XX Karyotype Research Articles

Disorders of sexual development in 46,XX individuals: an update

Abstract
 Disruption of the processes of sexual determination or sexual differentiation by any genetic or environmental factor may result in a disorder of sexual development (DSD) with discordance among chromosomal, gonadal, and anatomical sex.
 Materials and methods: In order to update concepts related to DSD with 46,XX karyotype without numeric or structural abnormalities, a search of information was carried out for the last 10 years in which three subcategories are described: Disorders of gonadal (ovarian) development, Disorders related to androgenic excess and other abnormalities (vaginal atresia, cloacal exstrophy, uterine abnormalities and labial adhesions).
 Conclusion: The great variability of phenotypical manifestations in this kind of DSD may create confusion in diagnostic approaches guided by clinical findings. This presentation variability, paired with a lack of knowledge of the pathophysiology, can contribute to delayed or non-conclusive diagnoses. For these reasons, deepening the knowledge of the causes and clinical manifestations of this class of clinical conditions will result in the well-being of the patient and his family.

Delayed Puberty in Girls with Primary Amenorrhea: A Report of Cases

Background:Female puberty starts when the pituitary hormone producing follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which will stimulate the ovaries to produce estrogen. Delayed puberty with primary amenorrhea in female is the lack of breast development followed by the absence of menses 3 years after the initiation of breast development. Sex chromosomes have an important role in determining the sex, germ cell differentiation of foetus, and reproductive functions of an offspring, thus, sex chromosomal aberrations frequently cause primary amenorrheaCase presentation: We report two delayed puberty cases with the chief complain of primary amenorrhea. Both cases showed hypoplasia of uterus and ovaries on pelvic imaging and hormonal assay showed low of FSH. The first case was gonadal dysgenesis with 46,XX karyotype and low level of estrogen and the second case was a turner syndrome with 45,X karyotype and normal level of estrogen. Conclusion:This study reported delayed puberty with primary amenorrhea cases due to different chromosomal aberration pattern which have similar clinical features. Therefore, cytogenetic examination is needed for any primary amenorrhea cases in order to accomplish the confirmatory diagnosis and for the clinicians to make a correct intervention and treatment.

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

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

New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder.

Hearing loss and impaired fertility are common human disorders each with multiple genetic causes. Sometimes deafness and impaired fertility, which are the hallmarks of Perrault syndrome, co-occur in a person. Perrault syndrome is inherited as an autosomal recessive disorder characterized by bilateral mild to severe childhood sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46, XX karyotype. Since the initial clinical description of Perrault syndrome 70years ago, the phenotype of some subjects may additionally involve developmental delay, intellectual deficit and other neurological disabilities, which can vary in severity in part dependent upon the genetic variants and the gene involved. Here, we review the molecular genetics and clinical phenotype of Perrault syndrome and focus on supporting evidence for the eight genes (CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, RMND1, TWNK) associated with Perrault syndrome. Variants of these eight genes only account for approximately half of the individuals with clinical features of Perrault syndrome where the molecular genetic base remains under investigation. Additional environmental etiologies and novel Perrault disease-associated genes remain to be identified to account for unresolved cases. We also report a new genetic variant of CLPP, computational structural insight about CLPP and single cell RNAseq data for eight reported Perrault syndrome genes suggesting a common cellular pathophysiology for this disorder. Some unanswered questions are raised to kindle future research about Perrault syndrome.

Disorders of Sex Development.

Disorders of Sex Development.

46,XX DSD: Developmental, Clinical and Genetic Aspects.

Differences in sex development (DSD) in patients with 46,XX karyotype occur by foetal or postnatal exposure to an increased amount of androgens. These disorders are usually diagnosed at birth, in newborns with abnormal genitalia, or later, due to postnatal virilization, usually at puberty. Proper diagnosis and therapy are mostly based on the knowledge of normal development and molecular etiopathogenesis of the gonadal and adrenal structures. This review aims to describe the most relevant data that are correlated with the normal and abnormal development of adrenal and gonadal structures in direct correlation with their utility in clinical practice, mainly in patients with 46,XX karyotype. We described the prenatal development of structures together with the main molecules and pathways that are involved in sex development. The second part of the review described the physical, imaging, hormonal and genetic evaluation in a patient with a disorder of sex development, insisting more on patients with 46,XX karyotype. Further, 95% of the etiology in 46,XX patients with disorders of sex development is due to congenital adrenal hyperplasia, by enzyme deficiencies that are involved in the hormonal synthesis pathway. The other cases are explained by genetic abnormalities that are involved in the development of the genital system. The phenotypic variability is very important in 46,XX disorders of sex development and the knowledge of each sign, even the most discreet, which could reveal such disorders, mainly in the neonatal period, could influence the evolution, prognosis and life quality long term.

