A conserved NR5A1-responsive enhancer regulates SRY in testis-determination.

The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5' regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY. Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.

A mesomelic skeletal dysplasia, Kantaputra-like, not related to HOXD cluster region, and with phenotypic gender differences.

Mesomelic skeletal dysplasia is a heterogeneous group of skeletal disorders that has grown since the molecular basis of these conditions is in the process of research and discovery. Here, we report a Brazilian family with eight affected members over three generations with a phenotype similar to mesomelic Kantaputra dysplasia. This family presents marked shortening of the upper limbs with hypotrophy of the lower limbs and clubfeet without synostosis. Array-based CNV analysis and exome sequencing of four family members failed to show any region or gene candidate. Interestingly, males were more severely affected than females in this family, suggesting that gender differences could play a role in the phenotypic expressivity of this condition.

First evidence of gonadal hybrid dysgenesis in Chagas disease vectors (Hemiptera, Triatominae): gonad atrophy prevents events of interspecific gene flow and introgression.

BACKGROUND: Hybridization events between Triatoma spp. have been observed under both natural and laboratory conditions. The ability to produce hybrids can influence different aspects of the parent species, and may even result in events of introgression, speciation and extinction. Hybrid sterility is caused by unviable gametes (due to errors in chromosomal pairing [meiosis]) or by gonadal dysgenesis (GD). All of the triatomine hybrids analyzed so far have not presented GD. We describe here for the first time GD events in triatomine hybrids and highlight these taxonomic and evolutionary implications of these events. METHODS: Reciprocal experimental crosses were performed between Triatoma longipennis and Triatoma mopan. Intercrosses were also performed between the hybrids, and backcrosses were performed between the hybrids and the parent species. In addition, morphological and cytological analyzes were performed on the atrophied gonads of the hybrids. RESULTS: Hybrids were obtained only for the crosses T. mopan♀ × T. longipennis♂. Intercrosses and backcrosses did not result in offspring. Morphological analyses of the male gonads of the hybrids confirmed that the phenomenon that resulted in sterility of the hybrid was bilateral GD (the gonads of the hybrids were completely atrophied). Cytological analyses of the testes of the hybrids also confirmed GD, with no germ cells observed (only somatic cells, which make up the peritoneal sheath). CONCLUSIONS: The observations made during this study allowed us to characterize, for the first time, GD in triatomines and demonstrated that gametogenesis does not occur in atrophied gonads. The characterization of GD in male hybrids resulting from the crossing of T. mopan♀ × T. longipennis♂ highlights the importance of evaluating both the morphology and the cytology of the gonads to confirm which event resulted in the sterility of the hybrid: GD (which results in no gamete production) or meiotic errors (which results in non-viable gametes).

Loss of function of FIGNL1, a DNA damage response gene, causes human ovarian dysgenesis.

Ovarian dysgenesis (OD), an XX disorder of sex development, presents with primary amenorrhea, hypergonadotrophic hypogonadism, and infertility. In an Ashkenazi Jewish patient with OD, whole exome sequencing identified compound heterozygous frameshifts in FIGNL1, a DNA damage response (DDR) gene: c.189del and c.1519_1523del. Chromosomal breakage was significantly increased in patient cells, both spontaneously, and following mitomycin C exposure. Transfection of DYK-tagged FIGNL1 constructs in HEK293 cells showed no detectable protein in FIGNL1c.189del and truncation with reduced expression in FIGNL1c.1519_1523del (64% of wild-type [WT], P = .003). FIGNL1 forms nuclear foci increased by phleomycin treatment (20.6 ± 1.6 vs 14.8 ± 2.4, P = .02). However, mutant constructs showed reduced DYK-FIGNL1 foci formation in non-treated cells (0.8 ± 0.9 and 5.6 ± 1.5 vs 14.8 ± 2.4 in DYK-FIGNL1WT, P < .001) and no increase with phleomycin treatment. In conclusion, FIGNL1 loss of function is a newly characterized OD gene, highlighting the DDR pathway's role in ovarian development and maintenance and suggesting chromosomal breakage as an assessment tool in XX-DSD patients.

