test. Multidisciplinary managements recommended for DSD cases.

A Small Supernumerary Xp Marker Chromosome Including Genes NR0B1 and MAGEB Causing Partial Gonadal Dysgenesis and Gonadoblastoma

2021 ◽  
pp. 1-9
Author(s):  
Mirian Yumie Nishi ◽  
José Antônia Diniz Faria Júnior ◽  
Ana Cristina Victorino Krepischi ◽  
Daniela Rodrigues de Moraes ◽  
Silvia Souza da Costa ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Marker Chromosome ◽  
Copy Number Variations ◽  
Breast Development ◽  
Chromosomal Microarray ◽  
Primary Amenorrhea ◽  
Chromosomal Microarray Analysis ◽  
Fish Analysis ◽  
Sex Development ◽  
Partial Gonadal Dysgenesis

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 <i>NR0B1/DAX1</i> 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 <i>NR0B1/DAX1</i> gene, may have been the main cause of dysgenetic testes development, although the role of <i>MAGEB</i> and other genes mapped to the Xp21 segment could not be completely ruled out.

scholarly journals Laparoscopy Diagnostic and Bilateral Gonadectomy in a Patient with Complete Androgen Insensitivity Syndrome (CAIS) – A Rare Case of Primary Amenorrhoea with 46XY Karyotype

2018 ◽  
Vol 11 (4) ◽  
pp. 2069-2072
Author(s):  
IB Putra Adnyana ◽  
TGN Chandragiram ◽  
Ketut Surya Negara
Keyword(s):  
Histopathological Examination ◽  
Operative Procedure ◽  
Elevated Serum ◽  
Serum Testosterone ◽  
Testicular Tissue ◽  
Androgen Insensitivity Syndrome ◽  
Breast Development ◽  
Primary Amenorrhea ◽  
Complete Androgen Insensitivity Syndrome ◽  
Androgen Insensitivity

Bilateral laparoscopic gonadectomy is reported as an operative procedure of removing the intraabdominal gonads in individuals with complete androgen insensitivity syndrome (CAIS). We present a case of 18 year old patient who had history of primary amenorrhea. The clinical evaluation shows a female phenotype, excellent breast development, absence of hair in the groins and axillary areas and short blind vagina. In ultrasonographic examination uterus was absent. Hormonal assay showed elevated serum testosterone levels of 1,037 ng/dL. A karyotype was also performed which revealed a 46 XY. Laparoscopy diagnostic revealed absence of internal genitalia except bilateral gonads appearing as testes. The testes were removed to avoid the risk of malignancy. Histopathological examination revealed that both the masses were composed of testicular tissue. Laparoscopy allows to clearly identify, locate as well as gonadectomy in the same time. This approach results in rapid recovery with minimal blood loss and should be considered for all patient with intraabdominal gonads.

scholarly journals Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers

2020 ◽  
Vol 21 (2) ◽  
pp. 685 ◽  
Author(s):  
Antonietta Arcella ◽  
Fiona Limanaqi ◽  
Rosangela Ferese ◽  
Francesca Biagioni ◽  
Maria Antonietta Oliva ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Genetic Diagnosis ◽  
Tumor Development ◽  
Cost Effective ◽  
Circulating Tumor Dna ◽  
Copy Number Variations ◽  
Disease Classification ◽  
Individual Risk ◽  
Molecular Features ◽  
Increased Risk

Recently, several studies focused on the genetics of gliomas. This allowed identifying several germline loci that contribute to individual risk for tumor development, as well as various somatic mutations that are key for disease classification. Unfortunately, none of the germline loci clearly confers increased risk per se. Contrariwise, somatic mutations identified within the glioma tissue define tumor genotype, thus representing valid diagnostic and prognostic markers. Thus, genetic features can be used in glioma classification and guided therapy. Such copious genomic variabilities are screened routinely in glioma diagnosis. In detail, Sanger sequencing or pyrosequencing, fluorescence in-situ hybridization, and microsatellite analyses were added to immunohistochemistry as diagnostic markers. Recently, Next Generation Sequencing was set-up as an all-in-one diagnostic tool aimed at detecting both DNA copy number variations and mutations in gliomas. This approach is widely used also to detect circulating tumor DNA within cerebrospinal fluid from patients affected by primary brain tumors. Such an approach is providing an alternative cost-effective strategy to genotype all gliomas, which allows avoiding surgical tissue collection and repeated tumor biopsies. This review summarizes available molecular features that represent solid tools for the genetic diagnosis of gliomas at present or in the next future.

scholarly journals Turner's Syndrome: Approach to Diagnosis and Treatment

2018 ◽  
Vol 13 (3) ◽  
pp. 61-62
Author(s):  
Sadhana Sah ◽  
Ganesh Dangal ◽  
Aruna Karki ◽  
Hema Pradhan ◽  
Ranjana Shrestha ◽  
...  
Keyword(s):  
Short Stature ◽  
Estrogen Therapy ◽  
Tanner Stage ◽  
Breast Development ◽  
Primary Amenorrhea ◽  
Turner's Syndrome ◽  
Turner’S Syndrome ◽  
Secondary Sexual Characteristics ◽  
Karyotypic Abnormality ◽  
Sexual Characteristics