Laparoscopic gonad-sparing procedure in Ovotesticular disorder of sex development – Case video technique

Ovotesticular disorder of sex development (OTD) is a rare condition. There's a lack of literature addressing gonad-sparing surgery for OTD. Report the laparoscopic partial gonadectomy technique - gonad-sparing surgery - in an 11-year-old child, 46, XX karyotype with OTD with atypical genitalia. After a complete diagnostic evaluation the patient underwent feminizing genitoplasty followed by laparoscopic partial gonadectomy (gonad-sparing surgery). The patient was positioned on supine position and Trendelenburg. One 5mm port was placed on the umbilicus and two 3mm ports in both flanks. A gonadal wedge biopsy was performed to achieve histopathological confirmation before resection. The testicular component of the ovotestis is clearly identified based on macroscopic aspects, and resected with laparoscopic scissors and limited use of electrocautery. This case was classified as bipolar or terminal ovotestis. At the 5-month follow-up, the patient attained menarche. No adverse outcomes have been recorded. Postoperative third year follow-up hormone evaluation revealed a= female pattern characteristic and ultrasound demonstraed uterine volume increase, as well as bilateral ovarian tissue development with follicles. Gonad-sparing procedure is feasible and desirable whenever possible, especially in 46, XX patients with female sex of rearing, since it preserves the fertility potential. The risk of malignancy must be monitored.

Etiology of ambiguous genitalia in newborns with XX karyotype: A cross-sectional observational study.

Objective: To determine the etiology of ambiguous genitalia in newborn females with XX karyotype. Study Design: Cross Sectional Observational study. Setting: Children Hospital and Institute of Child Health Multan (CH&amp; ICH). Period: July 2018 to December 2019. Material &amp; Methods: Fifty two patients were enrolled after taking informed consent from parents/guardians. Various causes of ambiguous genitalia like CAH, maternal intake of virilizing drugs during pregnancy and isolated local genital defect were noted. Results: Out of 52 patients, mean gestational age was 38.23 ± 2.36 weeks and 10 (20.2 %) had gestational age up to 36 weeks while 42 (80.8%) had gestational age more than 36 weeks. Mean age was 12.37 ± 4.21 days. Mean weight was 2965.43 ± 412.23 grams while 24 (46.1%) had weight up to 2500 grams and 28 (53.9%) had weight more than 2500 grams. Congenital adrenal hyperplasia in our study cases was noted in 45 (86.5%). Congenital local genital defects in our study cases were noted in 6 (11.5%) while maternal ingestion of virilizing drugs during pregnancy was noted in 1 (2%). CAH was not associated with gestational age or weight of newborn with p value 0.680 and 0.595 respectively. Conclusion: Congenital adrenal hyperplasia in our study cases was the commonest reason of ambiguous genitalia in newborn females with XX karyotype followed by congenital local defects and maternal use of virilizing drugs. High index of suspicion is required for the diagnosis of potential life threatening disorder like CAH.

Generation of a human induced pluripotent stem cell line (SMUSHi001-A) from a patient with 46, XX male sex reversal syndrome carrying the SRY gene

The 46, XX male sex reversal syndrome (SRS) is a rare disease with a gender dysplasia phenotype. Scientists concur that SRS is associated with translocation of the sex-determining region Y gene (SRY). We obtained peripheral blood mononuclear cells (PBMCs)from an 18-year-old male with SRS to generate an induced pluripotent stem cell (iPSC) line (SMUSHi001-A). Karyotyping analysis of the patient PBMCs revealed a normal 46, XX karyotype carrying the SRY gene. Pluripotent markers were successfully detected in SMUSHi001-A which can be differentiated into three germ layers in vitro. This cell line will provide a cell model for exploring the pathogenesis and potential therapeutic methods of SRS.