Mini review: Breast cancer care in individuals with differences of sexual development.

Disorders or differences of sexual development encompasses an important group of conditions that affects up to 1 in 5,000 live births. Many individuals living in the female gender includes Turner syndrome, congenital adrenal hyperplasia and conditions with 46XY karyotype such as gonadal dysgenesis (Swyer syndrome). Individuals are commenced on high dose oestrogen to initiate and maintain development of secondary sexual characteristics such as breasts which is paramount in them identifying in the female gender. We highlight the first case of a patient with Swyer syndrome who was treated with long term oestrogen therapy and later developed breast cancer. In individuals with gonadal dysgenesis, testicular malignancy is a recognised risk and is screened for. Prolonged exposure to exogenous and endogenous hormones can increase the risk of breast cancer however how much this risk increases in those taking high dose hormones is not documented in the literature. We aim to highlight the importance of breast cancer treatment and surgical reconstruction in this group and whether they should be considered for early breast cancer screening. CONCLUSION: It is imperative that triple assessment is undertaken in every patient with a breast lump, regardless of gender identification. Clinicians must not delay investigations in this patient group due to a misunderstanding of their condition. Those on long term hormone supplementation should be entered into the breast screening program at an earlier age with Magnetic Resonance Imaging surveillance. Careful consideration of post treatment endocrine therapy is required and under the care of the multi-disciplinary team.

Environmental oestrogens disrupt testicular descent and damage male reproductive health: Mechanistic insight.

Environmental oestrogens (EEs) as environmental pollutants have been paid much attention due to their impact on congenital malformation of male genitourinary system. Exposure to EEs for prolonged time could hinder testicular descent and cause testicular dysgenesis syndrome. Therefore, it is urgent to understand the mechanisms by which EEs exposure disrupt testicular descent. In this review, we summarize recent advances in our understanding of the process of testicular descent, which is regulated by intricate cellular and molecular networks. Increasing numbers of the components of these networks such as CSL and INSL3 are being identified, highlighting that testicular descent is a highly orchestrated process that is essential to human reproduction and survival. The exposure to EEs would lead to the imbalanced regulation of the networks and cause testicular dysgenesis syndrome such as cryptorchidism, hypospadias, hypogonadism, poor semen quality and testicular cancer. Fortunately, the identification of the components of these networks provides us the opportunity to prevent and treat EEs induced male reproductive dysfunction. The pathways that play an important role in the regulation of testicular descent are promising targets for the treatment of testicular dysgenesis syndrome.

Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

Frasier syndrome: A case report / El síndrome de Frasier, caso clínico

Introduction: Frasier syndrome is a genetic disorder produced by a mutation in intron 9 of the WT1 gene, responsible for renal and genital dysfunctions. Clinical findings: It is characterized by discrepancy between the individual karyotype and the individual phenotype and corticosteroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. Patients usually have a female phenotype with a 46 XY karyotype, which increases the risk of gonadoblastoma in 50% of cases. Kidney disease requires kidney transplantation in adulthood. Cardiovascular and bone-derived comorbidities such as hyperlipidaemia and osteopenia/osteoporosis, respectively, are also common. Main diagnoses: Mutations of the WT1 gene can lead to different clinical entities, most notably Denysh-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. We present a clinical case of a woman who debuted in childhood with difficult-to-control nephrotic syndrome, the lack of pubertal development, primary amenorrhoea and the absence of ovaries on imaging tests in adolescence, alerted to an underlying genetic problem that, after cytogenetic studies, allowed a diagnosis of Frasier syndrome. Therapeutic interventions: It is recommended to remove the gonads due to increased risk of developing gonadoblastoma. Treatment of associated dyslipidaemia and osteopenia is also necessary. Conclusion: Frasier syndrome is an unusual cause of infertility due to gonadal dysgenesis and is associated with kidney problems.(AU)

