XY Gonadal Dysgenesis Research Articles

Primary amenorrhea with Swyer syndrome: a rare case report

Swyer syndrome with complete gonadal dysgenesis is associated with an absence of testicular differentiation in a phenotypic female with a 46, XY karyotype. The diagnosis is usually made at adolescence when primary amenorrhea is investigated. Here is an interesting case report of 18-year-old unmarried girl, who presented with primary amenorrhea and non-development of breasts. Her body built was musculin with broad shoulders, prominent Adam’s apple and deep voice. Examination of her secondary sexual charaistisctcs revealed no breast development, absent axillary hair and sparse pubic hairs with female type of external genitalia. Laboratoryanalyses revealed serum follicle-stimulating hormone and luteinizing hormone levels compatible with hypergonodotropichypogonadism. Pelvicultrasonography showed an infantile uterus and streak gonads. Chromosome analysis revealed 46, XYkaryotype. Laparoscopic removal of streak gonads was done as there is a risk of gonadoblastoma in such cases. The patient was started on hormonal replacement therapy. Swyersyndrome results mainly due to mutation in certain genes such as SRY gene, which leads to failure of development of testis.
 Birdem Med J 2020; 10(2): 130-132

A Case of 45,X/46,XY Mosaicism Presenting as Swyer Syndrome

Swyer syndrome is a difference of sex development that is typically associated with mutations in genes responsible for testicular development. It is speculated that some cases may result from cryptic 45,X/46,XY mosaicism leading to abnormal gonadal development. The presence or absence of a 45,X lineage is important for prognosis and management. We present a case of apparent Swyer syndrome associated with a 46,XY chromosomal complement in lymphocytes and 45,X/46,XY mosaicism on analysis of her noncancerous gonad. Gonadal histology was consistent with a 45,X phenotype. This case demonstrates the clinical variability in the presentation of 45,X/46,XY mosaicism and highlights the importance of thorough genetic testing that includes consideration of chromosomal mosaicism. We will discuss the implications of this diagnosis for management.

Беременность и роды у пациентки с нарушением половой дифференцировки (синдром Свайера)

Беременность и роды у пациентки с нарушением половой дифференцировки (синдром Свайера)

DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation.

In humans, pathogenic variants in the DHH gene underlie cases of 46,XY gonadal dysgenesis. DHH is part of the Hedgehog family of proteins, which require extensive processing, including self-cleavage of the precursor for efficient signalling. In our work, we have assessed the effect of several human DHH pathogenic variants involved in recessive complete or partial gonadal dysgenesis, on protein processing and sub-cellular localization. We found that a subset of variants was unable to perform self-cleavage, which correlated albeit not perfectly with an altered subcellular localization of the resulting proteins. For the processing-proficient variants, we used structural modelling tools and molecular dynamic (MD) simulations to predict the potential impact of the variants on protein conformation and/or interaction with partners. Our study contributes to a better understanding of the molecular mechanisms involved in DHH dysfunction leading to 46,XY disorders of sex development.