Laparoscopic Davydov Procedure for Creation of Neovagina in MRKH Syndrome

Introduction: The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a condition in which there is an absence of the uterus and the upper part (2/3) of the vagina. Women with MRKH syndrome show normal development of secondary sexual characteristics and a normal 46, XX karyotype. MRKH syndrome is a common cause of primary amenorrhea. Ultrasonography examination confirms kidneys, presence of the ovaries, and absence of uterus. Treatment should include a multidisciplinary approach to create a functional vagina. One of the procedures is laparoscopic Davydov vaginoplasty.&#x0D; Aim: To report MRKH syndrome case treated with laparoscopic Davydov vaginoplasty.&#x0D; Method: Ms. A, 21 years old, P0A0, came to FER clinic Moh. Hoesin Hospital Palembang with complaint, never had menstruation, the patient admitted her breast, and her pubic had growth. She wants to get married in the next six months. From the US result, there was non visualized uterus, genital band (+), and both ovaries within normal limit ~ MRKH Syndrome. Karyotype Examination: 46, XX. Patient was diagnosed with primary amenorrhea caused by MRKH syndrome and was planned for neovagina (Davydov Procedure).&#x0D; Result: A woman 21-year-old, P0A0, was diagnosed with primary amenorrhea caused by MRKH syndrome. The Davydov procedure was done to create a neovagina. Intraoperative, after protrusion of the wood mold as a marker shown, an incision is made to the left and right side so that the mold penetrates the abdominal cavity, then the mold is pulled into the vaginal canal slowly. The anterior and posterior peritoneal layers are drawn into the vaginal canal. The anterior and posterior peritoneal layers were withdrawn with an ovum clamp and then interrupted suture. The anterior and posterior peritoneal layers were sutured in a circular method to form a vaginal cuff. The vaginal wall is sutured (interrupted) to hold mold fixed.&#x0D; Conclusion: MRKH syndrome is a disorder that occurs in females and mainly affects the reproductive system. This condition causes the vagina and the uterus to be underdeveloped or even absent at birth. Patients with diagnosed MRKH syndrome require interdisciplinary care. Davydov procedure is a laparoscopically-assisted technique, which has an advantage over traditional approaches. It has shorter operating time, lower intraoperative complications, shorter hospital stay, and no external scars. Postoperatively, sexual function is similar to women without gynecological disorders.

Laparoscopic Davydov Procedure for Creation of Neovagina in MRKH Syndrome

Introduction: The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a condition in which there is an absence of the uterus and the upper part (2/3) of the vagina. Women with MRKH syndrome show normal development of secondary sexual characteristics and a normal 46, XX karyotype. MRKH syndrome is a common cause of primary amenorrhea. Ultrasonography examination confirms kidneys, presence of the ovaries, and absence of uterus. Treatment should include a multidisciplinary approach to create a functional vagina. One of the procedures is laparoscopic Davydov vaginoplasty.&#x0D; Aim: To report MRKH syndrome case treated with laparoscopic Davydov vaginoplasty.&#x0D; Method: Ms. A, 21 years old, P0A0, came to FER clinic Moh. Hoesin Hospital Palembang with complaint, never had menstruation, the patient admitted her breast, and her pubic had growth. She wants to get married in the next six months. From the US result, there was non visualized uterus, genital band (+), and both ovaries within normal limit ~ MRKH Syndrome. Karyotype Examination: 46, XX. Patient was diagnosed with primary amenorrhea caused by MRKH syndrome and was planned for neovagina (Davydov Procedure).&#x0D; Result: A woman 21-year-old, P0A0, was diagnosed with primary amenorrhea caused by MRKH syndrome. The Davydov procedure was done to create a neovagina. Intraoperative, after protrusion of the wood mold as a marker shown, an incision is made to the left and right side so that the mold penetrates the abdominal cavity, then the mold is pulled into the vaginal canal slowly. The anterior and posterior peritoneal layers are drawn into the vaginal canal. The anterior and posterior peritoneal layers were withdrawn with an ovum clamp and then interrupted suture. The anterior and posterior peritoneal layers were sutured in a circular method to form a vaginal cuff. The vaginal wall is sutured (interrupted) to hold mold fixed.&#x0D; Conclusion: MRKH syndrome is a disorder that occurs in females and mainly affects the reproductive system. This condition causes the vagina and the uterus to be underdeveloped or even absent at birth. Patients with diagnosed MRKH syndrome require interdisciplinary care. Davydov procedure is a laparoscopically-assisted technique, which has an advantage over traditional approaches. It has shorter operating time, lower intraoperative complications, shorter hospital stay, and no external scars. Postoperatively, sexual function is similar to women without gynecological disorders.

