[Swyer syndrome with gonadal non-dysgerminoma malignant germ cell tumors: a report of 15 cases in a national medical center].

Objective: To evaluate the incidence, treatment, and survival outcomes of Swyer syndrome with gonadal non-dysgerminoma malignant germ cell tumor (MGCT-NDG). Methods: A retrospective study was performed on Swyer syndrome patients with MGCT-NDG between January 2011 and December 2022 in Peking Union Medical College Hospital to investigate their characteristics and outcomes. Results: A total of 15 patients (4.9%, 15/307) with Swyer syndrome were identified in 307 MGCT-NDG patients. The average age at diagnosis of MGCT-NDG and Swyer syndrome were (16.8±6.7) and (16.7±6.6) years, respectively. Six cases were preoperatively diagnosed as Swyer syndrome, of which 4 cases received bilateral gonadectomy with or without hysterectomy, while the other 2 cases underwent removal of gonadal tumor and unilateral gonadectomy with hysterectomy, respectively. Of the 9 patients postoperatively diagnosed as Swyer syndrome, unilateral gonadectomy, removal of gonadal tumor, and unilateral gonadectomy with hysterectomy were performed in 6 patients, 2 patients, and 1 patient, respectively. Mixed malignant germ cell tumor (MGCT;10 cases), yolk sac tumor (4 cases), and immature teratoma (1 case) were the pathological subtypes, in the descending order. There were International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰ in 6 cases, stage Ⅱ in 3 cases, stage Ⅲ in 5 cases, and stage Ⅳ in 1 case, respectively. Eleven patients received reoperation for residual gonadectomy after a average delay of (7.9±6.2) months, including 8 MGCT-NDG patients and 1 gonadoblastoma patient, no tumor involved was seen in the remaining gonads in the other 2 cases. Ten patients experienced at least one recurrence, with a median event free survival of 9 months (5, 30 months), of which 2 patients received surgery only at the time of initial treatment. All patients with recurrence received surgery and combined with postoperative chemotherapy. After a median follow-up of 25 months (15, 42 months), 10 patients were disease-free, 3 patients died of the tumor, 1 died of side effects of leukemia chemotherapy, and 1 survived with disease. Conclusion: The incidence rate of Swyer syndrome in patients with MGCT-NDG is about 4.9%; timely diagnosis and bilateral gonadectomy should be emphasized to reduce the risk of reoperation and second carcinogenesis in this population.

Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein.

Missense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15-20% of cases [Ostrer, 2014, Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab., 99, 1503-1509]. Functional studies demonstrated that all of these mutations cause a protein gain-of-function that alters co-factor binding and increases phosphorylation of the downstream MAP kinase pathway targets, MAPK11, MAP3K and MAPK1. This dysregulation of the MAP kinase pathway results in increased CTNNB1, increased expression of WNT4 and FOXL2 and decreased expression of SRY and SOX9. Unique and recurrent pathogenic mutations cluster in three semi-contiguous domains outside the kinase region of the protein, a newly identified N-terminal domain that shares homology with the Guanine Exchange Factor (residues Met164 to Glu231), a Plant HomeoDomain (residues Met442 to Trp495) and an ARMadillo repeat domain (residues Met566 to Glu862). Despite the presence of the mutation clusters and clinical data, there exists a dearth of mechanistic insights behind the development imbalance. In this paper, we use structural modeling and functional data of these mutations to understand alterations of the MAP3K1 protein and the effects on protein folding, binding and downstream target phosphorylation. We show that these mutations have differential effects on protein binding depending on the domains in which they occur. These mutations increase the binding of the RHOA, MAP3K4 and FRAT1 proteins and generally decrease the binding of RAC1. Thus, pathologies in MAP3K1 disrupt the balance between the pro-kinase activities of the RHOA and MAP3K4 binding partners and the inhibitory activity of RAC1.

Presence of viable germ cells in testicular regression syndrome remnants: Is routine excision indicated? A systematic review.

