Gonadal Dysgenesis Research Articles

Downregulation of Serotonergic System Components in an Experimentally Induced Cryptorchidism in Rabbits.

Cryptorchidism (CO) or undescended testes is defined as the failure of one or both testes to be positioned inside the scrotum. Typically, cryptorchidism is detected at birth or shortly thereafter, and in humans, it is considered to be part of the testicular dysgenesis syndrome (TDS), a complex pathology regarding the male reproductive system that apparently involves the interaction of both genetic and environmental harmful factors, mainly during embryonic development. Serotonin (5-HT) is an ancient molecule that participates in a broad range of body functions, and in recent years, its importance in reproduction has started to be elucidated. In male pathologies such as infertility, varicocele, erectile dysfunction, and primary carcinoid tumors, an increase in 5-HT concentration or its metabolites in the blood, semen, and urine has been directly related; nevertheless, the role of 5-HT in CO remains unknown. In the present work, our goal was to answer two important questions: (1) whether some serotonergic system components are present in adult male Oryctolagus cuniculus (chinchilla rabbit) and (2) if there are changes in their expression in an experimental model of CO. Using histological, molecular, and biochemical approaches, we found the presence of some serotonergic system components in the adult chinchilla rabbit, and we demonstrated that its expression is downregulated after CO was pharmacologically induced. Although we did not test the role of 5-HT in the etiology of CO, our results suggest that this indoleamine could be important for the regulation of steroidogenesis and spermatogenesis processes in the chinchilla rabbit during adulthood. Finally, in parallel experimental series, we found downregulation of kynurenine concentration in COI rabbits when compared to control ones, suggesting that CO could be affecting the kynurenine pathway and probably testicular immune privilege which in turn could lead to infertility/sterility conditions in this disorder.

Mutations in STARD8 (DLC3) May Cause 46,XY Gonadal Dysgenesis

Introduction: 46,XY gonadal dysgenesis is a condition that is characterised by undeveloped testes in individuals with a male karyotype. Mutations in many genes that underlie this condition have been identified; however, there are still a considerable number of patients with an unknown genetic background. Recently, a mutation in the STARD8 X-linked gene in two sisters with 46,XY gonadal dysgenesis has been reported. It was localised within the START domain, whose homologue in Drosophila is responsible for maintaining testes integrity during their development. Methods: We analysed the potential pathogenicity of another STARD8 mutation, p.R887C, that was identified in a patient with 46,XY asymmetric gonadal dysgenesis. For this purpose, molecular dynamics simulations were performed. Results: These simulations revealed the full rearrangement of the helix containing the p.R887C substitution upstream from the START domain, which may cause STARD8 protein dysfunction and contribute to 46,XY gonadal dysgenesis. A comparison of the phenotypes of the three described 46,XY gonadal dysgenesis patients that harbour STARD8 mutations indicated that alterations of this gene can result in a partial or complete gonadal dysgenesis phenotype. Conclusion: Based on these and previous results, it is reasonable to include STARD8 in gene panels for 46,XY gonadal dysgenesis.

Anti-Müllerian hormone, testicular descent and cryptorchidism.

Anti-Müllerian hormone (AMH) is a Sertoli cell-secreted glycoprotein involved in male fetal sex differentiation: it provokes the regression of Müllerian ducts, which otherwise give rise to the Fallopian tubes, the uterus and the upper part of the vagina. In the first trimester of fetal life, AMH is expressed independently of gonadotropins, whereas from the second trimester onwards AMH testicular production is stimulated by FSH and oestrogens; at puberty, AMH expression is inhibited by androgens. AMH has also been suggested to participate in testicular descent during fetal life, but its role remains unclear. Serum AMH is a well-recognized biomarker of testicular function from birth to the first stages of puberty. Especially in boys with nonpalpable gonads, serum AMH is the most useful marker of the existence of testicular tissue. In boys with cryptorchidism, serum AMH levels reflect the mass of functional Sertoli cells: they are lower in patients with bilateral than in those with unilateral cryptorchidism. Interestingly, serum AMH increases after testis relocation to the scrotum, suggesting that the ectopic position result in testicular dysfunction, which may be at least partially reversible. In boys with cryptorchidism associated with micropenis, low AMH and FSH are indicative of central hypogonadism, and serum AMH is a good marker of effective FSH treatment. In patients with cryptorchidism in the context of disorders of sex development, low serum AMH is suggestive of gonadal dysgenesis, whereas normal or high AMH is found in patients with isolated androgen synthesis defects or with androgen insensitivity. In syndromic disorders, assessment of serum AMH has shown that Sertoli cell function is preserved in boys with Klinefelter syndrome until mid-puberty, while it is affected in patients with Noonan, Prader-Willi or Down syndromes.