Is there an association between prostate-specific antigen and androgen levels in 46, XX patients with congenital adrenal hyperplasia?

Congenital adrenal hyperplasia (CAH), a genetic disease characterized by defective cortisol synthesis and excessive levels of sex hormones, can cause precocious puberty in both sexes in untreated individuals and virilization in female patients with a 46, XX karyotype. The female paraurethral (Skene's) gland has been reported as prostate analogous. Growth of prostate tissue is associated with androgen production; therefore, prostate-specific antigen (PSA) levels may represent a marker of virilization in 46, XX patients with CAH. To describe PSA levels in 46, XX patients and evaluate whether higher PSA levels are associated with androgenization and the severity of the disease. Sixty-six patients with CAH and a 46, XX karyotype were included, irrespective of age. Serum PSA, testosterone, 17-hydroxyprogesterone (17-OHP) and androstenedione levels were measured. Patients' age, age at diagnosis, forms of the disease, Prader classification, bone age assessment, sex of rearing, surgery, and the presence of clinical complications were obtained from their medical records. The mean age of patients was 11.45±10.74 years. Forty-three patients (65%) were diagnosed neonatally at a median of 0.08 years (mean 1.47±2.34 years), with registers of 17-OHP measurements (Guthrie test) being available in 51%. Testosterone, 17-OHP and androstenedione were significantly high. PSA was detectable in 25% of cases (levels >0.01ng/ml), with a mean of 0.03±0.09ng/ml, and only in patients over five years of age. A correlation was found between PSA and age (p<0.001), age at diagnosis (p=0.002), testosterone (p=0.001) and androstenedione (p=0.023). There was no correlation between PSA and the forms of CAH or Prader classification. A sub-analysis of the patients over five years of age in whom PSA was detectable also showed that there was a correlation between PSA (p<0.05) and age at analysis, age at diagnosis, testosterone and androstenedione levels. Limitations of this study include the small sample size due to the rareness of the disease, its retrospective nature, the absence of a control group, the fact that the sample was selected at two referral centers, which could have resulted in a selection bias, and the use of different reference values in the different laboratories conducting the PSA tests. PSA is detectable in 25% of 46, XX patients with CAH, only after five years of age. PSA level increases significantly with age, age at diagnosis, and testosterone and androstenedione levels, confirming a correlation between PSA levels and elevated androgen levels.

Pituitary Stalk Interruption Syndrome in a 40-Year-Old Female With Absent Uterus and Ovaries

Background: A patient with multiple pituitary hormone deficiencies due to a rare congenital pituitary defect also presented with an absent uterus and ovaries. Coexisting Müllerian agenesis was suspected, however hormone replacement unraveled a different story. Case Presentation: A 40-year-old female presented with generalized body weakness and euvolemic hyponatremia. She also had cold intolerance, constipation, primary amenorrhea and dyspareunia. As a child, she was worked up for short stature but was lost to follow up. Physical examination showed Tanner stage 1 breast and pubic hair, and absence of axillary hair. She had no facial anomalies, visual abnormalities or anosmia. Hormone panel was consistent with panhypopituitarism: ACTH 5.69 pg/mL (<46 pg/mL), cortisol 1.9 ug/dL (4.30-22.40 μg/dL), TSH 3.375 uIU/mL (0.55-4.78 uIU/mL), FT4 0.51 ng/dL (0.55-4.78 uIU/mL), FT3 1.79 pg/mL (2.30-4.20 pg/mL), LH <0.07 mIU/mL (1.9-12.5 mIU/mL), FSH 0.95 mIU/mL (2.5-10.2 mIU/mL) and IGF-1 40.8 ng/dL (109-284 ng/mL). Bone age was delayed (16-year-old) but with most ossification centers fused. Pituitary MRI showed hypoplastic anterior pituitary, ectopic posterior pituitary and absent pituitary stalk suggestive of Pituitary Stalk Interruption Syndrome (PSIS). Low estradiol 19.35 pg/mL (19.5-144.2 pg/mL) in the setting of low LH and FSH was compatible with hypogonadotrophic hypogonadism. She had female-range serum testosterone level <0.007 ng/mL (0.1209-0.5946 ng/mL) and karyotype of 46XX. Transvaginal ultrasound revealed a blind vaginal pouch with absent uterus, fallopian tubes and ovaries; hence Müllerian agenesis was also considered. Hormonal replacement with prednisone, levothyroxine and conjugated equine estrogen was started. Secondary osteoporosis was treated with alendronate, calcium and vitamin D on top of estrogen therapy. Six months after initiation of estrogen, there was appearance of a small anteverted uterus and atrophic right ovary. Müllerian agenesis was ruled out and hypogonadotropic hypogonadism was proved to be the cause of the initial absence of the uterus and ovaries on imaging. Conclusion: Increased awareness of PSIS is important since early and accurate diagnosis is crucial for timely initiation of hormone replacement. This case also demonstrates the need for reassessment after hormonal replacement in patients with severe estrogen deficiency and apparent Müllerian agenesis.