Introducción: El síndrome de Frasier es un trastorno genético producido por una mutación en el intrón 9 del gen WT1, responsable de disfunciones a nivel renal y genital. Principales síntomas: Se caracteriza por disgenesia gonadal con discrepancia entre cariotipo-fenotipo y síndrome nefrótico resistente a corticoides debido a glomeruloesclerosis focal y segmentaria. Las pacientes presentan habitualmente fenotipo femenino con cariotipo 46 XY, lo que aumenta el riesgo de gonadoblastoma en un 50% de los casos. La enfermedad renal obliga a trasplante renal en la edad adulta. Son habituales también las comorbilidades derivadas a nivel cardiovascular y óseo como hiperlipidemia y osteopenia/osteoporosis, respectivamente. Diagnósticos principales: Las mutaciones del gen WT1 pueden conducir en distintas entidades clínicas entre las que destaca el síndrome de Denys-Drash, el síndrome de Frasier o la glomeruloesclerosis focal y segmentaria aislada. Se presenta un caso clínico de una mujer que debutó en la infancia con síndrome nefrótico de difícil control y que, durante la adolescencia, ante la falta de desarrollo puberal, la amenorrea primaria y la ausencia de ovarios en las pruebas de imagen alertaron de un problema genético subyacente que, tras estudios citogenéticos, permitió el diagnóstico de síndrome de Frasier. Intervenciones terapéuticas: Se recomienda la exéresis de las gónadas debido al riesgo incrementado de gonadoblastoma. El tratamiento de la dislipemia y la osteopenia asociadas también es necesario. Conclusión: El síndrome de Frasier es una causa inusual de infertilidad debido a una disgenesia gonadal y se asocia con problemas a nivel renal.(AU)

New observations on minifascicular neuropathy with sex-dependent gonadal dysgenesis: a case series with nerve ultrasound assessment.

BACKGROUND: Gonadal dysgenesis with minifascicular neuropathy (GDMN) is a rare autosomal recessive condition associated with biallelic DHH pathogenic variants. In 46, XY individuals, this disorder is characterized by an association of minifascicular neuropathy (MFN) and gonadal dysgenesis, while in 46, XX subjects only the neuropathic phenotype is present. Very few patients with GDMN have been reported so far. We describe four patients with MFN due to a novel DHH likely pathogenic homozygous variant and the results of nerve ultrasound assessment. METHODS: This retrospective observational study included 4 individuals from 2 unrelated Brazilian families evaluated for severe peripheral neuropathy. Genetic diagnosis was performed with a peripheral neuropathy next-generation sequencing (NGS) panel based on whole exome sequencing focused analysis that included a control SRY probe to confirm genetic sex. Clinical characterization, nerve conduction velocity studies, and high-resolution ultrasound nerve evaluation were performed in all subjects. RESULTS: Molecular analysis disclosed in all subjects the homozygous DHH variant p.(Leu335Pro). Patients had a striking phenotype, with marked trophic changes of extremities, sensory ataxia, and distal anesthesia due to a sensory-motor demyelinating polyneuropathy. One 46, XY phenotypically female individual had gonadal dysgenesis. High-resolution nerve ultrasound showed typical minifascicular formation and increased nerve area in at least one of the nerves assessed in all patients. CONCLUSION: Gonadal dysgenesis with minifascicular neuropathy is a severe autosomal recessive neuropathy characterized by trophic alterations in limbs, sensory ataxia, and distal anesthesia. Nerve ultrasound studies are very suggestive of this condition and may help to avoid invasive nerve biopsies.

Gonadal tumors in a contemporary cohort of patients with differences in sex development undergoing surgery - A multi-site study from the Pediatric Urologic Oncology Working Group of the societies for pediatric urology.