Clinical characteristics and surgical treatment of children with 45, X/46, XY differences of sex development

This study retrospectively analyzes the clinical data of 18 children with 45,X/46,XY differences of sex development (DSD), summarizes their clinical features and explores gonadal and Müllerian duct remnants surgical treatment methods. The clinical data of 18 children with karyotype 45,X/46,XY diagnosed in the Department of Urology of Hunan Children's Hospital from March 2011 to October 2021 were collected. All children underwent HCG stimulation testing, laparoscopic exploration, urethroscopy and bilateral gonadal biopsy. After DSD multidisciplinary team (MDT) meeting, some children underwent gonadectomy and genitalia reconstructive surgeries. The median age at first diagnosis was 1 year and 4 months (range: 10 months ∼ 16 years and 3 months). 5 children presented with female gender; they all maintained their gender assignment. The external masculinisation score (EMS) of patients raised as female was 1 (0∼3) [median (range)]. 13 children presented with male gender, 10 maintained a male gender, 3 were assigned a neutral gender. The EMS of the children raised as male was 5 (2-8) [median (range)], the EMS of the children raised as neutral gender was 4 (3.5-9.5) [median (range)]. The HCG stimulation test was positive in 11 cases, partially positive in 2 case, and negative in 5 cases. There was no relationship between the percentage of chimerism (45X ratio) and the appearance and severity of genital abnormalities. (t=-1.08, P=0.298). There was 1 case of complete gonadal dysgenesis (CGD), 10 cases of mixed gonadal dysgenesis (MGD), 5 cases of partial gonadal dysgenesis (PGD), 1 case of bilateral normal testes and 1 case of ovotesticular DSD (split-lateral type). No gonadal specimen showed germ cell tumor changes. Five cases selected to maintain the female gender, among which 3 cases underwent bilateral gonadectomy and genitalia reconstructive surgeries. Among the 10 children who chose to maintain the male gender, unilateral streak gonadectomy was performed in 4 (57.1%) with MGD, unilateral dysgenetic orchiectomy in 1 (25%) with PGD, and right ovariectomy in 1 with OTDSD. Nine of them underwent genitalia reconstructive surgeries. Four of them preserved their uterus and vagina did not have any complications during the follow-up period. Hypospadias combined with cryptorchidism and residual Müllerian duct structures is the most common phenotype of children with 45, X/46, XY DSD. Mixed gonadal dysgenesis (MGD) is the most common gonadal type. Gender assignment should be carefully selected after a thorough evaluation, while genitalia reconstructive surgery can be considered in selected patients. In children who choose the male gender, the Müllerian duct can be preserved.

SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis.

Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause. Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings. By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02. SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family.