Cardiac Arrest in a Child with Non-classic Lipoid Congenital Adrenal Hyperplasia Associated with a New STAR Gene Mutation

Abstract Introduction: Steroidogenic acute regulatory (STAR) protein regulates steroid hormone synthesis by transporting cholesterol into mitochondria. STAR gene mutations lead to lipoid congenital adrenal hyperplasia (LCAH), the rare but most severe form of congenital adrenal hyperplasia in children. We present an unusual case with an episode of cardiac arrest in a young girl during an acute febrile illness and later she was diagnosed with adrenal insufficiency secondary to a non-classic LCAH. Case: 2-year 11-month-old previously healthy white female was brought to an urgent care clinic due to severe lethargy and a seizure-like activity during a fever illness. She was found to have an undetectable blood glucose level and went into cardiac arrest shortly after arrival. CPR was performed for approximately 11 minutes. She then developed sever respiratory distress and was intubated. She was transferred to the PICU with IV sodium bicarbonate given en route. On admission, her body weight was 13.26 kg (36.80th percentile), height 90 cm (17.56th percentile), and BMI 16.17 (62.88th percentile). Her physical exam revealed normal external female genitalia and normal skin pigmentation. Lab evaluation revealed normal sodium and potassium but elevated anion gap, hyperuricemia, elevated creatinine kinase, abnormal liver function tests and abnormal coagulation profile. Brain MRI revealed findings consistent with hypoxic-ischemic encephalopathy. Renal function improved within 24 hours and hepatic function returned to normal after 20 days. Due to her severe hypoglycemic event, a high-dose ACTH stimulation test was performed. The results were consistent with adrenal insufficiency: baseline cortisol level, 7.3 μg/dL; 30 minutes cortisol, 7.8 μg/dL; 60 minutes cortisol, 9 μg/dL (normal response, ≥18 mcg/mL at 30 or 60 minutes). The baseline ACTH level was significantly elevated, 1688 pg/mL (0–46) as well as the renin activity, 24.3 ng/hour (1.7–11.2). Genetic testing revealed a 46 XX karyotype. STAR gene analysis identified compound heterozygosity; a novel deletion (c.811delC, p.Leu271Cysfs*50) and a previously reported missense mutation (c.661G&amp;gt;A, p.Gly221Ser). The girl is now 11 years old and exhibits normal growth, normal cognitive development, and she has developed early signs of puberty (Tanner stage 2 for breast). She takes daily hydrocortisone, fludrocortisone and stress dose hydrocortisone as needed. Conclusion: In non-classic LACH, the onset is generally late or not acute. Initial clinical features are variable and nonspecific. For this reason, non-classic LCAH may be overlooked. Adrenal crisis is a life-threatening complication, and it is important that clinicians are aware of the clinical features of non-classic LCAH and consider it in the differential diagnoses. Genetic testing for STAR should be considered in individuals with non-autoimmune primary adrenocortical insufficiency.

34. Chromosomal microarray characterization of a prenatal case of 46,XX SRY-positive Disorder of Sex Development (DSD)

Nonsyndromic SRY-positive testicular 46,XX disorder of sex development (DSD) is most frequently de novo. Affected individuals often have normal male external genitalia and present as adults with infertility, or come to clinical attention after puberty due to signs of undermasculinization. Genital anomalies range from small testes to cryptorchidism, micropenis, and/or hypospadias to presence of both testicular and ovarian tissue (ovotesticular DSD or true hermaphroditism). Diagnosis is typically made by chromosome analysis showing a 46,XX karyotype and metaphase fluorescence in situ hybridization (FISH) demonstrating an SRY signal translocated to a derivative X chromosome.