MON-075 Autonomy and Self-Determination in a Patient with XY Gonadal Dysgenesis

Background:XY gonadal dysgenesis is characterized by the presence of male chromosomes with atypical testes differentiation. Due to an impaired ability to make testosterone, patients are often under-virilized at birth and present with ambiguous genitalia. For multidisciplinary teams specialized in disorders of sex development (DSD), gonadal dysgenesis presents challenges in sex assignment, initiation of hormonal therapy, and timing of surgical interventions. Recent discussions have reconsidered early interventions in favor of preserving self-determination in decisions regarding gender and anatomy.Case:LT initially presented at 3 years old, after her grandmother noted her abnormal appearing genitalia. Examination revealed clitoromegaly, 1.8 cm in length and 0.8 cm in width, with a blind, open introitus. XY gonadal dysgenesis was diagnosed, based on a pelvic MRI, cystourtheroscopy/vaginoscopy, genetic and hormonal testing.LT was lost to follow-up for 6 years. At 11 years old, LT had been consistently raised as a female. When asked about gender identity, LT’s understanding of gender identity developed over time. At 11 years old, LT declared her gender identity as a “boy”, because boys are “strong”, and because she did not like make-up. LT denied any desire for breast development and explained that her family told her that breasts ‘make it hard to run fast.’On follow-up evaluation 6 months later, LT voiced her decision to be a girl, and said that she was very confident in this decision. LT and her parents both desired estrogen therapy for induction of puberty. After discussions regarding the permanent effects of therapy, LT started hormone therapy. Two months after initiation of therapy, she remained firm in her gender identity and expressed a desire to grow her hair long. She independently stated that she did not desire surgery at this time. She will receive formal psychological testing at her next clinical evaluation to evaluate her for body dysmorphia, anxiety, and depression.DiscussionLT’s case demonstrates the progression of developmental understanding of gender and expressed gender identity that may occur as learning progresses in patients with DSDs. This case also shows that a delay in surgery may not have significant developmental consequences to these patients as was previously suggested. In general, the American medical system has tended to perform early sex assignments and surgical interventions to align anatomy with the sex assignment. However, after thoughtful discussions regarding human rights concerns, many have recommended to delay surgical interventions until adolescence, when the patient can consent appropriately to interventions that cause permanent anatomic changes. As many of these interventions may be discussed in early adolescence, it is of the utmost importance that information is presented in an understandable and developmentally appropriate manner.

SUN-069 A 14 Year Old Female with Primary Amenorrhea

Background: Swyer Syndrome is an extremely rare disorder of sexual development. These patients often present with primary amenorrhea during adolescence and are phenotypically female with 46 XY chromosomes. Given the association of invasive gonadal malignancies with this disorder, suspicion should be high in patients who present with a stagnant or decreased rate of pubertal progression. We present a case of Swyer Syndrome in a 14-year-old female with primary amenorrhea in the setting of decreased pubertal progression. Case: A 14-year-old female presents with a chief complaint of primary amenorrhea. She first noticed breast budding 2 years prior but reports no significant increase in breast tissue over the last 2 years. She does not appreciate any other signs of puberty. She denies any acne, body odor, hirsutism, hair loss, or abdominal/pelvic pain. She denies any changes in her diet or physical activity and is not on any medication. No history of cancer, surgeries, or radiation exposure. There is no family history of infertility or delayed puberty. Her vitals on presentation are within normal limits. Her growth parameters are the following: weight-69.9 kilos, height-163 cm, and BMI-26.3. Physical exam shows a well-appearing adolescent with grossly female external genitalia and the breast exam is SMR II. No pubic or axillary hair appreciated on the exam. Although our patient did not meet the traditional definition of primary amenorrhea, a workup was started due to the slow progression of puberty. Initial blood testing shows normal blood count, electrolytes and thyroid levels. DHEA-S androstenedione, free and total testosterone were all within normal limits. Further results such as LH (25.4 uIU/mL), FSH (56.5 mIU/mL) and estradiol (22 pg/mL) along with low levels of AMH (0.52 ng/mL) and inhibin A (1pg/mL) confirms suspicion for ovarian insufficiency. Chromosomal analysis and pelvic ultrasound findings of a small uterus and ovaries led to our diagnosis of Swyer syndrome. Our patient had surgical resection of both ovaries and fallopian tubes and the ovarian pathology showed gonadoblastoma with invasive dysgerminoma in both gonads. She was started on hormone replacement after gonadectomy. Conclusion: Although Swyer syndrome is uncommon with an incidence of 1 in 80,000, this case illustrates that suspicion for Swyer Syndrome should be high in patients with slow progression of puberty and primary amenorrhea (1). Early diagnosis is critical, as patients with gonadal dysgenesis are at great risk for germ cell cancers. Though most of these patients have an identifiable genetic mutation, we were unable to elicit the exact mutation in our patient despite whole-genome sequencing.

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

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.