PHARMACOINFORMATICS ANALYSIS OF MORUS MACROURA FOR DRUG DISCOVERY AND DEVELOPMENT

Objective: Pharmacoinformatics is an innovative approach rapidly evolving in pharmaceutical research and drug development. This study focuses on analysing Morus macroura, a plant species with untapped pharmacological potential. This investigation aims to leverage pharmacoinformatics techniques to unveil the hidden potential of Morus macroura in drug discovery and development.
 Methods: The study includes analyses of protein-protein interactions, deep learning docking, adsorption tests, distribution, metabolism, excretion, molecular dynamics simulations and free energy calculation using Molecular Mechanics Generalized Born Surface Area (MMGBSA).
 Results: Nine active compounds were identified in Morus macroura, namely Andalasin A, Guangsangon K, Guangsangon L, Guangsangon M, Guangsangon N, Macrourone C, Mulberrofuran G, Mulberrofuran K, and Mulberroside C. These compounds exhibit protein-protein interaction activities against a cytochrome P450 monooxygenase that catalyses the conversion of C19 androgens. These plant compounds influence aromatase excess syndrome, deficiency, and ovarian dysgenesis. Regarding drug-likeness, Mulberroside C and Macrourone C demonstrated good absorption potential by adhering to Lipinski's rule of five. Deep learning docking simulations yielded affinity results of-9.62 kcal/mol for Guangsangon M,-10.44 kcal/mol for Macrourone C, and-10.99 kcal/mol for Guangsangon L. Subsequent molecular dynamics simulations indicated that Guangsangon L and Macrourone C remained stable during a 100 ns simulation.
 Conclusion: Morus macroura interacts with important proteins, particularly CYP19A1, which might influence health conditions like aromatase excess syndrome and ovarian dysgenesis. These findings provide potential paths for addressing specific health issues and advancing drug development. Molecular dynamics simulations indicated that Guangsangon L and Macrourone C remained stable during simulation.

DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives

Introduction: The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. The clinical phenotype of TRS often overlaps with that of partial gonadal dysgenesis (PGD). Previous studies have demonstrated a causal association between TRS/PGD and heterozygous missense variants of DHX37. Methods: We enrolled 11 Japanese 46,XY individuals (from 10 families) with TRS/PGD who exhibited undetected or hypoplastic testes, Müllerian duct regression, and low serum testosterone or anti-Müllerian hormone levels. The subjects underwent targeted sequencing of 36 known causative genes for DSD, PCR-based Sanger sequencing of DHX37, or whole-exome sequencing. Results: Previously described pathogenic variants or novel nonsense variants (SRY, NR5A1, and DMRT1) were observed in four out of 10 families. Additionally, we identified two heterozygous rare variants of DHX37 in four families: a previously reported pathogenic variant (c.923G>A, p.Arg308Gln) in three and a novel likely pathogenic variant (c.1882A>C, p.Thr628Pro) in one. The external genitalia of patients with the DHX37 variants varied from female-type to male-type without micropenis. Eighty percent of Japanese patients with TRS/PGD had monogenic disorders including DHX37 variant being the most commonly identified (40%). The external or internal genital phenotype of TRS/PGD overlaps between DHX37 variant carriers and others. Conclusions: DHX37 variant is one of the common genetic causes in Japanese patients with TRS/PGD without Müllerian derivatives. Genetic test is helpful in detecting DHX37-related TRS/PGD because of the phenotypic diversity of the external genitalia in this disorder.

Clinicopathological analysis of gonadal differentiation of sex development disorder

Objective: To investigate pathological features and differential diagnosis in the gonads with disorder of sex development. Methods: Thirty-six cases of clinically diagnosed hermaphroditism with gonadal biopsy in the Department of Pathology, the Seventh Medical Center of People's Liberation Army General Hospital from April 2007 to July 2021, were collected. All biopsy pathological sections were reviewed, and the gonadal cases with abnormal pathological morphology were screened out. The clinical and imaging data and karyotype of these cases were reviewed. Additional immunohistochemical staining was performed and relevant literature was reviewed. Results: Seven cases of ovotesticular disorder of sex development (OTDSD) were identified, which were characterized by the presence of testicular and ovarian differentiation in the same individual. All patients were under 15 years old and presented with abnormal appearance of external genitalia, and the ratio of male to female was 2∶5. Ultrasonography showed testicular structure in all female patients and cryptorchidism in all male patients. The most common karyotype was 46, XX. One case with undifferentiated gonadal tissue (UGT) and one case with streak gonads were screened out. UGT germ cells were neither in seminiferous tubules nor in follicles, but randomly distributed in an ovarial-type interstitial background, sometimes accompanied by immature sex cords. Streak gonads resembled UGT without germ cells. FOXL2 was positive in granulosa cells, but negative in Sertoli cells. SOX9 expression was opposite. OCT4 was weakly positively/negatively expressed in oocytes and positively expressed in the germ nuclei of UGT. Conclusions: Four differentiation patterns need to be identified in the gonadal biopsy: ovarian differentiation, testicular differentiation, undifferentiated gonadal tissue and streak gonad. The positive expression of SOX9 indicates testicular differentiation, while the positive expression of FOXL2 confirms ovarian differentiation, and the expression of both markers in the same tissue indicates ovotestis differentiation. It is very important to identify UGT, because that has a high probability of developing into gonadoblastoma in the future.