Ovotesticular Disorder of Sex Development in Korean Children: A Single-Center Analysis over a 30-Year Period.

To present clinical features that characterize ovotesticular disorder of sex development (OT-DSD) in the Korean population. Among the patient cohort who were initially suspected to have OT-DSD, the actual OT-DSD patients and those of other disorder of sex development were compared. Retrospective medical chart review of patients who were initially suspected to have OT-DSD from 1984 to 2018 on the basis of clinical examination. Tertiary care university hospital. Of 26 patients with initial diagnosis of OT-DSD, 3 were excluded because of incomplete records, and finally, 23 patients were subjected to analysis. Various examinations were performed before the surgical confirmation of gonad histopathology. Medical records were reviewed for clinical, anatomical, biochemical, and cytogenic characteristics, gender assignment, medical treatment, and histopathologic diagnosis. Characteristics of OT-DSD in a Korean population. Among 23 patients suspected to have OT-DSD, 13/23 (56.5%) were diagnosed as OT-DSD after histopathologic confirmation. Of the remaining 10 patients, 5/23 (21.7%) were diagnosed with mixed gonadal dysgenesis, 3 with Turner variant, 1 with 46,XX disorder of sex development, and 1 with Mayer-Rokitansky-Küster-Hauser syndrome. Among the 13 OT-DSD cases, 9 patients presented with the 46,XX karyotype, 1 with the 46,XY, and 3 with the 46,XX/XY karyotype. Nine patients were assigned as male and 4 as female at birth. The most common gonad histology was ovotestis 10/26 (38%), followed by ovary and testis. OT-DSD is one of the rarest disorders with various clinical presentations. A patient with ambiguous genitalia must be examined with a multidisciplinary approach with clinical suspicion for OT-DSD. Standardized procedure of evaluation and treatment is crucial.

Menarche in primary ovarian insufficiency after a month of hormone replacement therapy: a case report

BackgroundGynecologic anomalies, including uterine agenesis and ovarian dysgenesis, are some of the several differential diagnoses in adolescent females with primary amenorrhea and delayed puberty. Primary ovarian insufficiency is reported in the clinical practice of reproductive endocrinology can be determined by conducting sex hormone tests to evaluate the hypothalamic-pituitary-ovarian axis. However, confirmation of Mullerian agenesis by image modalities can be extremely challenging. Once the diagnosis is established, breakthrough bleeding usually occurs 2 to 3 years after hormonal replacement therapy.Case presentationWe report a case of a seventeen year old Taiwanese female, 46 XX karyotype, with ovarian dysgenesis and an initial tentative diagnosis of uterine agenesis who experienced a breakthrough bleeding after a month of hormonal replacement therapy.ConclusionsThe breakthrough bleeding after a month of estrogen therapy in primary ovarian insufficiency is uncommon, and the diagnosis of the absent uterus can have an extensive psychological impact on patients and their families.

Modified Vecchietti vaginoplasty using self-made single-port laparoscopy in Mayer-Rokitansky-Küster-Hauser syndrome