There is no consensus in the literature about the necessity for excision of testicular remnants in the context of surgery for an impalpable testis and testicular regression syndrome (TRS). The incidence of germ cells (GCs) within these nubbins varies between 0 and 16% in previously published series. There is a hypothetical potential future malignancy risk, although there has been only one previously described isolated report of intratubular germ-cell neoplasia. Our aim was to ascertain an accurate incidence of GCs and seminiferous tubules (SNTs) within excised nubbins and hence guide evidence-based practice. The systematic review protocol was designed according to the PRISMA guidelines, and subsequently published by the PROSPERO database after review (CRD42013006034). The primary outcome measure was the incidence of GCs and the secondary outcome was the incidence of SNTs. The comprehensive systematic review included articles published between 1980 and 2016 in all the relevant databases using specific search parameters and terms. Strict inclusion and exclusion criteria were ultilised to identify articles relevant to the review questions. Twenty-nine paediatric studies with a total of 1455 specimens were included in the systematic review. The mean age of the patients undergoing nubbin resection was 33 months and the TRS specimen was more commonly excised from the left (68%). The incidence of SNTs was 10.7% (156/1455) and the incidence of GCs, 5.3% (77/1455). Histological analysis excluding the presence of either SNTs or GCs was consistent with TRS, fibrosis, calcification or haemosiderin deposits. There is limited evidence on subset analysis that GCs and SNTs may persist with increasing patient age. This systematic review has identified that 1 in 20 of resected testicular remnants has viable GCs and 1 in 10 has SNTs present. There is insufficiently strong evidence for the persistence of GCs and SNTs with time or future malignant potential. Intra-abdominal TRS specimens may contain more elements and, therefore, require excision, although this is based on limited evidence. However, there is no available strong evidence to determine that a TRS specimen requires routine excision in an inguinal or scrotal position.

Cellular and molecular responses of adult testis to changes in nutrition: novel insights from the sheep model.

This review explores the cellular and molecular mechanisms that regulate spermatogenesis in the post-pubertal testis that is regressing in response to mild undernutrition, using the sexually mature male sheep as a model. Testis regression leads to reductions in daily sperm production and in the quality of ejaculated spermatozoa (poorer movement, DNA damage). There is also a reduction in spermatogenic efficiency that appears to be caused, at least partially, by increases in germ cell apoptosis. Sertoli cell number does not change with testis regression, although about 1% of Sertoli cells do appear to retain proliferative ability after puberty. On the other hand, Sertoli cell function is disrupted during testis regression, as evidenced by a disorganization of tight junctions and indications that cell differentiation and maturation are reversed. Disrupted Sertoli cell function can explain, at least partially, the increase in germ cell apoptosis and any decrease in the rate of spermatogenesis, the two major contributors to spermatogenic efficiency. These outcomes seem to be mediated by changes in two RNA-based processes: (i) the expression of small non-coding RNAs that are involved in the regulation of Sertoli cell function, spermatogenesis and germ cell apoptosis and (ii) alternative pre-mRNA splicing that affects the regulation of spermatogenesis but does not appear to affect germ cell apoptosis, at least during testis progression induced by undernutrition in the male sheep. These research outcomes can be extended to other animal models and are relevant to issues in human male fertility.

17α-HYDROXYLASE/17, 20-LYASE DEFICIENCY: CLINICAL AND MOLECULAR CHARACTERIZATION OF EIGHT CHINESE PATIENTS.