КЛИНИЧЕСКИЙ СЛУЧАЙ УСПЕШНОЙ РЕАЛИЗАЦИИ РЕПРОДУКТИВНОЙ ФУНКЦИИ У ПАЦИЕНТКИ С ДИСГЕНЕЗИЕЙ ГОНАД

An important problem is the problem of implementing reproductive function in patients with forms of infertility caused by genetic abnormalities. Previously, the prognosis for their reproductive function was considered unfavorable. In modern conditions, by improving IVF techniques using oocyte donation, treatment of infertility in these patients becomes possible. Therefore, studying the features of the tactics of managing such patients at the stage of preconception preparation, the features of IVF protocols, as well as the features of managing pregnancy and labor and delivery is relevant. The purpose of the study is to substantiate the possibility of successful implementation of reproductive function in a patient with gonadal dysgenesis. A clinical case of pregnancy and childbirth in a patient with a typical form of gonadal dysgenesis (karyotype 45 X0) is presented. The diagnosis was made at the age of 15 during a comprehensive examination for primary amenorrhea, and hormone replacement therapy was prescribed. The patient's pregnancy occurred after preparation of the endometrium with estrogens and gestagens as a result of the fourth IVF attempt with the donation of an egg fertilized by her husband's sperm, and was complicated by the threat of termination at 8 and 19 weeks. At 36 weeks, the pregnancy was complicated by severe preeclampsia, which required emergency caesarean section. The course of the postoperative period was uneventful with continuation of therapy for complications of gestation. It is recommended after cessation of lactation - HRT using drugs with an estrogenic component similar in chemical structure to natural ones, gestagenic - metabolically neutral. The study of this clinical case is of undoubted interest, taking into account the peculiarities of management tactics. It is necessary to implement a multidisciplinary approach to the management of such complex patients. Taking into account the peculiarities of the body condition in patients with gonadal dysgenesis and the absence of hormonal ovarian function, it is necessary to ensure optimal preconception preparation, the use of an individual approach to the implementation of the IVF protocol, and the prevention of complications during pregnancy. Fulfillment of these conditions will ensure a positive result of infertility treatment in patients with gonadal dysgenesis who previously did not have the opportunity to realize reproductive function.

A Risk of Gonadoblastoma in Familial Swyer Syndrome—A Case Report and Literature Review

A complete gonadal dysgenesis (CGD) with 46,XY karyotype is known as the Swyer syndrome and belongs to the group of 46,XY differences of sex development (DSD). The main problem in patients with Swyer syndrome is the delayed puberty and primary amenorrhea. Moreover, intrabdominal dysgenetic gonads in the patient with genetic material of a Y chromosome may conduce to the development of gonadal tumors, such as gonadoblastoma or germinoma. The management of such patients is based on preventive excision of dysgenetic gonads and long-term hormonal replacement therapy. Sporadic cases are considered more common than familial cases. This paper presents two siblings with Swyer syndrome in whom gonadoblastoma was found. A thorough review of familial CGD with 46,XY DSD in the literature from the last 15 years suggests that the risk of gonadal tumors could be increased in familial compared to sporadic cases (66.6% vs. 15–45%, respectively).