BACKGROUND: Disturbances in gonadal development lead to increased risk of gonadal malignancy in some but not all patients with differences in sex development (DSD). However, the natural history of these tumors is poorly described, and the literature remains sparse. OBJECTIVE: The objective of this study was to describe the incidence of germ cell neoplasia in situ (GCNIS) and germ cell tumor (GCT) in a contemporary cohort of patients with DSD undergoing surgery and to provide long-term oncologic outcomes for these patients. STUDY DESIGN: Patients with DSD who have undergone gonadectomy or gonadal biopsy were identified at four institutions. Clinical characteristics, pathology, and treatment details were obtained retrospectively. Patients were stratified into risk categories based on DSD diagnosis. Oncologic treatment and outcomes were recorded. Descriptive statistics are reported using parametric methods. RESULTS: 83 patients were identified. Distribution of diagnoses is summarized in the summary table. 14 (16.9%) patients underwent gonadal biopsy, and 71 (85.5%) patients underwent gonadectomy (50/71 gonadectomies were bilateral). 8/83 (9.6%) patients had GCNIS or GCT (7 GCNIS, 1 GCT). Median age at surgery was 2.95 years (y) (interquartile range [IQR] 0.6-12.2) and 14y (IQR 0.85-16.9) in patients without and with GCNIS/GCT, respectively. All 8 patients with GCNIS/GCT had high or intermediate risk DSD diagnoses (4 mixed gonadal dysgenesis, 3 Turner with Y, 1 partial gonadal dysgenesis). Of the patients with high-risk diagnoses, 8/54 (15%) had GCNIS/GCT. No patient received adjuvant therapy, no patient had a recurrence, and all patients were living with mean follow up 6.4y. DISCUSSION: The risk of gonadal malignancy is heterogeneous in the DSD population and can vary based on DSD diagnosis as well as maturation, testicularization, and location of the gonads. The most recent consensus recommendations on gonadal management emphasize risk stratification and consideration of gonadal surveillance based on gender of rearing, but supporting literature remains sparse. In this contemporary cohort of DSD patients who underwent gonadal surgery, most patients did not have evidence of adverse pathology, all patients with malignant or premalignant pathology had a high/intermediate risk DSD diagnosis, and all patients with GCNIS/GCT were treated with surgery alone without recurrence. CONCLUSIONS: The distribution of patients with premalignant and malignant gonadal pathology and DSD in this cohort aligns with prior literature, and oncologic outcomes were excellent. These data add valuable information to the current literature and highlight the necessity to develop appropriate screening regimens for retained gonads.

A novel DEAH-box helicase 37 mutation associated with differences of sex development.

Objective: To determine the genetic etiology of a family pedigree with two patients affected by differences of sex development (DSD). Methods: Assess the clinical characteristics of the patients and achieve exome sequencing results and in vitro functional studies. Results: The 15-year-old proband, raised as female, presented with delayed puberty and short stature associated with atypical genitalia. Hormonal profile showed hypergonadotrophic hypogonadism. Imaging studies revealed the absence of a uterus and ovaries. The karyotype confirmed a 46, XY pattern. Her younger brother presented with a micropenis and hypoplastic scrotum with non-palpable testis and hypospadias. Laparoscopic exploration was performed on the younger brother. Streak gonads were found and removed due to the risk of neoplastic transformation. Post-operative histopathology showed the co-existence of Wolffian and Müllerian derivatives. Whole-exome sequencing identified a novel mutation (c.1223C>T, p. Ser408Leu) in the Asp-Glu-Ala-His-box helicase 37 gene, which was found to be deleterious by in silico analysis. Segregation analysis of the variant displayed a sex-limited, autosomal dominant, maternal inheritance pattern. In vitro experiments revealed that the substitution of 408Ser by Leu caused decreased DHX37 expression both at the mRNA and protein levels. Moreover, the ß-catenin protein was upregulated, and the p53 protein was unaltered by mutant DHX37. Conclusions: We described a novel mutation (c.1223C>T, p. Ser408Leu) of the DHX37 gene associated with a Chinese pedigree consisting of two 46, XY DSD patients. We speculated that the underlying molecular mechanism might involve upregulation of the ß-catenin protein.