To introduce the minimally invasive Vecchietti procedure based on single-port laparoscopy with self-made surgical instruments for the surgical management of Mayer-Rokitansky-Küster-Hauser syndrome (MRKH). Surgical video article. The approval of the Institutional Review Board and written consent from the patient were obtained. University hospital. A 22-year-old woman presented with primary amenorrhea and inability to participate in penetrative sexual intercourse. A gynecological examination revealed a phenotypically normal vulva and absence of the vagina. A normal 46,XX karyotype was expressed. Magnetic resonance imaging and ultrasonic imaging of the abdomen and pelvis indicated that the ovaries were normal in size and there was vaginal agenesis with rudimentary uterus. No other congenital malformations were present. The modified Vecchietti procedure involved a transvaginal operation and laparoscopic surgery. The epidural catheter was stretched and made into two wires that were tucked into the core of the Veress needle and then folded into four strings for perineal puncture. A transverse incision of about 3 cm was made in the center of the navel, layer by layer into the abdomen, and placed in a self-made single port (made of a small wound protector and an 8-inch glove), introducing the laparoscope. Under laparoscopic surveillance, the Veress needle was inserted through the vesicorectal space guided by the index finger, which was placed in the rectum. The epidural catheter was pumped from the core into the abdominal cavity under laparoscopy. Subsequently, cystoscopy was performed to ensure that no bladder perforation occurred during the needle insertion. The ball-shaped acrylic device and the two rubber stoppers were attached to the epidural catheter of the vulva. An epidural puncture needle with wire perforated the peritoneum through McBurney's point and the opposite McBurney's point, pulling the epidural catheter out of the abdominal cavity. The epidural catheter was curled around the gauze rolls until the ball-shaped device could be accommodated into the newly created cavity at a sufficient depth. After the surgery, the top of neovagina was lifted about 1 cm every day by tightening gauze rolls to increase the traction, until a neovagina 9 cm long was achieved. The clinical and anatomical data such as the operative time, intraoperative bleeding, duration of hospitalization, and measurement of the final length of the newly created canal 30 days after surgery and 3 months after surgery. The operative time was 30 minutes, and the intraoperative blood loss was 10 mL. The duration of hospitalization was 10 days. Before discharge, the vaginal depth was 9 cm at 5 days after the surgery, and the self-made traction system was removed. A plastic mold was then inserted using povidone-iodine. The vaginal dilator had to be worn day and night. The patient was advised to sit at the corner of a hard bed or chair from time to time to enhance the dilated effect of the vaginal mold. Three months after the surgery, it could be worn each night until regular sexual intercourse was initiated. The canal length 30 days and 3 months after the surgery was nearly 9 cm. The modified Vecchietti vaginoplasty is a simple, safe, cost-effective, and minimally invasive procedure, offering an anatomic and functional neovagina for MRKH patients.

Protein\u2013protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer\u2013Rokitansky\u2013K\xfcster\u2013Hauser syndrome

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disease, characterised by the aplasia of vagina and uterus in women with a 46,XX karyotype. Most cases are sporadic, but familial recurrence has also been described. Herein, we investigated an Italian cohort of 36 unrelated MRKH patients to explore the presence of pathogenic copy number variations (CNVs) by array-CGH and MLPA assays. On the whole, aberrations were found in 9/36 (25%) patients. Interestingly, one patient showed a novel heterozygous microduplication at Xp22.33, not yet described in MRKH patients, containing the PRKX gene. Moreover, a novel duplication of a specific SHOX enhancer was highlighted by MLPA. To predict the potential significance of CNVs in MRKH pathogenesis, we provided a network analysis for protein-coding genes found in the altered genomic regions. Although not all of these genes taken individually showed a clear clinical significance, their combination in a computational network highlighted that the most relevant biological connections are related to the anatomical structure development. In conclusion, the results described in the present study identified novel genetic alterations and interactions that may be likely involved in MRKH phenotype determination, so adding new insights into the complex puzzle of MRKH disease.

The current status of 492 adult women with Turner syndrome: a questionnaire survey by the Foundation for Growth Science

Current status and its background of Adult Turner Syndrome (TS) are not clarified well. Via a questionnaire survey of 492 adult women with TS, this study investigated the association between menstruation, Kaufmann therapy (menstrual induction therapy), social status (education, employment & marriage), complications, transition from pediatric to adult care, and sex chromosome karyotype using statistical methods. Spontaneous menarche occurred in 22.0% and more frequently among patients with the 45,X/46,XX karyotype. Over 60% of these subjects, menstruation did not persist regularly. Kauffmann therapy was performed in 69.4%; the most common formulation was a conjugated estrogen and progesterone combination. Marriage and higher education advancement rates were low in adults with TS, whereas their employment rate was similar to that of the age-matched general female population. Patients receiving Kauffmann therapy had higher complication rates, greater education length, and higher employment rates. The higher-education advancement rate was observed among patients with 45,X/46,X,Xi and 46,X,Xi karyotypes. Transition from pediatrician to adult specialist was not smooth, subjects were treated in pediatric departments (60.7%), gynecological department (21.4%), internal medicine departments (13.3%), and others. While reason is not clear, the largest number of TS patients are treated in general pediatrics and the percentage of receiving Kauffmann therapy and having complication were significantly lower than in pediatric and adult department of endocrinology (& metabolism). This Study revealed many novel findings of adult TS.