Gender determination and long-time follow-up analysis of mixed gonadal dysgenesis

Mixed gonadal dysgenesis (MGD) is a rare disorder of sexual development. The management of MGD is challenging since the disease significantly impacts a patient's growth, hormone balance, and gonadal development. This article used a large population and a long follow-up period for its analysis. This study aims to summarize the gender determination basis and analyze the long-term follow-up of mixed gonadal dysgenesis. A total of 45 patients' clinical data were summarized and analyzed. Patients were divided by gender. Next, we followed up regarding the occurrence of complications after surgery, the patients' satisfaction with external genitalia appearance, the growth of the patients, counting the surgical pattern the incidence of surgical complications and the development of the patients' growth. All patients included in this study underwent chromosomal karyotype analysis, abdomen exploration, and pathological biopsy. After sex determination, 7 patients who were raised as female underwent clitoroplasty, and bilateral gonadectomy. 38 male patients underwent urethroplasty+one-sided gonadectomy. Patient follow-up started in the third month after surgery. Female patients reported no surgery-related complications, while 14 male patients showed surgery-related complications. Additionally, 20 male patients (60.6%) had a lower height compared to normal peers, 12 of which (36.4%) were lower than the second standard deviation of the height of normal peers. The clinical manifestations of mixed gonadal dysgenesis are variable, and the management is complicated. Children's gonadal function, external genital conditions, psychological evaluation, and parents' wishes should be considered before sex determination. In China, most patients are raised as males with a high incidence of postoperative complications. We found that short stature is a common feature in male patients, thus their height and growth should be carefully supervised. Patients should pay attention to their sexual function and sexual potential during adulthood.

Expanding the phenotype of copy number variations involving NR0B1 (DAX1).

46,XY gonadal dysgenesis (GD) is a disorder of sex development due to incomplete gonadal differentiation into testes, resulting in female to ambiguous external genitalia. Duplications at the Xp21.2 locus involving the NR0B1 (DAX1) gene have previously been associated with 46,XY GD. More recently, a complex structural variant not directly involving NR0B1 has been reported in 46,XY GD illustrating that the mechanism of how copy number variants (CNVs) at Xp21.2 may cause 46,XY gonadal dysgenesis is not yet fully understood. Here, we report on three families in which a duplication involving the NR0B1 gene was detected in the context of prenatal screening. This is the first report of duplications involving NR0B1 in three phenotypically normal males in two families. Fertility problems were present in one adult male carrier. The data reported here from an unbiased screening population broaden the phenotype associated with CNVs involving NR0B1, and this may aid clinicians in counseling and decision making in the prenatal context.

A novel regulatory sex-skewing method that inhibits testicular DPY30 expression to increase female rate of dairy goat offspring.

The demand for goat milk products has increased exponentially with the growth of the global population. The shortage of dairy products will be addressed extraordinarily by manipulating the female rate of goat offspring to expand the goat population and goat milk yield. No studies have reported bioinformatic analyses of X- and Y-bearing sperm of dairy goats, although this will contribute to exploring novel and applied sex-skewing technologies. Regulatory subunit of the histone methyltransferase complex (DPY30) was determined to bethe key differentially expressed protein (DEP) among 15 DEPs identified in the present study. The spatiotemporal expression of DPY30 strongly suggested a functional involvement of the protein in spermatogenesis. DPY30 promoted meiosis via upregulating SYCP3, which played a crucial role in mediating sex ratio skewing in goats. Although DPY30 suppressed the self-renewal of spermatogonia stem cells through AKT/PLZF, DPY30 inhibition in the testis did not induce testicular dysgenesis. Based on the biosafety assessment in mice testes, lentivirus-mediated DPY30 knockdown in bucks' testes increased X-bearing sperm proportion and female kids' rate (22.8 percentage points) without affecting sperm quality, pregnancy rate, and kidding rate. This study provides the first evidence of the DEGs in the sexed sperm of dairy goats. DPY30 inhibition in the testes of bucks increased the female kids' rate without influencing reproductive performance. The present study provides evidence for expanding the female dairy goat population to address the concern of dairy product shortage.