OBJECTIVE: 17α-hydroxylase/17, 20-lyase deficiency (17OHD) is caused by mutations in the cytochrome P450 17A1 (CYP17A1) gene. To better understand 17OHD, a rare disease, we described the clinical features and performed CYP17A1 gene analysis in 8 affected Chinese patients. METHODS: Patients with complete (7/8) or partial (1/8) 17OHD were derived from 6 families. The diagnosis was established according to their clinical, biochemical, hormonal, and radiological characteristics. Long-term follow-up of some patients was also designed. RESULTS: Patients with 17OHD suffered from varying degrees of hypokalemia and hypertension. Symptoms in female patients with partial 17OHD manifested as secondary amenorrhea, recurrent ovarian cysts, elevated estradiol level, and lower follicle-stimulating hormone and luteinizing hormone levels; primary amenorrhea was typical in patients with complete 17OHD. Adrenal masses and decreased bone mineral density (BMD) were discovered in 2 patients, respectively. During long-term follow-up, 4 patients developed low BMD, while 3 individuals underwent respiratory infections and recurrent urinary tract infections. CYP17A1 gene analysis revealed 7 different kinds of mutation, including 1 novel mutation, L266V. CONCLUSION: The clinical characteristics of partial 17OHD were different from those of complete 17OHD. Low BMD and infections were common in patients with 17OHD on long-term steroid treatment. Seven mutations were identified in the CYP17A1 gene, and 1 was novel. ABBREVIATIONS: ACTH = adrenocorticotropic hormone BMD = bone mineral density CAH = congenital adrenal hyperplasia CT = computed tomography DEXA = dual-energy X-ray absorptiometry DEX = dexamethasone 17OHD = 17α-hydroxylase/17, 20-lyase deficiency.

Longitudinal hormonal evaluation in a patient with disorder of sexual development, 46,XY karyotype and one NR5A1 mutation.

Steroidogenic factor 1 (encoded by the NR5A1 gene) is a critical regulator of reproduction, controlling transcription of key genes involved in sexual dimorphism. To date, NR5A1 variants have been found in individuals with a 46,XY karyotype and gonadal dysgenesis, as well as with a wide spectrum of genital anomalies and, in some patients, with adrenal insufficiency. We describe evolution of gonadal function, from the neonatal period to puberty, in a patient with a 46,XY karyotype, a disorder of sexual development, and a mutation (c.691_699dupCTGCAGCTG) in the NR5A1 gene. The patient, ascertained at birth due to ambiguous genitalia, showed normal values of plasma testosterone in the late neonatal period. Evaluation of the hormonal profile over time indicated severe tubular testicular hypofunction suggestive for a 46,XY disorder of gonadal development. A comprehensive review of published reports of 46,XY and disordered sexual development related to the NR5A1 gene confirmed the clinical and hormonal variability in patients with NR5A1 mutations. Analysis of multiple data allowed us to define the most common features associated with NR5A1 mutations. We further confirmed the indication to perform NR5A1 screening in patients with 46,XY karyotype and disordered sexual development even when Müllerian structures appear to be absent and plasma testosterone levels are within the normal range for age.

Malignant ovarian germ cell tumor - role of surgical staging and gonadal dysgenesis.

OBJECTIVE: To evaluate the effect of comprehensive surgical staging and gonadal dysgenesis on the outcomes of patients with malignant ovarian germ cell tumor. METHODS: We performed a retrospective review of patients with ovarian germ cell tumors who were treated at our institution between 1976 and 2012. RESULTS: Malignant ovarian germ cell tumors (MOGCTs) were identified in 50 females. The median age was 24 years (range 13 to 49). Of all MOGCT patients, 42% had dysgerminoma, 20% immature teratoma, 16% endodermal sinus tumor, and 22% mixed germ cell tumor. Univariate analyses revealed that the lack of surgical staging (p=0.048) and endodermal sinus tumor (p=0.0085) were associated with disease recurrence, while age at diagnosis, ethnicity, and stage of the disease were not. Multivariate analyses revealed that the lack of surgical staging (p=0.029) and endodermal sinus tumor (p=0.016) were independently associated with disease recurrence. In addition, 7 patients (14%) had 46 XY karyotype, including 6 with pure dysgerminoma and 1 with mixed germ cell tumor. Five had Swyer syndrome and 2 had complete androgen insensitivity syndrome. Concurrent gonadoblastoma was found in 5 of the patients. No difference was found in the mean age at presentation, stage distribution, or recurrence rate for MOGCT patients with or without XY phenotype. CONCLUSIONS: Comprehensive surgical staging was associated with a lower rate of recurrence. Fourteen percent of phenotypic females with MOGCT and 29% of those with dysgerminoma had XY karyotype. The clinical outcome of these patients is similar to that of MOGCT patients with XX karyotype.