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

PurposeXY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. MethodsWe performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. ResultsThirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10−10). Five variants are de novo (P value = 1.5 × 10−5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. ConclusionDHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.

Pregnancy and childbirth in a patient with Swyer syndrome

Pregnancy and childbirth in a patient with Swyer syndrome

"Spectrum of 46 XY Disorders of Sex Development": A Hospital-based Cross-sectional Study.

Background:Disorders of sex development (DSD) are a wide range of relatively rare conditions having diverse pathophysiology. Identification of an underlying cause can help in treating any coexisting hormone deficiencies and can help with anticipating any other immediate or long-term health concerns.Objective:To study the clinical and biochemical profile of patients with 46 XY DSD along with androgen receptor (AR) gene mutation status in selected group of patients.Methods:A cross-sectional study was conducted after enrolling the eligible DSD patients. Thorough elicitation of history and detailed clinical examination was done. Assays for luteinizing hormone, follicle-stimulating hormone, testosterone, dihydrotestosterone, androstenedione, AMH & Inhibin B (where indicated), and human chorionic gonadotropin stimulation were done as per protocol.Results:In total, 48 patients were included in the study. Ambiguous genitalia (58.3%) followed by hypospadias (33.3%) were common presentation. Androgen biosynthetic defect were the most commonly encountered diagnosis followed by androgen insensitivity syndrome (AIS). Swyer syndrome was diagnosed in 4.2% of cases; partial gonadal dysgenesis, ovotesticular DSD, and vanishing testis syndrome contributed to 2% of cases each. Eight cases (16.7%) who presented with isolated proximal and midshaft hypospadias for whom no diagnosis was found were categorized in the “etiology unclear” group. AR gene mutation analysis designed against specific exons did not yield any results.Conclusion:46 XY DSD is a heterogeneous group of patients with a varying age of presentation and a diverse clinical profile. Most patients are reared as males and maintained the same gender identity except in isolated cases. Diagnosis of AIS remains a clinical challenge as a definite hormonal criterion does not exist and genetic mutations in AR gene may be negative. Flanking region sequencing, whole genome sequencing, and promoter region sequencing may reveal pathogenic variants. Variations in other genes regulating AR pathway may also be candidates to be studied.

Swyer syndrome with dysgerminomas: ambiguity of pathologic diagnosis

Swyer syndrome with dysgerminomas: ambiguity of pathologic diagnosis

No evidence that Y-chromosome differentiation affects male fitness in a Swiss population of common frogs.

The canonical model of sex-chromosome evolution assigns a key role to sexually antagonistic (SA) genes on the arrest of recombination and ensuing degeneration of Y chromosomes. This assumption cannot be tested in organisms with highly differentiated sex chromosomes, such as mammals or birds, owing to the lack of polymorphism. Fixation of SA alleles, furthermore, might be the consequence rather than the cause of recombination arrest. Here we focus on a population of common frogs (Rana temporaria) where XY males with genetically differentiated Y chromosomes (nonrecombinant Y haplotypes) coexist with both XY° males with proto-Y chromosomes (only differentiated from X chromosomes in the immediate vicinity of the candidate sex-determining locus Dmrt1) and XX males with undifferentiated sex chromosomes (genetically identical to XX females). Our study finds no effect of sex-chromosome differentiation on male phenotype, mating success or fathering success. Our conclusions rejoin genomic studies that found no differences in gene expression between XY, XY° and XX males. Sexual dimorphism in common frogs might result more from the differential expression of autosomal genes than from sex-linked SA genes. Among-male variance in sex-chromosome differentiation seems better explained by a polymorphism in the penetrance of alleles at the sex locus, resulting in variable levels of sex reversal (and thus of X-Y recombination in XY females), independent of sex-linked SA genes.