46,XX males with SRY gene translocation: cytogenetics and molecular characterization

PurposeXX male syndrome also known as De la Chapelle syndrome/Testicular Disorder of Sex Development (DSD) is a rare genetic abnormality, identified by a partial or complete mismatch between phenotypic and genotypic gender of an individual. The present study describes the pertinent clinical, biochemical, cytogenetics, and molecular findings in four phenotypically normal males, presented with gonadal dysgenesis and hypergonadotrophic hypogonadism.MethodClinical characteristics and biochemical parameters in four patients were assessed. Further, chromosomal analysis has been performed using conventional karyotyping. FISH and Y chromosome microdeletion assays were carried out to confirm the presence of male-specific genes followed by microarray analysis.ResultChromosomal analysis revealed a 46,XX karyotype, FISH showed the presence of 2 normal X chromosomes along with translocation of the SRY gene on the short (p) arm of one of the X chromosome. Molecular analysis for Y chromosome microdeletion revealed the presence of the SRY gene with a complete absence of azoospermic factor regions (AZFa, AZFb, and AZFc) on the long (q) arm of the Y chromosome. Chromosomal microarray revealed no significant copy number variation.ConclusionsThe peculiar translocation of the SRY gene in 46,XX males strongly supports the inclusion of cytogenetic testing for establishing diagnosis and genetic counseling for infertility and/or hormonal imbalances in individuals. The present study provides insight into the cascade of events triggered by the SRY gene in the XX genome, which reinforces the differentiation towards the formation of testes while actively inhibiting ovarian development.

Indications for genetic diagnosis in children with growth hormone deficiency and born small for gestational age.

The aim of the study is to analyze patients who do not respond adequately to human recombinant growth hormone (rhGH) treatment. Four boys were analyzed: three patients diagnosed with SNP at the ages of 1) 8 years and 2 months, 2)13years and 2 months, 3) 16 years and 6 months, and patient 4) at the age of 6 years and 11 months - born small for gestational age (SGA). They underwent rhGH treatment. The expected growth improvement was not observed in all boys. Patient 1 was diagnosed with aortic coarctation, and after each attempt to increase the rhGH dose, nocturnal vomiting occurred - epilepsy was diagnosed. Patient 2 had severe foot pain. Patient 3 had delayed puberty - hypogonadotropic hypogonadism was diagnosed. Patient 4 had dysmorphic features. Genetic tests revealed the following: 1) mixed gonadal dysgenesis - modifying treatment; 2) Fabry disease - enzyme treatment and rhGH improved growth; 3)Kallmann syndrome - discontinuing rhGH for testosterone supplementation; 4) KBG syndrome. 1. The presence of dysmorphic features and symptoms atypical for growth hormone deficiencies could warrant genetic diagnostics before initiating treatment. 2. Lack of significant improvement in growth is an indication for reevaluation of patients who have not completed growth. 3. Genetic studies in this patient group often elucidate the causes of slow growth rate. 4. The case authors have developed aproposal for amulticentre program aimed at establishing indications for genetic diagnosis in children diagnosed with SNP and SGA treated with rhGH.

Мозаичная форма дисгенезии гонад при варианте синдрома Тернера с наличием Y-хромосомы

Мозаичная форма дисгенезии гонад при варианте синдрома Тернера с наличием Y-хромосомы