9p partial monosomy and disorders of sex development: review and postulation of a pathogenetic mechanism.

Deletion of the distal segment of 9p causes a syndrome comprising trigonocephaly, minor anomalies, and intellectual disability. Patients with this condition also frequently present with genitourinary abnormalities including cryptorchidism, hypospadias, ambiguous genitalia, or 46,XY testicular dysgenesis. The region responsible for the gonadal dysgenesis has been localized to 9p24.3 with the likely responsible gene identified as DMRT1. Similar to patients with other molecular causes of 46,XY gonadal dysgenesis, patients with partial del 9p have an increased risk of gonadoblastoma. We present two patients with 46,XY gonadal dysgenesis due to partial 9p monosomy. Both patients were also diagnosed with gonadoblastoma following gonadectomy at an early age. Chromosomal microarray analyses refined the cytogenetic abnormalities and allowed potential genotype-phenotype relationships to be determined. We also review the literature as it pertains to partial 9p monosomy, genital abnormalities and gonadoblastoma and note that a large percentage of affected patients present with two copy number variations. We propose that a two-hit mechanism may be involved in the incomplete penetrance and variable expressivity of partial 9p monosomy and an abnormal genital phenotype. The significant percentage of gonadoblastoma in patients with 46,XY complete gonadal dysgenesis due to partial 9p monosomy also continues to support the necessity of gonadectomy in this patient population.

Microscopic dysgerminoma associated with anti-Ma2 paraneoplastic encephalitis in a patient with gonadal dysgenesis.

We present a 27-yr-old female with gonadal dysgenesis (46, XY), who presented to our hospital with poor consciousness, aphasia, restlessness, and visual hallucination. Physical examination revealed normal breast development and normal external female genetalia. Computed tomography scan of the head and neck revealed the presence of brain edema, hydrocephalous, and a localized hypodense lesion in the hypothalamus. Her serum was positive for the anti-Ma2, which is associated with paraneoplastic encephalitis syndrome. Computed tomography of the abdomen revealed the presence of a 7.5×5.3×3.0 cm solid pelvic mass. Interestingly, a single microscopic focus of dysgerminoma was identified in a background of stromal fibrosis and focal dystrophic calcifications. No ovarian stroma or testicular tissue was identified. To our knowledge, this is the first case of gonadal dysgenesis presenting with anti-Ma2 paraneoplastic encephalitis with dysgerminoma. A discussion about paraneoplastic encephalitis with a microscopic dysgerminoma associated with anti-Ma2 antibody is presented.

The 17ß-hydroxysteroid dehydrogenase type 3 deficiency: a case report of an 18-year patient and review of the literature.

UNLABELLED: Deficiency of 17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3), an enzyme converting androstenedione (A) to testosterone (T), is a rare cause of autosomal recessive 46,XY disorder of sexual development (DSD). A 18-years phenotypically female patient from southern Italy presented with primary amenorrhea. She had deep voice, macrocephaly, enlarged and bulbous nasal tip, macrostomia, facial acne, breast asymmetry, hypoplasia of the first finger of right hand, proximal implant of the fifth metatarsus bilaterally as well as an increased muscle mass and hirsutism, with hair distribution on face, neck, chest, abdomen, pubic region and on upper and lower limbs. Genital exam showed thickened labra majora with absence of labra minora and a blind-ending pseudo-vagina with clitoris enlargement. Karyotype analysis showed a male genotype (46,XY). Hormonal evaluation showed decreased T (188 ng/dL-6.5 nmol/L) and increased A (10 ng/mL-34,96 nmol/L), considering male reference ranges, resulting in a decreased T/A ratio (0,186). MRI identified testicles in inguinal regions. Human Chorionic Gonadotropin test showed T/A ratio permanently under 0,8. These evidences were suggestive of a 46,XY DSD due to 17ßHSD3 deficiency. An homozygous mutation (IVS3 -1 G>C or c.326-1G>C) of the 17ßHSD3 gene was discovered. Psychologist identified a well determined female gender identity. It was decided to proceed with gonadectomy and vaginal enlargement by use of dilatators. CONCLUSION: The case described represents a new case of DSD due to 17ßHSD3 deficiency. This patient, raised as a girl, is diagnosed in a very late stage. The identified mutation, previously reported only in Dutch and Brazilian population, is one of 27 presently known mutations of 17ßHSD3 gene and is never reported in Italian population.