CLINICAL CASE OF A SUCCESSFUL PREGNANCY WITH THE COMPLETE FORM OF GONADAL DYSGENESIS - SWYER SYNDROME

Swyer syndrome (46,XY complete gonadal dysgenesis) is a rare chromosomal pathology. This pathology occurs with a frequency of 1 in 80,000. In genetic analysis, mutations are most often found in the following genes: the SRY gene, the NR5A1 gene, the SOX9 gene, the MAP3K1 gene. Patients with this disease develop phenotypically as women, but due to the absence of gonads and eggs, independent pregnancy is impossible. This article describes a clinical case of a successful onset, course of pregnancy and delivery in a woman with Swyer syndrome using assisted reproductive technology.

The XY Female: Exploring Care for Adolescent Girls with Complete Androgen Insensitivity Syndrome

ABSTRACT Differences in Sex Development (DSD) encompasses many diagnoses, where the development of chromosomal make-up, gonadal development or anatomical development is atypical. XY, DSD is a classification under the recent international consensus statement, and XY females commonly encapsulate disorders of androgen synthesis and androgen action. Complete Androgen Insensitivity Syndrome (CAIS) is the most common XY, DSD diagnosis, which results in an individual having XY chromosomes, but the person is phenotypically female. This article explores the care and management of children and young people with a DSD and focuses on the diagnosis of CAIS in adolescence. Medical and surgical management is discussed, alongside sexual function, gender identity and the psychological impact of the diagnosis. The involvement of the multidisciplinary team is stressed, together with an emphasis on the investment that is needed in psychological and nursing support for girls with CAIS, and their families.

Sex chromosomes control vertical transmission of feminizing Wolbachiasymbionts in an isopod.

Microbial endosymbiosis is widespread in animals, with major ecological and evolutionary implications. Successful symbiosis relies on efficient vertical transmission through host generations. However, when symbionts negatively affect host fitness, hosts are expected to evolve suppression of symbiont effects or transmission. Here, we show that sex chromosomes control vertical transmission of feminizing Wolbachia endosymbionts in the isopod Armadillidium nasatum. Theory predicts that the invasion of an XY/XX species by cytoplasmic sex ratio distorters is unlikely because it leads to fixation of the unusual (and often lethal or infertile) YY genotype. We demonstrate that A. nasatum X and Y sex chromosomes are genetically highly similar and that YY individuals are viable and fertile, thereby enabling Wolbachia spread in this XY-XX species. Nevertheless, we show that Wolbachia cannot drive fixation of YY individuals, because infected YY females do not transmit Wolbachia to their offspring, unlike XX and XY females. The genetic basis fits the model of a Y-linked recessive allele (associated with an X-linked dominant allele), in which the homozygous state suppresses Wolbachia transmission. Moreover, production of all-male progenies by infected YY females restores a balanced sex ratio at the host population level. This suggests that blocking of Wolbachia transmission by YY females may have evolved to suppress feminization, thereby offering a whole new perspective on the evolutionary interplay between microbial symbionts and host sex chromosomes.

EP16.28: Prenatal diagnosis of a Swyer syndrome as a result of gender discrepancy in NIPT and ultrasound

EP16.28: Prenatal diagnosis of a Swyer syndrome as a result of gender discrepancy in NIPT and ultrasound

Successful pregnancy in a patient with Swyer syndrome, or pure 46,XY gonadal dysgenesis

Swyer syndrome, or pure 46,XY gonadal dysgenesis, is a rare disorder of sex development, characterised by the failure of sex gland development (ovaries or testes) in a phenotypic female patient. A 24-year-old woman with this syndrome presented at a tertiary academic hospital in South Africa, complaining of primary amenorrhoea and infertility. After gonadectomy and fertility treatment, a rare successful pregnancy outcome was achieved. A patient with Swyer syndrome, in a specialist fertility programme, can maintain a normal pregnancy and delivery.

Genetic Causes of Rare Pediatric Ovarian Tumors.