Undetectable anti-Mullerian hormone and inhibin B do not preclude the presence of germ cell tumours in 45,X/46,XY or 46,XY gonadal dysgenesis.

OBJECTIVE: Individuals with 45,X/46,XY or 46,XY gonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone (AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. DESIGN, PATIENTS AND MEASUREMENTS: Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999-2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. RESULTS: Thirteen males and 16 females were included, 20 with 46,XY and 9 with 45,X/46,XY DSD. Three females had dysgerminoma alongside gonadoblastoma; two gonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. CONCLUSIONS: Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XY or 46,XY gonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.

Mutation analysis of WNT4 gene in SRY negative 46,XX DSD patients with Mullerian agenesis and/or gonadal dysgenesis- An Indian study.

Developmental disruption of the Mullerian duct and gonads in females leads to Mullerian agenesis and gonadal dysgenesis, respectively. These two structural abnormalities are coming under the 46,XX DSD (Disorders of Sexual Development) classification, the majority of cases the aetiology remains elusive. Without the SRY gene, WNT4 plays a key role in female reproductive structure development. Since there are no studies that explored the involvement of the WNT4 gene in Indian 46,XX DSD patients, we analysed the role of WNT4 in Indian 46,XX DSD patients with Mullerian agenesis and/or Gonadal dysgenesis. In our study, we recruited 103 adolescent girls with primary amenorrhea. After the cytogenetic and SRY gene analysis, we included thirty-two 46,XX DSD patients with Mullerian agenesis and/or gonadal dysgenesis for WNT4 gene mutation analysis. PCR sequencing was performed for all the coding exons of the WNT4 gene. Bioinformatic tools like Mutation Taster, Human Splicing Finder, and miRDB were used. We observed single nucleotide variations in three patients. One patient showed a known synonymous polymorphism (c.861C > T; p.G287G, rs544988174). miRDB data revealed the absence of microRNA regulatory sites in this region. The other two cases carried a nucleotide substitution in intronic regions and did not affect the normal splicing mechanism. In conclusion, we could not find any indication about WNT4 involvement in the disease condition. In the future, WNT4 promoter analysis in these patients and molecular characterization of the WNT4 coding and promoter region in more patients are needed to link WNT4 variants with these structural abnormalities.

Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models.

BACKGROUND: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. SUMMARY: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. KEY MESSAGES: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Effects of genomic instability in populations of Drosophila melanogaster from regions of Ukraine with different impact of radiation factors.

PURPOSE: To investigate differences in the gonadal dysgenesis frequency as one of the indicators of genome instability through natural populations of Drosophіla melanogaster, selected from Ukrainian regions with different radiation impacts. Follow-up study of the dynamics of this indicator under chronic exposure in laboratory conditions for 10 generations. MATERIALS AND METHODS: The study was conducted in two stages. The first one included trapping of insects in regions with different radiation loads with subsequent assessment of both the time of maturation and the index of the gonadal dysgenesis through the first (F1) generation, obtained in laboratory conditions. At the second stage, the dynamics of this indicator were investigated for the F1-descendants of each ten consequent generations, which were developed under laboratory conditions both with and without additional gamma-exposure with different characteristics of the dose rate 1.2 × 10-8, 0.3 × 10-8 and 0.12 × 10-8 Gy/sec. RESULTS: Differences in the gonadal dysgenesis frequency as one of the indicators of genome instability were revealed in F1-descendants of natural populations of Drosophіla melanogaster, selected from regions of different radiation impact. Under conditions of additional low rate chronic irradiation in laboratory conditions for 10 generations, significant differences in changes in the level and dynamics of this indicator were established depending on the accumulated dose of Drosophila populations from the city of Netishyn (Khmelnytskyi NPP) and Magarach city. There were no signs of adaptation. CONCLUSIONS: The discrepancy between the real and expected biological effects has reflected the difference in the intensity of the radiation background, which was traditionally determined by the gamma-emitters and did not take into account the wide range of other genotoxic elements from nuclear power emissions. A complex, non-monotonic type of frequency dynamics of gonadal dysgenesis could be determined by the interaction of radiation damage, protection and recovery.