Mutations in NR5A1 associated with ovarian insufficiency.

BACKGROUND: The genetic causes of nonsyndromic ovarian insufficiency are largely unknown. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-steroidogenic axis. Mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure, but growing experimental evidence from studies in mice suggests a key role for this factor in ovarian development and function as well. METHODS: To test the hypothesis that mutations in NR5A1 cause disorders of ovarian development and function, we sequenced NR5A1 in four families with histories of both 46,XY disorders of sex development and 46,XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. None of the affected subjects had clinical signs of adrenal insufficiency. RESULTS: Members of each of the four families and 2 of the 25 subjects with isolated ovarian insufficiency carried mutations in the NR5A1 gene. In-frame deletions and frameshift and missense mutations were detected. Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity. Mutations were associated with a range of ovarian anomalies, including 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency. We did not observe these mutations in more than 700 control alleles. CONCLUSIONS: NR5A1 mutations are associated with 46,XX primary ovarian insufficiency and 46,XY disorders of sex development.

46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism.

Familial recurrence risks are poorly understood in cases of de novo mutations. In the event of parental germ line mosaicism, recurrence risks can be higher than generally appreciated, with implications for genetic counseling and clinical practice. In the course of treating a female with pubertal delay and hypergonadotropic hypogonadism, we identified a new missense mutation in the SRY gene, leading to somatic feminization of this karyotypically normal XY individual. We tested a younger sister despite a normal onset of puberty, who also possessed an XY karyotype and the same SRY mutation. Imaging studies in the sister revealed an ovarian tumor, which was removed. DNA from the father's blood possessed the wild type SRY sequence, and paternity testing was consistent with the given family structure. A brother was 46, XY with a wild type SRY sequence strongly suggesting paternal Y-chromosome germline mosaicism for the mutation. In disorders of sexual development (DSDs), early diagnosis is critical for optimal psychological development of the affected patients. In this case, preventive karyotypic screening allowed early diagnosis of a gonadal tumor in the sibling prior to the age of normal puberty. Our results suggest that cytological or molecular diagnosis should be applied for siblings of an affected DSD individual.

Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.

BACKGROUND: The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off. RESULTS: Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517-595 kb upstream of the SOX9 promoter. CONCLUSIONS: These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.

17beta-hydroxysteroid dehydrogenase type 3 deficiency as a result of a homozygous 7 base pair deletion in 17betaHSD3 gene.

17-beta-Hydroxysteroid dehydrogenase type 3 (17betaHSD-3) converts delta4 androstenedione (A) to testosterone (T) in the testes. This enzyme plays a key role in androgen synthesis and it is essential for normal fetal development of male genitalia. 17betaHSD-3 deficiency is a rare cause of 46,XY disorders of sexual development. Here, we report a 16-year-old 46,XY patient with 17betaHSD-3 deficiency raised as a female and significantly virilized in puberty. A homozygous 7 base pair deletion on exon 10 was determined in HSD17B3 gene (c.777-783del_GATAACC). Our patient had one of the very rare mutations, which was previously unencountered in Turkish patients with 17betaHSD type 3, and she is the second reported case with this deletion.

The earlier described mutation (c.307c > T [p.R103X]) in the SRD5A2 gene causing a 46,XY female phenotype.

Deletions and mutations in the 5-alpha-reductase type 2 (SRD5A2) gene have been identified in 46,XY disorders of sexual differentiation (DSD). The clinical spectrum is heterogeneous, varying from a normal female external genital appearance to clitoromegaly and isolated micropenis or microphallus associated with hypospadias of various degrees. We describe a 46,XY DSD patient with a homozygous c.307C>T (p.R103X) mutation in the SRD5A2 gene. The case presented with a normal female external genital phenotype.