Ovarian tumors in childhood and adolescence are distinguished from those that arise in adulthood by their histological subtype. These tumors may arise as the first manifestation of a cancer predisposition syndrome. Correct diagnosis of the syndrome may offer the possibility of surveillance for other members of the patients family. To summarize current knowledge about paediatric ovarian tumors that may be associated with genetically defined cancer syndromes. Juvenile granulosa cell tumors occur in those with Ollier disease and Maffucci syndrome; they are caused by postzygotic IDH1 and IDH2 gene mutations. Sertoli-Leydig cell tumors usually arise in association with DICER1 syndrome, which is caused by germline DICER1 gene mutations. Sex cord tumors with annular tubules and Sertoli cell tumors may arise in patients with Peutz-Jeghers syndrome; this syndrome is caused by germline STK11 gene mutations. The majority of germ cell tumors develop in the context of gonadal dysgenesis. In XY gonadal dysgenesis, the presence of a Y chromosome material renders the patient at increased risk for developing gonadal malignancy. Characteristically, these patients develop gonadoblastoma, which has the potential to evolve into dysgerminoma and exhibit malignant behavior. Sex-chromosome aneuploidy syndromes or mutations in genes involved in gonadal development and differentiation may cause gonadal dysgenesis. Small cell carcinoma of the ovary of a hypercalcaemic type is usually caused by loss-of-function mutations in the SMARCA4 gene. Ovarian tumors are uncommon during childhood and adolescence. It is always necessary to consider gonadal dysgenesis or any of the inherited cancer syndromes. These patients require interdisciplinary care, careful noting of personal and family history, precise clinical examination, laboratory testing, and differential diagnosis by a clinician with a good knowledge of genetic syndromes. Expert pathological review may be required for correct diagnoses. This is necessary for appropriate management and to establish an association with hereditary cancer syndromes. The work was supported by the Ministry of Health of the Czech Republic - Conceptual Development of Research Organization, Faculty Hospital of Ostrava /2015. We thank to Lenka Foretová, M.D., Ph.D., (MMCI, Brno) and Radoslava Tomanová, M.D., (Institute of Pathology, University Hospital Ostrava) for rewarding advice, Mrs. Jana Němcová (Department of Medical Genetics, University Hospital Ostrava), Bc. Ludmila Stuchlá and Mrs. Lenka Zivčáková (Medical Library, University Hospital Ostrava) for help during manuscript preparation. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 10. 3. 2019 Accepted: 16. 4. 2019.

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum.

46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). To report a gene for 46,XY GD etiology, especially for ETRS. Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. Tertiary Referral Center for differences/disorders of sex development (DSD). We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.

A Rare Case of Swyer Syndrome

Swyer syndrome is caused by abnormal sex differentiation during the embryonic period, resulting in incomplete intrauterine masculinization and undifferentiated gonads. The present case report describes a patient with Swyer syndrome associated with gonadoblastoma. At age of 16 years, this patient reported with primary amenorrhea at Gynae Department of the BIRDEM general Hospital. A physical examination revealed that the patient was at Tanner stage 4 with respect to axillary hair, breasts and pubic hair; she had normal vagina and a small cervix. As her examination findings revealed normal, she was referred to Endocrine outpatient (OPD) for further evaluation. Her karyotyping revealed 46XXY, abdominal ultrasonography revealed adnexal tumor in both sides. On laparotomy, complex tumor was found in both adnexal regions and both ovaries were resected and histopathology revealed gonadoblastoma. The patient was subjected to subsequent chemotherapy. She was treated with a combination of estrogens and progestogens to induce cyclical bleeding, which she discontinued after 3 years. She was lost to follow up for 16 years and again reported to endocrine OPD with irregular menstrual bleeding. Presence of any residual gonadal functional tissue was searched both biochemically and by imaging and the result was negative. Her menstruation was stopped by progestogens and which later on withdrawn successfully without any further onset of menstruation. In conclusion, this report describes an extremely rare case of Swyer syndrome with gonadoblastoma and spontaneous menstruation after a long period of discontinuation of hormone replacement treatment.&#x0D; Birdem Med J 2019; 9(2): 174-176