Turner's syndrome is the most common karyotypic abnormality causing gonadal failure and primary amenorrhea. It is characterized by short stature and absence of secondary sexual characteristics. It is diagnosed by increased plasma FSH and LH level with low level of estrogen i.e. hypergonadotrophic hypogonadism. Ultrasound abdomen reveals streak ovaries and atrophic uterus. Karyotype confirms the diagnosis of Turner's syndrome (45XO). We present here a 15 years girl who presented with primary amenorrhea with short stature with breast development corresponds to Tanner stage I. Her FSH was raised. Ultrasound abdomen showed uterine agenesis and streak ovaries. Karyotype showed 45XO which confirmed the diagnosis of Turner's syndrome. She is now on estrogen therapy and her height has increased and breast development corresponds to Tanner stage II. Keywords: hypergonadotrophic hypogonadism, primary amenorrhea, Turner's syndrome

scholarly journals TATA-Binding Protein Mutants That Are Lethal in the Absence of the Nhp6 High-Mobility-Group Protein

2004 ◽  
Vol 24 (14) ◽  
pp. 6419-6429 ◽  
Author(s):  
Peter Eriksson ◽  
Debabrata Biswas ◽  
Yaxin Yu ◽  
James M. Stewart ◽  
David J. Stillman
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Synthetic Lethality ◽  
Binding Protein ◽  
High Mobility ◽  
Tata Binding Protein ◽  
High Mobility Group ◽  
Multicopy Plasmid ◽  
Pol Ii ◽  
Pol Iii

ABSTRACT The Saccharomyces cerevisiae Nhp6 protein is related to the high-mobility-group B family of architectural DNA-binding proteins that bind DNA nonspecifically but bend DNA sharply. Nhp6 is involved in transcriptional activation by both RNA polymerase II (Pol II) and Pol III. Our previous genetic studies have implicated Nhp6 in facilitating TATA-binding protein (TBP) binding to some Pol II promoters in vivo, and we have used a novel genetic screen to isolate 32 new mutations in TBP that are viable in wild-type cells but lethal in the absence of Nhp6. The TBP mutations that are lethal in the absence of Nhp6 cluster in three regions: on the upper surface of TBP that may have a regulatory role, near residues that contact Spt3, or near residues known to contact either TFIIA or Brf1 (in TFIIIB). The latter set of mutations suggests that Nhp6 becomes essential when a TBP mutant compromises its ability to interact with either TFIIA or Brf1. Importantly, the synthetic lethality for some of the TBP mutations is suppressed by a multicopy plasmid with SNR6 or by an spt3 mutation. It has been previously shown that nhp6ab mutants are defective in expressing SNR6, a Pol III-transcribed gene encoding the U6 splicing RNA. Chromatin immunoprecipitation experiments show that TBP binding to SNR6 is reduced in an nhp6ab mutant. Nhp6 interacts with Spt16/Pob3, the yeast equivalent of the FACT elongation complex, consistent with nhp6ab cells being extremely sensitive to 6-azauracil (6-AU). However, this 6-AU sensitivity can be suppressed by multicopy SNR6 or BRF1. Additionally, strains with SNR6 promoter mutations are sensitive to 6-AU, suggesting that decreased SNR6 RNA levels contribute to 6-AU sensitivity. These results challenge the widely held belief that 6-AU sensitivity results from a defect in transcriptional elongation.

scholarly journals The Activity of Mammalian brm/SNF2α Is Dependent on a High-Mobility-Group Protein I/Y-Like DNA Binding Domain

1999 ◽  
Vol 19 (6) ◽  
pp. 3931-3939 ◽  
Author(s):  
Brigitte Bourachot ◽  
Moshe Yaniv ◽  
Christian Muchardt
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
High Mobility ◽  
High Mobility Group ◽  
Binding Motif ◽  
High Mobility Group Protein ◽  
Interaction Domain ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Group Protein

ABSTRACT The mammalian SWI-SNF complex is a chromatin-remodelling machinery involved in the modulation of gene expression. Its activity relies on two closely related ATPases known as brm/SNF2α and BRG-1/SNF2β. These two proteins can cooperate with nuclear receptors for transcriptional activation. In addition, they are involved in the control of cell proliferation, most probably by facilitating p105Rb repression of E2F transcriptional activity. In the present study, we have examined the ability of various brm/SNF2α deletion mutants to reverse the transformed phenotype ofras-transformed fibroblasts. Deletions within the p105Rb LXCXE binding motif or the conserved bromodomain had only a moderate effect. On the other hand, a 49-amino-acid segment, rich in lysines and arginines and located immediately downstream of the p105Rb interaction domain, appeared to be essential in this assay. This region was also required for cooperation of brm/SNF2α with the glucocorticoid receptor in transfection experiments, but only in the context of a reporter construct integrated in the cellular genome. The region has homology to the AT hooks present in high-mobility-group protein I/Y DNA binding domains and is required for the tethering of brm/SNF2α to chromatin.

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