Sertoli cell tumor and intratubular germ cell neoplasia located in separate gonads in an adolescent patient with complete androgen insensitivity: a case report and review of literature.

Complete androgen insensitivity syndrome (AIS) is an X-linked disorder of sex development. Surgical management entails timely gonadectomy given the risk of malignant transformation. Our patient presented at age 15 years with primary amenorrhea. Initial laboratory testing showed elevated testosterone, luteinizing hormone, anti-Müllerian hormone levels, and 46,XY karyotype. Imaging studies showed no uterus, ovaries, and identified two candidate gonads. She underwent bilateral gonadectomy. Pathology reports revealed Sertoli cell and intratubular germ cell tumors located in separate gonads. Our case is the first report of the youngest patient with AIS with bilateral gonadal tumors derived from different histological origins. We also review literature for reports of AIS patients with gonadal tumors. Currently, there is no consensus for the timing of gonadectomy in AIS patients. However, given the varying potential for malignant transformation of gonads in AIS patients with different phenotypes, development of a standardized treatment guideline is indicated.

[Features of pubescence in patients with pure gonadal dysgenesis in the course of a hormonally active tumor--case report]. / Cechy dojrzewania plciowego u pacjentek z czysta dysgenezja gonad w przebiegu hormonalnie czynnego guza--opis przypadków.

Germ cell tumors are the most frequent ovarian neoplasms among girls and young women under the age of 25. Female patients with gonadal dysgenesis are at higher risk of germ cell tumors. Two cases of women with pure gonadal dysgenesis were described. A hormonally active tumor secreting estrogens, caused the development of sexual features and genital tract bleeding what imitated premature puberty. It needs to be emphasized that the presence of sexual features does not exclude dysgenesis - a pathology that is connected with an increased risk of gonadal tumors--and that the ultrasound evaluation, during which the presence of follicles in gonads is evaluated, is essential.

Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.

Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.

Non-obvious diagnosis and breast development in pure gonadal dysgenesis.

Pure gonadal dysgenesis is a situation when the karyotype is 46, XY, but for various reasons there is a disorder of differentiation of Wolffian and Mullerian structures and in consequence the phenotype is female. It is known that abdominal gonads and the presence of Y chromosome allow to qualify this condition as a high risk of tumor. In most cases breast development is limited because of lack or low level of estrogen. A 27-year-old patient with differences of sexual development (DSD), was admitted to the Department of Endocrinological Gynecology for a control examination. In the history: dysgerminoma, primary amenorrhea and ambiguous karyotype. The patient has not taken hormonal replacement therapy. The breast development is Tanner stage V.

Acute Lymphoblastic Leukemia Developing in a Patient with 46, XY Pure Gonadal Dysgenesis (Swyer Syndrome) with Malignant Gonadal Germ Cell Tumor: A Case Report and Literature Review.

A female phenotype with strip-like gonads, 46, XY pure gonadal dysgenesis (PGD) has a high tendency to develop into gonadal germ cell tumors. We described one patient with 46, XY PGD, who had a gonadal mixed germ cell tumor (GCT) and acute lymphoblastic leukemia (ALL). This is a unique case because two malignancies developed and relapsed in one person with chromosome abnormality, and the patient is the youngest reported so far. There is an association between her GCT and ALL, as the two malignancies may share a common clonal origin and the NRAS mutation likely plays a role in tumor genesis. We organized MDT to formulate a suitable plan of treatment. We completed the surgery and full cycles of chemotherapy for GCT and controlled ALL by chemotherapy and bone marrow transplantation. However, unfortunately, the young life finally ended following a rare transplant rejection. We concluded that ALL likely shares common clonal origin with GCT and that gene mutations may play a role in neoplasia, which requires further exploration. In the face of such complex conditions, we need to balance the treatment of both diseases to prolong survival and improve the patients' quality of life.