Anomalies in Human Sex Determination: Usefulness of a Combined Cytogenetic Approach to Characterize an Additional Case with Xp Functional Disomy Associated with 46,XY Gonadal Dysgenesis

Objective: Disorders of sexual development (DSD) are a heterogeneous group of genital defects affecting chromosomal, gonadal and anatomical sex. 46,XY DSD is a subset of DSD which covers a wide range of phenotypes in which 46,XY gonadal dysgenesis (GD) is the most severe form. In this study, we report on the clinical and molecular cytogenetic findings of a study on a Tunisian girl with the syndromic form of 46,XY DSD. Methods: This case was a phenotypic female patient having several congenital anomalies including growth retardation. Karyotype, fluorescence in situ hybridization and array Comparative Genome Hybridization (array CGH) were performed. Results: The proband exhibited a de-novo 46,X,der(Y) karyotype. Array CGH revealed a pathogenic 27.5Mb gain of an Xp21.2 chromosome segment leading to Xp functional disomy. No deletion was observed in the Y-chromosome. The duplicated region encompassed the NR0B1 (DAX1) and MAGEB genes, located within the dosage sensitive sex (DSS) reversal locus, known as promote genes responsible for human sex reversal and testis repression. The extra-dosage and interactions of these genes with different specific genes could result in the impairment of the male sex pathway. Over-dosage of KAL1 and IL1RAPL1 genes fall within the somatic features observed in the patient. Conclusion: To the best of our knowledge, we report on the fourth case of Xp21.2-pter duplication within Xp;Yp translocation associated with XY GD. Our findings suggest that when duplicated, the NR0B1 and MAGEB genes could be a major cause of XY GD. Therefore, we emphasize the usefulness of a combined cytogenetic approach in order to provide an accurate genetic diagnosis for those patients having syndromic XY DSD in a clinical setting.

Swyer syndrome presenting as dysgerminoma: A case report / Journal of the ASEAN Federation of Endocrine Societies

@#Complete gonadal dysgenesis with 46,XY karyotype is a clinical condition characterized by the absence of testicular tissue but typical Mullerian structures in a phenotypically female individual. The condition presents as primary amenorrhoea or delayed puberty. Eventually, malignant neoplasms may arise. We report a case of a 16-year-old patient with Swyer syndrome presenting with primary amenorrhoea and with previous diagnosis four years earlier of a malignant dysgerminoma in the right ovary.

NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review.

RATIONALE: Disorders/differences of sex development (DSD) include a diverse group of congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is discordant. It involves several variant genes, and one of them is NR5A1. NR5A1 encodes a signal transduction regulator in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal pathway, and pathogenic mutation in this gene is a cause of 46,XY DSD. PATIENT CONCERNS: A 12-year-old individual raised as a girl was admitted to the hospital due to hirsutism and a deep voice that began at 11 years old. The individual exhibited testicular hypoplasia, clitoral hypertrophy, and female external genitalia. DIAGNOSES: The patient was diagnosed 46,XY partial gonadal dysgenesis. The cytogenetics revealed a 46,XY karyotype and DNA sequencing shown a variant in NR5A1. Pelvic magnetic resonance imaging showed absence of uterus and ovaries. The abdominopelvic ultrasound revealed bilateral testicle in bilateral groin. Pathology confirmed testes dysgenesis. INTERVENTIONS: The patient underwent bilateral orchiectomy at age 12 years and was given a feminizing hormonal treatment of 0.5 mg/day of estradiol valerate tablets. OUTCOMES: The patient recovered well after surgery and hormonal treatment and had a regression in hirsutism and clitoromegaly. LESSONS: 46,XY DSD is a rare disease that the development of chromosomal, gonadal, or anatomical sex is discordant, when diagnosed 46,XY DSD, the identification of an NR5A1 variant should be considered.