Rudimentary and Incipient-Yolk Sac Tumour- Testis

Yolk sac tumour of testis configures as a germ cell neoplasm comprised of cellular articulations or structures simulating embryonic or foetal yolk sac, allantois and extra-embryonal mesenchyme. Testicular yolk sac tumour is pre-eminently comprised of prepubertal subtype which is non-concordant to germ cell neoplasia in situ, emerges as a ‘pure’ neoplasm and demonstrates multiple gains within chromosome 1q, 20q or 22 and losses within chromosomes 1p, 4 or 6q. Postpubertal subtype is concurrent to germ cell neoplasia in situ (GCNIS), preponderantly configures as a component of ‘mixed tumour’ and occurs due to testicular dysgenesis syndrome, subfertility or as single nucleotide polymorphism (SNP) variants within KITLG, SPRY4 or DMRT1 genes and expounds gain of isochromosome 12p. Upon microscopy, neoplasm may configure distinctive configurations as microcystic or reticular pattern, macrocystic pattern, myxomatous pattern, sarcomatoid or spindle shaped cellular pattern, solid pattern, glandular or alveolar pattern, endodermal sinus or perivascular pattern, hepatoid pattern, papillary pattern, parietal pattern or poly-vesicular vitelline pattern. Yolk sac tumour appears immune reactive to alpha fetoprotein (AFP), glypican 3, SALL4, pancytokeratin, villin or CK7. Neoplastic cells appear immune non-reactive to OCT3/4, CD30, CD117, placental alkaline phosphatase (PLAP), podoplanin (D2-40), inhibin, GATA3 or p63. Testicular yolk sac tumour requires segregation from neoplasms as teratoma, seminoma, embryonal carcinoma, rete testis with hyaline globules and microcystic leydig cell tumour. Tumefaction preponderantly depicts elevated levels of serum alpha fetoprotein (AFP). Testicular yolk sac tumour may be optimally subjected to surgical manoeuvers as orchiectomy.

Primary ovarian insufficiency: update on clinical and genetic findings.

Primary ovarian insufficiency (POI) is a disorder of insufficient ovarian follicle function before the age of 40 years with an estimated prevalence of 3.7% worldwide. Its relevance is emerging due to the increasing number of women desiring conception late or beyond the third decade of their lives. POI clinical presentation is extremely heterogeneous with a possible exordium as primary amenorrhea due to ovarian dysgenesis or with a secondary amenorrhea due to different congenital or acquired abnormalities. POI significantly impacts non only on the fertility prospect of the affected women but also on their general, psychological, sexual quality of life, and, furthermore, on their long-term bone, cardiovascular, and cognitive health. In several cases the underlying cause of POI remains unknown and, thus, these forms are still classified as idiopathic. However, we now know the age of menopause is an inheritable trait and POI has a strong genetic background. This is confirmed by the existence of several candidate genes, experimental and natural models. The most common genetic contributors to POI are the X chromosome-linked defects. Moreover, the variable expressivity of POI defect suggests it can be considered as a multifactorial or oligogenic defect. Here, we present an updated review on clinical findings and on the principal X-linked and autosomal genes involved in syndromic and non-syndromic forms of POI. We also provide current information on the management of the premature hypoestrogenic state as well as on fertility preservation in subjects at risk of POI.

Magnetic Resonance Imaging Findings in Mayer- Rokitansky-Küster-Hauser (MRKH) Syndrome: A Report of Two Cases

Introduction: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a kind of Müllerian duct anomaly characterized by the absence or underdevelopment of the uterus and the top two-thirds of the vagina. MRKH syndrome is characterized by primary amenorrhea in young women who exhibit typical development of secondary sexual characteristics and normal external genitalia. These individuals have normal and functioning ovaries and a karyotype of 46, XX. Gonadal dysgenesis is the most prevalent cause of primary amenorrhea, followed by this condition. This case report aims to elaborate on MRI findings in females with typical and atypical types of MRKH syndrome. Case Description: The authors describe two female patients who presented with primary amenorrhea, normal external genitalia, and typical secondary sexual characteristics. These patients underwent MRI to identify the uterine and vaginal structure and additional non-gynaecologic abnormalities. Conclusion: MRI is the best imaging technique for the accurate evaluation of pelvic anatomy, uterine aplasia, uterine development, vaginal structure, and location of the ovaries, hence essential in the diagnosis, classification, and surgical planning of MRKH syndrome.

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.